Proyectos de Investigación


Prof. María Vallet-Regí obtained an Advanced Grant from the ERC: "polyValent mEsopoRous nanosystem for bone DIseases" (VERDI)

- Objective: Finding simple solutions to complex problems has been a challenge for humankind for decades. VERDI aims at designing a multifunctional nanosystem to heal complex bone diseases. This is an engineering challenge that will be tackled through the use of building blocks designed on the basis of cutting-edge technology. These building blocks will be assembled into a versatile multifunctional nanosystem that can be adapted through slight variations for the treatment of three diseases of clinical relevance: bone infection, bone cancer and osteoporosis. The novelty of this proposal is the design of a nanosystem that may address several diseases using a unique, versatile and scalable strategy. Mesoporous silica nanoparticles are selected as the main component of the nanoplatform because of their biocompatibility, robustness, loading capacity and versatile surface modification. The nanosystem will be modified by rational selection of building blocks, with targeting and/or therapeutic abilities, to tackle either one or a combination of pathologies. These features will enable us to deliver a library of nanomedicines using a toolbox of building blocks, customizing a specific nanosystem depending on the disease to be treated. The risks associated to VERDI are numerous, such as the great complexity of producing completely asymmetrical nanoparticles (NPs), the risk that modifying a drug or therapeutic peptide will affect its therapeutic efficacy, and the difficulty of achieving effective in vivo bone targeted NPs. A contingency plan for each risk has been elaborated. The expertise and capacities of my research group guarantees successful results, which we expect to lead to a revolution in the therapy of bone cancer, bone infection and osteoporosis. Additionally, the application of a single technology for the treatment of three different but frequently associated diseases will favour industrial scale-up process, thereby promoting the transition of nanomedicine from bench to bedside.

- The project is awarded on May 11, 2016 and starts on October 1, 2016.

- One-day workshop with VERDI Project participants and clinics of Hospital OCTOBER 12. Junuary 24, 2017. 

- One-day workshop with VERDI Project participants, researchers from Aragon Institute of Materials Science and health professionals from Niño Jesús and Princesa hospitals. February 14, 2017.











- One-day workshop with VERDI Project participants and CNIO researchers. February 16, 2017.


  - Maria Vallet-Regí visited to the Hospital del Mar. March 31, 2017.



One day meeting of members of the VERDI project, researchers of the Institute of Science of Materials of Aragón and clinics of hospitals Child Jesús ​​and The Princess. February 14, 2017.

One day meeting of members of the VERDI project with researchers of the CNIO. February 16, 2017.

Day meeting of members of the VERDI project, "8 months VERDI". Display of results. May 29, 2017.

On Thursday, May 25th at 17.30 hours, the Royal National Academy of Pharmacy in collaboration with the José Casares Gil Foundation of friends of the RANF organizes the "ERC. Ten years after" Conference by Dr. José Labastida, Director of Scientific Department of the European Research Council who will be introduced by the full member, Mrs. María Vallet.

Day meeting members of VERDI project. Discussion and analysis of recent conferences and meetings. July 5, 2017.

Day meeting of members of the VERDI Project. VERDI seminar. July 19, 2017.

The BIOCERAMICS 29. 29th Sumposium and Annual Meeting of the International Society for Ceramics in Medicine, was held on october 25-27, 2017Toulouse. . Prof. María Vallet-Regí imparted the Keynote lecture entitled: "Tools to prepare stimuli-responsive nanocarriers", and Prof. Ana Fontecha imparted the communication:"3D printed mesoporous bioactive glass scaffolds doped with silver nanoparticles for bone infecion treatment".

EUROMAT 2017. On 17-22 September Euromat 2017 is being celebrated. Ten members of the research group GIBI are participating with ten oral and two posters contributions. Additionally Profa. Maria Vallet is participating as coordinator of biomaterials and healthcare area, which comprises 6 different symposiums and as member of scientific committee.Prof Salinas, Arcos, Manzano, Colilla, Izquierdo and Dr. Baeza are participating as organiser and chair in different symposiums.

Prof. María Vallet-Regí opinion leaders paper is highlighted in the opening ceremony ESB 2017. 28th ANNUAL CONFERENCE OF THE EUROPEAN SOCIETY FOR BIOMATERIALS. Atenas. September 4-8 2017. 

Prof. María Vallet-Regí partiped in Workshop: Women in Biomaterials Science of ESB 2017.

Prof. María Vallet-Regí particed in special fellow session. Important Biomaterials Science Controversies. ESB 2017. 28th ANNUAL CONFERENCE OF THE EUROPEAN SOCIETY FOR BIOMATERIALS. Atenas. September 4-8 2017. 

- Prof. María Vallet-Regí with several participants in the congress including Prof. Nicholas Peppas, Prof. Aldo Boccaccini, Prof. Jiang Chang and the chair Maria Chatzinikolaidou.

Prof. María Vallet-Regí imparted the Plenary Lecture entitled: "Response-triggering stimuli in drug release". ICONAN 2017. International Conference on Nanomedicine and nanobiotechnology. Barcelona. September 25-27, 2017.

Prof. María Vallet-Regí imparted the conference entitled: "Multifunctional Nanosystems". 2nd SUMMER SCHOOL OF EUROPEAN & INTERNATIONAL SOCIETIES FORNANOMEDICINE (ESNAM/ISNM).  Vall d’Hebron University Hospital. Barcelona. September, 28-29 2017.

- Prof. Avi Schroeder imparted the conference entitled: "Personalized Nanomedicines: Principles for engineering nanoparticles loaded with drugs and molecular machines". VERDI Seminar. Pharmacy Faculty. UCM. November 22, 2017.

- Video. VERDI, polyValent mEsopoRous nanosystem for bone DIseases.

María Vallet-Regí presented and coordinated the Workshop "Nanosystems mesoporous multipurpose for diseases from bone". Real Pharmacy Academy and José Casares Gil Foundation. November 2, 2017.

Dr. María Vallet-Regí coordinated the International Symposium. Mesoporous Materials: from 1991 to 2018. Fundación Areces. Madrid, April, 10-11, 2018. Program.

Interview with Dr. María Vallet-Regí at the Areces Foundation: "Mesoporous materials are also helping to regenerate tissues". April 10, 2018.

Day meeting of members of the VERDI Project. VERDI seminar. Jun 22, 2018.  


Oct 25-27, 2017. Prof. María Vallet-Regí imparted the Keynote Lecture: “Tools to prepare stimuli-responsive nanocarriers”. BIOCERAMICS 29. 29TH SYMPOSIUM AND ANNUAL MEETING OF THE INTERNATIONAL SOCIETY FOR CERAMICS IN MEDICINE. Toulouse, France.

- Nov 8-11, 2017. Prof. María Vallet-Regí imparted the conference entitled: "Controlled release in nanoparticles of mesoporous silica using catechol-based coatings". XXI NATIONAL SYMPOSIUM ON ORGANIC CHEMISTRY. Potrero de los Funes, San Luís, Argentine.

- Feb 23, 2018. Meeting with Gorka Orive of the Faculty of Pharmacy of the University of the Basque Country of Vitoria, advisor of the company BTI of Vitoria and of the company GEROA Diagnostics. VERDI seminar. Pharmacy Faculty. UCM.  

Apr 10-11, 2018. International Symposium. Mesoporous materials: from 1991 to 2018.

- Apr 23, 2018. Meeting of Drs. José Luis Pablos and Pablo Ortiz from Hospital Doce de Octubre, Dr. Juan José Montoya from the Company Canaan and Mª Rocío Villegas, Dr. Alejandro Baeza and Professor María Vallet from UCM about the patent "Compositions of nanocapsules for the controlled release of agents of therapeutic interest". Pharmacy Faculty. UCM.  

- May 24-26, 2018. SEIMC 2018. XXI NATIONAL CONGRESS OF THE SPANISH SOCIETY OF INFECTIOUS DISEASES AND CLINICAL MICROBIOLOGY. Poster: "Adjustment of the dose of levofloxacin released from mesoporous silica nanoparticles".  Bilbao, Spain.

- June 6, 2018. Working meeting of Drs. María Vallet, Antonio Salinas, Isabel Izquierdo, Alejandro Baeza and Daniel Lozano with Dr. Pedro Esbrit of the Fundación Jiménez Díaz and also member of the VERDI team. Pharmacy Faculty. UCM. 

- June 22, 2018. Day meeting of members of the VERDI Project. VERDI seminar. Pharmacy Faculty. UCM. 

- June 27, 2018. Prof. María Vallet-Regí imparted the Invited Conference: "Biomaterials". Course Economic Power and Scientific Power. Menendez Pelayo International University. Santander, Spain. 

- July 13, 2018. Prof. María Vallet-Regí imparted the Plenary Lecture: "Mesoporous silica nanoparticles: a good nanotransporter." BAC 2018. ANNUAL BIOTECHNOLOGY CONGRESS. Girona, Spain.

- July 27, 2018. Day meeting of members of the VERDI Project. “20 months VERDI”. Display of results. 

- Sept 9-12, 2018. Prof. María Vallet-Regí imparted the Plenary Lecture: The Mesoporous silica nanopaticle: a good nanocarrier. 9th EUROPEAN SILICON DAYS. Saarbrücken, Germany.

- Oct 8-11, 2018. Prof. María Vallet-Regí imparted the Invited Conference: “Desing of drug nanocarriers”. 2ND BIENNIAL CONFERENCE BIOMATERIALS AND NOVEL TECHNOLOGY FOR HEALTHCARE. Scuderie AldoBrandini.  Frascatti, Rome (Italy).  Programa.-

Nov 12, 2018. Prof. Alberto Gabizón imparted the conference entitled: “ Translational Nanomedicine and Cancer: Quo vadis?”. VERDI seminar. Pharmacy Faculty. UCM.

- Jan 11, 2019. Workshop 29 M VERDI. Pharmacy Faculty. UCM.

- March 12, 2019. Prof. María Vallet Regí imparted the Featured Conference entitled "Polyvalent mesoporous nanosystem as drug carriers". 6th INTERNATIONAL CONFERENCE ON MULTIFUNCTIONAL HYBRID AND NANOMATERIALS, Sitges, Spain. 11-15 March 2019.

- "VERDI" After 30 months. June 26, 2019.

- 36 month of VERDI. November 20, 2019 

- Osteoporosis Workshop - VERDIJanuary 9, 2020

- July 6, 2020. UPM press release. Professor María Vallet from the Universidad Complutense de Madrid and Dr. Alejandro Baeza, professor at the Universidad Politécnica de Madrid, are developing a methodology to anchor nanoparticles on the surface of bacteria capable of penetrating into tumour tissues by increasing the effect of nanomedicines.






Ion-doped binary SiO2-CaO and ternary SiO2-CaO-P2O5 mesoporous bioactive glasses were synthesized and characterized to evaluate the influence of P2O5 in the glass network structure. Strontium, copper and cobalt oxides in a proportion of 0.8 mol% were selected as dopants because the osteogenic and angiogenic properties reported for these elements. Although the four glass compositions investigated presented analogous textural properties, TEM analysis revealed that the structure of those containing P2O5 exhibited an increased ordered mesoporosity. Furthermore, 29Si NMR revealed that the incorporation of P2O5 increased the network connectivity and that this compound captured the Sr2+, Cu2+ and Co2+ ions preventing themto behave as modifiers of the silica network. In addition, 31P NMR results revealed that the nature of the cation directly influences the  characteristics of the phosphate clusters. In this study, we have proven that phosphorous oxide entraps doping-metallic ions, granting these glasses with a greater mesopores order.

Journal of Non-Crystalline Solids 455 (2017) 90–97



A novel pH-sensitive nanocarrier based on mesoporous silica nanoparticles with self-immolative polymers blocking the pore openings is presented. Triggered release by acid pH is demonstrated, together with their in vitro biocompatibility and effective cell internalisation, which makes this new material a promising candidate for future applications in cancer treatment.  

RSC Advances, 2017, 7, 132–136




 Bone infection is a feared complication following surgery or trauma that remains as an extremely difficult disease to deal with. So far, the outcome of therapy could be improved with the design of 3D implants, which combine the merits of osseous regeneration and local multidrug therapy so as to avoid bacterial growth, drug resistance and the feared side effects. Herein, hierarchical 3D multidrug scaffolds based on nanocomposite bioceramic and polyvinyl alcohol (PVA) prepared by rapid prototyping with an external coating of gelatin-glutaraldehyde (Gel-Glu) have been fabricated. These 3D scaffolds contain hree antimicrobial agents (rifampin, levofloxacin and vancomycin), which have been localized in different compartments of the scaffold to obtain different release kinetics and more effective ombined therapy. Levofloxacin was loaded into the mesopores of nanocomposite bioceramic part, vancomycin was localized into PVA biopolymer part and rifampin was loaded in the external coating of Gel-Glu. The obtained results show an early and fast release of rifampin followed by sustained and prolonged release of vancomycin and levofloxacin, respectively, which are mainly governed by the progressive in vitro degradability rate of these scaffolds. This combined therapy is able to destroy Gram-positive and Gram-negative bacteria biofilms as well as inhibit the bacteria growth. In addition, these multifunctional scaffolds exhibit excellent bioactivity as well as good biocompatibility with complete cell colonization of preosteoblast in the entire surface, ensuring good bone regeneration. These findings suggest that these hierarchical 3D multidrug scaffolds are promising candidates as platforms for local bone infection therapy.

Acta Biomaterialia 49 (2017) 113–126 



The application of nanotechnology to medicine constitutes a major field of research nowadays. In particular, the use of mesoporous silica and carbon nanoparticles has attracted the attention of numerous researchers due to their unique properties, especially when applied to cancer treatment. Many strategies based on stimuli-responsive nanocarriers have been developed to control the drug release and avoid premature release. Here, we focus on the use of the subtle changes of pH between healthy and diseased areas along the body to trigger the release of the cargo. In this review, different approximations of pH-responsive systems are considered: those based on the use of the host-guest interactions between the nanocarriers and the drugs, those based on the hydrolysis of acid-labile bonds and those based on supramolecular structures acting as pore capping agents.

Bioengineering 2017, 4(1), 3




 Nanocarriers have emerged as a powerful alternative for cancer therapy. Indeed, they are promising candidates to tackle the acquired resistance of surviving cells against antiproliferative drugs – the so-called multidrug resistance (MDR) phenomenon – which has arisen as one of the major clinical issues of chemotherapy. Among nanocarriers, this review focuses on the recent approaches based on tailored mesoporous silica nanoparticles (MSNs) that could overcome this problem. Areas covered: Herein we summarize the current efforts developed to provide MSN-based nanosystems of enhanced dual therapeutic action against diseased cells. This can be accomplished by three main approaches: i) increasing nanosystems’ killing capability towards particular cells by enhancing both recognition and specificity; ii) increasing the apoptotic effect throughout co-delivery of several drugs; or iii) combining drug delivery with apoptosis induced by physical methods. Expert opinion: The development of multifunctional nanosystems able to exert the optimal therapeutic action through the minimal administration constitutes a major challenge in nanomedicine. Recent developments in advanced MSN-based platforms for drug delivery represent promising avenues in the management of MDR associated with cancer therapy. All strategies discussed in this manuscript demonstrate improvements against difficult-to-treat tumors.

Expert Opin. Drug Del. 14 (2) 229-243   2017




 The discovery and control of the biological roles mediated by nucleic acids have turned them into a powerful tool for the development of advanced biotechnological materials. Such is the importance of these gene-keeping biomacromolecules that even nanomaterials have succumbed to the claimed benefits of DNA and RNA. Currently, there could be found in the literature a practically intractable number of examples reporting the use of combination of nanoparticles with nucleic acids, so boundaries are demanded. Following this premise, this review will only cover the most recent and powerful strategies developed to exploit the possibilities of nucleic acids as biotechnological materials when in combination with mesoporous silica nanoparticles. The extensive research done on nucleic acids has significantly incremented the technological possibilities for those biomacromolecules, which could be employed in many different applications, where substrate or sequence recognition or modulation of biological pathways due to its coding role in living cells are the most promising. In the present review, the chosen counterpart, mesoporous silica nanoparticles, also with unique properties, became a reference material for drug delivery and biomedical applications due to their high biocompatibility and porous structure suitable for hosting and delivering small molecules. Although most of the reviews dealt with significant advances in the use of nucleic acid and mesoporous silica nanoparticles in biotechnological applications, a rational classification of these new generation hybrid materials is still uncovered. In this review, there will be covered promising strategies for the development of living cell and biological sensors, DNA-based molecular gates with targeting, transfection or silencing properties, which could provide a significant advance in current nanomedicine.

Biomater. Sci., 2017, 5, 353–377




 Osteoporosis is by far the most frequent metabolic disease affecting bone. Current clinical therapeutic treatments are not able to offer long-term solutions. Most of the clinically used antiosteoporotic drugs are administered systemically, which might lead to side effects in non-skeletal tissues. Therefore, to solve these disadvantages, researchers have turned to nanotechnologies and nanomaterials to create innovative and alternative treatments. One of the innovative approaches to enhance osteoporosis therapy and prevent potential adverse effects is the development of bonetargeting drug delivery technologies. It minimizes the systemic toxicity and also improves the pharmacokinetic profile and therapeutic efficacy of chemical drugs. This paper reviews the current available bone targeting drug delivery systems, focusing on nanoparticles, proposed for osteoporosis treatment. Bone targeting delivery systems is still in its infancy, thus, challenges are ahead of us, including the stability and the toxicity issues. Newly developed biomaterials and technologies with potential for safer and more effective drug delivery, require multidisciplinary collaboration between scientists from many different areas, such as chemistry, biology, engineering, medicine, etc, in order to facilitate their clinical applications.

AIMS Bioengineering. 4(2), 259-274    2017




The management of cancer in older aged people is becoming a common problem due to the aging of the population. There are many variables determining the complex situation that are interconnected. Some of them can be assessed, such as risk of mortality and risk of treatment complications, but many others are still unknown, such as the course of disease, the host-related factors that influence cancer aggressiveness, and the phenotype heralding risk of permanent treatment-related damage. This article presents a dynamic and personalized approach to older people with cancer based on our experience on aging, cancer, and their biological interactions. Also, novel treatments and management approaches to older individuals, based on their functional age and their social and emotional needs, are thoughtfully explored here.

The Oncologist 2017;22:1–8



Cancer-associated muscle dysfunction represents a deadly clinical problem, with ca. 80% mortality together with an increased toxicity from cancer treatment. . The normal bone remodeling might be disrupted by tumor cells that metastasize to bone in certain stages of cancer, which results in increased morbidity including muscle weakness. The reason for that muscle weakness might be attributed to the reduction on muscle mass or the reduction of muscle function. In fact, it has been demonstrated that in advanced cancers, it is probably caused by a combination of reductions, quantity and quality of muscle. This review focuses on the mechanisms that bone metastases promote skeletal muscle weakness

(2017) Int J Cancer Oncol 4(1): 1- 5




 The incidence and the mortality of cancer increase with age. This article explores the possibility of decreasing cancerrelated mortality in the aged with secondary prevention of cancer deaths that entails early diagnosis of cancer through the screening of asymptomatic older individuals. We establish that screening of asymptomatic individuals should be based on physiologic rather than chronologic age that may be estimated from a comprehensive geriatric assessment and possibly with the utilization of biologic markers of aging. It is reasonable to offer some form of screening for lung and colorectal cancer to individuals with a life expectancy of at least five years and screening for breast and prostate cancer to women and men respectively with a life expectancy of at least ten years. The ideal number of screening sessions and the ideal interval between screening sessions is unestablished. The aging of the population, the diversity of the older population, the development of new and more sensitive screening interventions, the discovery of new biologic markers of cancer and age represent the main challenges in studying the value of cancer screening in the aged. Probably the most reliable information may be obtained from rapid-learning databases in which information related to each person's physiologic age is included.Scientific Pages

Geriatr Med 2017, 1(1):14-22




The use of nanoparticles with the ability to transport drugs in a selective and controllable manner directly to diseased tissues and cells has improved the therapeutic arsenal for addressing unmet clinical situations. In recent years, a vast number of nanocarriers with inorganic, organic, hybrid and even biological nature have been developed especially for their application in the oncology field. The exponential growth in the field of nanomedicine would not have been possible without the also-rapid expansion of electron microscopy techniques, which allow a more precise observation of nanometric objects. The use of these techniques provides a better understanding of the key parameters which rule the nanoparticles’ synthesis and behavior. In this review, the recent advances made in the application of inorganic nanoparticles to clinical uses and the role which electron microscopy has played are presented.

J. Mater. Chem. B, 2017, 5, 2714--2725




A new platform constituted by engineered responsive nanoparticles transported by human mesenchymal stem cells is here presented as a proof of concept. Ultrasound-responsive mesoporous silica nanoparticles are coated with polyethylenimine to favor their effective uptake by decidua-derived mesenchymal stem cells. The responsive-release ability of the designed nanoparticles is confirmed, both in vial and in vivo. In addition, this capability is maintained inside the cells used as carriers. The migration capacity of the nanoparticle–cell platform towards mammary tumors is assessed in vitro. The efficacy of this platform for anticancer therapy is shown against mammary tumor cells by inducing the release of doxorubicin only when the cell vehicles are exposed to ultrasound.

Nanoscale, 2017, 9, 5528–5537




 Matrix degradation has a major impact on the release kinetics of drug delivery systems. Regarding ordered mesoporous silica materials for biomedical applications, their dissolution is an important parameter that should be taken into consideration. In this paper, we review the main factors that govern the mesoporous silica dissolution in physiological environments. We also provide the necessary knowledge to researchers in the area for tuning the dissolution rate of those matrices, so the degradation could be controlled and the material behaviour optimised.

J. Mater. Sci. (2017) 52:8761-8771




The application of mesoporous bioactive glasses (MBGs) containing controllable amount of different ions, with the aim to impart antibacterial activity, as well as stimulation of osteogenesis and angiogenesis, is attracting an increasing interest. In this contribution, in order to endow nano-sized MBG with additional biological functions, the framework of a binary SiO2-CaO mesoporous glass was modified with different concentrations of copper ions (2 and 5% mol.), through a one-pot ultrasound-assisted sol-gel procedure. The Cu-containing MBG (2% mol.) showed high exposed surface area (550 m2 g1), uniform mesoporous channels (2.6 nm), remarkable in vitro bioactive behaviour and sustained release of Cu2+ ions. Cu-MBG nanoparticles and their ionic dissolution extracts exhibited antibacterial effect against three different bacteria strains, E. coli, S. aureus, S. epidermidis, and the ability to inhibit and disperse the biofilm produced by S. epidermidis. The obtained results suggest that the developed material, which combines in single multifunctional agent excellent bioactivity and antimicrobial ability, offers promising opportunities for the prevention of infectious diseases and the effective treatment of bone defects.

Acta Biomaterialia 55 (2017) 493–504




 The selective transportation of therapeutic agents to tumoral cells is usually achieved by their conjugation with targeting moieties able to recognize these cells. Unfortunately, simple and static targeting systems usually show a lack in selectivity. Herein, a double sequential encrypted targeting system is proposed as a stimuli-responsive targeting analogue for selectivity enhancement. The system is able to recognize diseased bone tissue in the first place, and once there, a hidden secondary targeting group is activated by the presence of an enzyme overproduced in the malignant tissue (cathepsin K), thereby triggering the recognition of diseased cells. Transporting the cell targeting agent in a hidden conformation that contains a high selective tissular primary targeting, could avoid not only its binding to similar cell receptors but also the apparition of the binding-site barrier effect, which can enhance the penetration of the therapeutic agent within the affected zone. This strategy could be applied not only to conjugate drugs but also to drug-loaded nanocarriers to improve the efficiency for bone cancer treatments.

Chem. Eur. J. 2017, 23, 7174 – 7179




When exposed to body fluids, mesoporous bioactive glasses (MBGs) of the CaO−SiO2−P2O5 system develop a bone-bonding surface layer that initially consists of amorphous calcium phosphate (ACP), which transforms into
hydroxy-carbonate apatite (HCA) with a very similar composition as bone/dentin mineral. Information from various 1H-based solid-state nuclear magnetic resonance (NMR) experiments was combined to elucidate the evolution of the
proton speciations both at the MBG surface and within each ACP/HCA constituent of the biomimetic phosphate layer formed when each of three MBGs with distinct Ca, Si, and P contents was immersed in a simulated body fluid (SBF) for variable periods between 15 min and 30 days. Directly excited magic-angle-spinning (MAS) 1H NMR spectra mainly reflect the MBG component, whose surface is rich in water and silanol (SiOH) moieties. Double-quantum−single-quantum correlation 1H NMR experimentation at fast MAS revealed their interatomic proximities. The comparatively minor H species of each ACP and HCA component were probed selectively by heteronuclear 1H−31P NMR experimentation. The initially prevailing ACP phase comprises H2O and “nonapatitic” HPO42−/PO4 3− groups, whereas for prolonged MBG soaking over days, a well-progressed ACP → HCA transformation was evidenced by a dominating O1H resonance from HCA. We show that 1H-detected 1H → 31P crosspolarization NMR is markedly more sensitive than utilizing powder X-ray diffraction or 31P NMR for detecting the onset of HCA formation, notably so for P-bearing (M)BGs. In relation to the long-standing controversy as to whether bone mineral comprises ACP and/or forms via an ACP precursor, we discuss a recently accepted structural core−shell picture of both synthetic and biological HCA, highlighting the close relationship between the disordered surface layer and ACP.

J. Phys. Chem. C 2017, 121, 13223−13238





 Novel materials, based on Mesoporous Bioactive Glasses (MBGs) in the ternary system SiO2-CaO-P2O5, decorated with (3-aminopropyl)triethoxysilane (APTES) and subsequently with amino acid Lysine (Lys), by post-grafting method on the external surface of the glasses (named MBG-NH2 and MBG-Lys), are reported. The surface functionalization with organic groups did not damage the mesoporous network and their structural and textural properties were also preserved despite the high solubility of MBG atrices. The incorporation of Lys confers a zwitterionic nature to these MBG materials due to the presence of adjacent amine and carboxylic groups in the external surface. At physiologic pH, this coexistence of basic amine and carboxilic acid groups from anchored Lys provided zero surface charge named zwitterionic effect. This behaviour could give rise to potential applications of antibacterial adhesion. Therefore, in order to assess the influence of zwitterionic nature in in vitro bacterial adhesion, studies were carried out with  taphylococcus aureus. It was demonstrated that the efficient interaction of these zwitterionic pairs onto the MBG surfaces reduced bacterial adhesion up to 99.9% compared to bare MBGs. In order to test the suitability of zwitterionic MBGs materials as bone grafts, their cytocompatibility was investigated in vitro with MC3T3-E1 preosteoblasts. These findings suggested that the proposed surface functionalization strategy provided MBG materials with notable antibacterial adhesion properties, hence making these materials promising candidates for local bone infection therapy.

Acta Biomaterialia 57 (2017) 472–486




The development of targeted nanocarriers able to be selectively internalized within tumor cells, and therefore to deliver anti-tumor drugs specifically to diseased cells, constitutes one of the most important goals in nano-oncology. Herein, the development of Janus mesoporous silica particles asymmetrically decorated with two targeting moieties, one of them selective for folate membrane cell receptors (folic acid) and the other one able to bind to mitochondria membrane (triphenylphosphine, TPP), is described in order to achieve sequential cell to organelle vectorization. The asymmetric decoration of each side of the particle allows fine control in the targeting attachment process in comparison with the use of symmetric nanocarriers. The presence of folic acid induces a higher increase in particle accumulation inside tumor cells, and once there, these nanocarriers are guided close to mitochondria by the action of the TPP moiety. This strategy can be applied for improving the therapeutic efficacy of current nanomedicines.

ACS Appl. Mater. Interfaces 2017, 9, 26697−26706



Diabetes mellitus (DM) induces bone deterioration, while mechanical stimulation promotes osteocyte-driven bone formation. We aimed to evaluate the interaction of acute exposure (24 h) to high glucose (HG) with both the pro-survival effect conferred to osteocytic MLO-Y4 cells and osteoblastic MC3T3-E1 cells by mechanical stimulation and the interaction of these cells with osteoclast precursor RAW264.7 cells. We found that 24 h of HG (25 mM) preexposure prevented both cell survival and ERK and β-catenin nuclear translocation upon mechanical stimulation by fluid flow (FF) (10 min) in both MLO-Y4 and MC3T3-E1 cells. However, migration of RAW 264.7 cells was inhibited by MLO-Y4 cell-conditioned medium (CM), but not by MC3T3-E1 cell-CM, with HG or FF. This inhibitory effect was associated with consistent changes in VEGF, RANTES, MIP-1α, MIP-1β MCP-1, and GM-CSF in MLO-Y4 cell-CM. RAW264.7 proliferation was inhibited by MLO-Y4CMunder static orHGconditions, but it increased by FF-CM with or without HG. In addition, both FF and HG abrogated the capacity of RAW 264.7 cells to differentiate into osteoclasts, but in a different manner. Thus, HG-CM in static condition allowed formation of osteoclast-like cells, which were unable to resorb hydroxyapatite. In contrast, FF-CM prevented osteoclastogenesis even in HG condition. Moreover, HG did not affect basal RANKL or IL-6 secretion or their inhibition induced by FF in MLO-Y4cells. In conclusion, this in vitro study demonstrates thatHGexerts disparate effects on osteocyte mechanotransduction, and provides a novel mechanism by which DM disturbs skeletal metabolism through altered osteocyte-osteoclast communication.

J Cell Physiol. 2017;232:3611–3621




 This paper proposes a facile strategy for the zwitterionization of bioceramics that is based on the direct incorporation of L-lysine amino acid via the "-amino group onto mesoporous MCM-41 materials. Fourier transform infrared (FTIR) studies of lysine-grafted MCM-41 (MCM-LYS) simultaneously showed bands at 3080 and 1540 cm1 and bands at 1625 and 1415 cm1 corresponding to -NH3+/COO pairs, which demonstrate the incorporation of the amino acid on the material surface keeping its zwitterionic character. Both elemental and thermogravimetric analyses showed that the amount of grafted lysine was 8 wt. % based on the bioceramic total weight. Moreover, MCM-LYS exhibited a reduction of adhesion of S. aureus and E. coli bacteria in 33% and 50%, respectively at physiological pH, as compared with pristine MCM-41. Biofilm studies onto surfaces showed that lysine functionalization elicited a reduction of the area covered by S. aureus biofilm from 42% to only 5% (88%). This research shows a simple and effective approach to chemically modify bioceramics using single amino acids that provides zwitterionic functionality, which is useful to develop new biomaterials that are able to resist bacterial adhesion.

Bioengineering 2017, 4, 80




Titulo:       Handbook of Sol-Gel Science and Technology. 2nd Ed.Capítulo:  Sol-Gel Silica-Based Biomaterials and Bone Tissue Regeneration.Autor:       M. Vallet-Regí, A. Salinas.Editores:   L. Klein, M. Aparicio, Mario, A. JitianuEditorial:  The Springer. 2017, ISBN 978-3-319-32100-4




Titulo:   Handbook of Solid State Chemistry - Volume 4 Nano and Hybrid Materials.Capítulo: Materials for tissue engineeringAutores: M. Vallet-Regí, A.J.  SalinasEditores:  R. Dronskowski, S. Kikkawa, A. SteinEditorial: Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2017.   ISBN: 978-3-527-32587-0.




Titulo: Comprehensive Biomaterials II, 2nd EditionAutores: Montserrat Colilla and María Vallet-RegíCapítulo: Ordered Mesoporous Silica Materials.Editor: Paul Ducheyne Kevin Healy Dietmar E. Hutmacher David W. Grainger C. James KirkpatrickEditorial: Elsevier 2017. ISBN- 9780081006917.



Titulo:   Bioactive glasses, 2nd Edition.Capítulo: Use of bioactive glasses as bone substitutes in orthopedics and traumatologyAutores: A.J. Salinas. M. Vallet-Regi, J. Heikkila  Editores:  Heimo YlanenEditorial: Elsevier, 2017. ISBN-978-0-08-100936-9




 A novel singlet-oxygen sensitive drug delivery nanocarrier able to release its cargo after exposure to visible (Vis) light from a common lamp is presented. This nanodevice is based on mesoporous silica nanoparticles (MSN) decorated with porphyrin-caps grafted via reactive oxygen species (ROS)-cleavable linkages.In the presence of Vis light porphyrin-nanocaps produce singlet oxygen molecules that break the sensitive-linker, which triggers pore uncapping and therefore allows the release of the entrapped cargo (topotecan, TOP). This new system takes advantage of the non-toxicity and greater penetration capacity of Vis radiation and a double antitumor effect due to the drug release and the ROS production. In vitrotests with HOS osteosarcoma cancer cells reveal that TOP is able to be released in a controlled fashion inside the tumor cells. This research work constitutes a proof of concept that opens up promising expectations in the search for new alternatives for the treatment of cancer.

Nanoscale, 2017, 9, 15967–15973


Silica mesoporous nanomaterials have been proved to have meaningful application in biotechnology and biomedicine. Particularly, mesoporous bioactive glasses are recently gaining importance thanks to their bone regenerative properties. Moreover, the mesoporous nature of these materials makes them suitable for drug delivery applications, opening new lines in the field of bone therapies. In this work, we have developed innovative nanodevices based on the implementation of adenosine triphosphate (ATP) and e-poly-llysine molecular gates using a mesoporous bioglass as an inorganic support. The systems have been previously proved to work properly with a fluorescence probe and subsequently with an antibiotic (levofloxacin) and an antitumoral drug (doxorubicin). The bioactivity of the preparedmaterials has also been tested, giving promising results. Finally, in vitro cell culture studies have been carried out; demonstrating that this gated devices can provide useful approaches for bone cancer and bone infection treatments.

Acta Biomaterialia 50 (2017) 114–126




Nanotechnology has provided new tools for addressing unmet clinical situations, especially in the oncology field. The development of smart nanocarriers able to deliver chemotherapeutic agents specifically to the diseased cells and to release them in a controlled way has offered a paramount advantage over conventional therapy. Areas covered: Among the different types of nanoparticle that can be employed for this purpose, inorganic porous materials have received significant attention in the last decade due to their unique properties such as high loading capacity, chemical and physical robustness, low toxicity and easy and cheap production in the laboratory. This review discuss the recent advances performed in the application of porous inorganic and metal-organic materials for antitumoral therapy, paying special attention to the application of mesoporous silica, porous silicon and metal-organic nanoparticles. Expert opinion: The use of porous inorganic nanoparticles as drug carriers for cancer therapy has the potential to improve the life expectancy of the patients affected by this disease. However, much work is needed to overcome their drawbacks, which are aggravated by their hard nature, exploiting the advantages offered by highly the ordered pore network of these materials.

Expert Opin. Drug Del. 14, 783-796   2017



 This manuscript reports an effective new alternative for the management of bone infection by the development of an antibiotic nanocarrier able to penetrate bacterial biofilm, thus enhancing antimicrobial effectiveness. This nanosystem, also denoted as “nanoantibiotic”, consists in mesoporous silica nanoparticles (MSNs) loaded with an antimicrobial agent (levofloxacin, LEVO) and externally functionalized with N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (DAMO) as targeting agent. This amine functionalization provides MSNs of positive charges, which improves the affinity towards the negatively charged bacteria wall and biofilm. Physical and chemical properties of the nanoantibiotic were studied using different characterization techniques, including Xray diffraction (XRD), transmission electron microscopy (TEM), N2 adsorption porosimetry, elemental chemical analysis, dynamic light scattering (DLS), zeta ( )-potential and solid-state nuclear magnetic resonance (NMR). “In vial” LEVO release profiles and the in vitro antimicrobial effectiveness of the different released doses were investigated. The efficacy of the nanoantibiotic against a S. aureus biofilm was also determined, showing the practically total destruction of the biofilm due to the high penetration ability of the developed nanosystem. These findings open up promising expectations in the field of bone infection treatment.

Biomed. Glasses 2018; 4:1–12




A novel multifunction al nanodevice based in doxorubicin (DOX)-loaded mesoporous silica nanoparticles (MSNs) as nanoplatforms for the assembly of different building blocks has been developed for bone cancer treatment. These building blocks consists of: i) a polyacrylic acid (PAA) capping layer grafted to MSNs via an acid-cleavable acetal linker, to minimize premature cargo release and provide the nanosystem of pH-responsive drug delivery ability; and ii) a targeting ligand, the plant lectin concanavalin A (ConA), able to selectively recognize, bind and internalize owing to certain cell-surface glycans, such as sialic acids (SA), overexpressed in given tumor cells. This multifunctional nanosystem exhibits a noticeable higher internalization degree into human osteosarcoma cells (HOS), overexpressing SA, compared to healthy preosteoblast cells (MC3T3-E1). Moreover, the results indicate that small DOX loading (2.5 mg mL1) leads to almost 100% of osteosarcoma cell death in comparison with healthy bone cells, which significantly preserve their viability. Besides, this nanodevice has a cytotoxicity on tumor cells 8-fold higher than that caused by the free drug. These findings demonstrate that the synergistic combination of different building blocks into a unique nanoplatform increases antitumor effectiveness and decreases toxicity towards normal cells. This line of attack opens up new insights in targeted bone cancer therapy.

Acta Biomaterialia 65 (2018) 393–404




This manuscript reviews the recent progress on mesoporous silica nanoparticles as drug delivery systems. Their intrinsic structural, textural and chemical features permit to design versatile multifunctional nanosystems with the capability to target the diseased tissue and release the cargo on demand upon exposition to internal or external stimuli. The degradation rate of these nanocarriers in diverse physiological fluids is overviewed obeying their significance for their potential translation towards clinical applications. To conclude, the balance between the benefits and downsides of this revolutionary nanotechnological tool is also discussed.

Molecules 2018, 23, 47




This work aims to provide an effective and novel solution for the treatment of infection by using nanovehicles loaded with antibiotics capable of penetrating the bacterial wall, thus increasing the antimicrobial effectiveness. These nanosystems, named ‘‘nanoantibiotics”, are composed of mesoporous silica nanoparticles (MSNs), which act as nanocarriers of an antimicrobial agent (levofloxacin, LEVO) localized inside the mesopores. To provide the nanosystem of bacterial membrane interaction capability, a polycationic dendrimer, concretely the poly(propyleneimine) dendrimer of third generation (G3), was covalently grafted to the external surface of the LEVO-loaded MSNs. After physicochemical characterization of this nanoantibiotic, the release kinetics of LEVO and the antimicrobial efficacy of each released dosage were evaluated. Besides, internalization studies of the MSNs functionalized with the G3 dendrimer were carried out, showing a high penetrability throughout Gram-negative bacterial membranes. This work evidences that the synergistic combination of polycationic dendrimers as bacterial membrane permeabilization agents with LEVO-loaded MSNs triggers an efficient antimicrobial effect on Gramnegative bacterial biofilm. These positive results open up very promising expectations for their potential application in new infection therapies.

Acta Biomaterialia 68 (2018) 261–271




Beneficial effects in bone cell growth and antibacterial action are currently attributed to Ga3+ ions. Thus, they can be used to upgrade mesoporous bioactive glasses (MBGs), investigated for tissue engineering, whenever they released therapeutic amounts of gallium ions to the surrounding medium. Three gallium-enriched MBGs with composition (in mol %) xSiO2–yCaO–zP2O5–5Ga2O3, being x = 70, y = 15, z = 10 for Ga_1; x = 80, y = 12, z = 3 for Ga_2; and x = 80, y = 15, z = 0 for Ga_3, were investigated and compared with the gallium-free 80SiO2–15CaO–5P2O5 MBG (B). 29Si and 31P MAS NMR analyses indicated that Ga3+ acts as network modifier in the glass regions with higher polymerization degree and as network former in the zones with high concentration of classical modifiers (Ca2+ ions). Ga_1 and Ga_2 exhibited a quick in vitro bioactive response because they were coated by an apatite-like layer after 1 and 3 days in simulated body fluid. Although we have not conducted biological tests in this paper (cells or bacteria), Ga_1 released high but non-cytotoxic amounts of Ga3+ ions in Todd Hewitt Broth culture medium that were 140 times higher than the IC90 of Pseudomonas aeruginosa bacteria, demonstrating its potential for tissue engineering applications.

Materials 2018, 11, 367




Biomedical application of nanoparticles is largely associated to their fate in biological media which, in turn, is related to their surface properties. Surface functionalization plays a key role in determining biodegradation, cytotoxicity and biodistribution through interactions which may be mediated by the macromolecules occurring in biological media. A typical example is given by several proteins which lead to the formation of coated nanoparticles referred as protein corona. In this work we focus on mesoporous silica nanoparticles which, due to their intrinsic textural features, show potential as carriers for sustained drug release. Mesoporous silica nanoparticles functionalized by different biopolymers such as hyaluronic acid and chitosan were synthesized and characterized through small angle X-rays scattering, thermal analysis, and infrared spectroscopy. Biopolymercoated mesoporous silica nanoparticles were used to investigate the interaction with bovine serum albumin, and to point out the role of different biopolymer coating. Gold-conjugated-bovine serum albumin was used to gain evidence on the occurrence of surface bound proteins enabling direct observation by transmission electron microscopy. Our findings provide insights on how different biopolymers affect the formation of a protein corona around functionalized mesoporous silica nanoparticles.

Chemical Engineering Journal 340 (2018) 42–50




Mesoporous silica nanoparticles (MSNPs) have many potential applications in biomedical fields. However, when MSNPs are exposed to plasma, protein adsorption leads to opsonization and decreases blood circulation time. A new multifunctional nanodevice based on polyethylenimine (PEI) coated core-shell Fe3O4@SiO2 MSNPs with a zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) surface was designed to minimize unspecific protein adhesion. Particle size measurements demonstrated an excellent non-fouling capacity in solutions containing Bovine Serum Albumin (BSA) and Fetal Bovine Serum (FBS) plasma proteins. The system was used in this study to co-deliver two different cargos: siRNA and daunorubicin. Anti-TWIST siRNA plays critical role in modulating knockdown of TWIST and sensitizing cells to chemotherapeutics such as daunorubicin for ovarian cancer therapy. The drug was released in response to externally controlled oscillating magnetic fields (OMF). siRNA (siGFP) silenced expression of green fluorescence protein (GFP) in Ovcar8 cancer cells, demonstrating the incorporation of core shell MSNPs into cells and siGFP delivery. The synergistic effect of the co-release of anti-TWIST-siRNA loaded in the PEI and daunorubicin loaded in NPs’ pores caused increased cytotoxicity in Ovcar8 of up to 50% from both zwitteronic and non-zwitteronic NPs. The system is the first example of silencing by antihttps TWITS-siRNA/daunorubicin co-delivered using zwitterionic core-shell nanoparticles with low-fouling adsorption. This engineered multifunctional approach may provide therapeutic potential for the treatment of currently incurable ovarian cancer.

Chemical Engineering Journal 340 (2018) 114–124




In 2005, our group described for the first time the structural characterization at the atomic scale of bioactive glasses and the influence of the glasses’ nanostructure in their reactivity in simulated body fluids. In that study, two bioactive sol-gel glasses with composition 80%SiO2–20%CaO and 80%SiO2–17%CaO–3%P2O5 (in mol-%) were characterized by High-Resolution Transmission Electron Microscopy (HRTEM). Such characterization revealed unknown features of the glasses’ structure at the local scale that allowed the understanding of their different in vitro behaviors as a  consequence of the presence or absence of P2O5. Since then, the nanostructure of numerous bioactive glasses, including melt-prepared, sol-gel derived, and mesoporous glasses, was investigated by HRTEM, Nuclear Magnetic Resonance (NMR) spectroscopy, Molecular Dynamics (MD) simulations, and other experimental techniques. These studies have shown that although glasses are amorphous solids, a certain type of short distance order, which greatly influences the in vitro and in vivo reactivity, is always present. This paper reviews the most significant advances in the understanding of bioactive glasses that took place in the last years as a result of the growing knowledge of the glasses’ nanostructure.

Materials 2018, 11, 415




Multifunctional-therapeutic three-dimensional (3D) scaffolds have been prepared. These biomaterials are able to destroy the S. aureus bacterial biofilm and to allow bone regeneration at the same time. The present study is focused on the design of pH sensitive 3D hierarchical meso-macroporous 3D scaffolds based on MGHA nanocomposite formed by a mesostructured glassy network with embedded hydroxyapatite nanoparticles, whose mesopores have been loaded with levofloxacin (Levo) as antibacterial agent. These 3D platforms exhibit controlled and pH-dependent Levo release, sustained over time at physiological
pH (7.4) and notably increased at infection pH (6.7 and 5.5), which is due to the different interaction rate between diverse Levo species and the silica matrix. These 3D systems are able to inhibit the S. aureus growth and to destroy the bacterial biofilm without cytotoxic effects on human osteoblasts and allowing an adequate colonization and differentiation of preosteoblastic cells on their surface. These findings suggest promising applications of these hierachical MGHA nanocomposite 3D scaffolds for the treatment and prevention of bone infection.

Acta Biomaterialia 65 (2018) 450–461


The use of cells with migratory properties towards different pathological sites holds great promise in the development of future therapeutics [1,2]. Some of these cell types can exert some positive effect on the development of a variety of diseases [3]. Furthermore, these effects could be improved by also transporting some drug of interest within the migrating cells [4]. However, the number of different drugs that can be
introduced within the vehicle cells without compromising their viability or migratory behavior is very low. For this reason, the introduction of drug-loaded nanoparticles appears as an interesting strategy to increase the amount of drug that the cells can carry, allowing us to also ensure the retention of the active molecule inside the cell during its journey in the bloodstream.

 Insights Stem Cells. 4, (1), 1-2 (2018)


A novel smart hierarchical ultrasound-responsive mesoporous silica nanocarrier for cancer therapy is presented here. This dynamic nanosystem has been designed to display different surface characteristics during its journey towards tumor cells. Initially, the anticancer-loaded nanocarriers are shielded with a polyethylene glycol layer. Upon exposure to high frequency ultrasound, the polymer shell detaches from the nanoparticles, exposing a positively charged surface. This favors the internalization in human osteosarcoma cells, where the release of topotecan takes place, drastically enhancing the cytotoxic effect.

Nanoscale, 2018, 10, 6402–6408



Inventors (p.o. of signature): María Vallet Regí, Rocio Villegas Díaz, Alejandro Baeza García, Pablo Luis Ortiz Romero, José Luis Pablos Álvarez, Alicia Usategui Corral
Title: Nanocapsules with controlled degradation for sustained collagenase release in clinical applications
Patent No.: EP18382005.9.
Entity: UCM (60%) Foundation for Biomedical Research of the 12 de Octubre Hospital (40%).
Date of publication. 09/01/2018.



Inventors (p.o. of signature): María Vallet Regí, Alejandro Baeza García, Gonzálo Villaverde Cantizano, Rafael Castillo Romero, Manuel Ramírez Orellana, Gustavo Melen Frajlich, África González Murillo, Arantzazu Alfranca González
Title: Ligands for enhanced imaging and drug delivery to neuroblastoma cells
Patent No.: EP18382207.1
Entity: UCM (50%) Hospital Infantil Univ. Niño Jesús (37.5%) Hospital Univ. The Princess (12.5%).
Date of publication. 26/03/2018.


In the last two decades, zinc oxide (ZnO) semiconductor Quantum dots (QDs) have been shown to have fantastic luminescent properties, which together with their low-c ost, low-toxicity and biocompatibility have turned these nanomaterials into one of the main candidates for bio-imaging. The discovery of other desirable traits such as their ability to produce destructive reactive oxygen species (ROS), high catalytic efficiency, strong adsorption capability and high isoelectric point, also make them promising nanomaterials for therapeutic and diagnostic functions. Herein, we review the recent progress on the use of ZnO based nanoplatforms in drug delivery and theranostic in several diseases such as bacterial infection and cancer.

Nanomaterials 2018, 8, 268


The high density of the extracellular matrix in solid tumors is an important obstacle to nanocarriers for reaching deep tumor regions and has severely limited the efficacy of administrated nanotherapeutics. The use of proteolytic enzymes prior to nanoparticle administration or directly attached to the nanocarrier surface has been proposed to enhance their penetration, but the low in vivo stability of these macromolecules compromises their efficacy and strongly limits their application. Herein, we have designed a multifunctional nanocarrier able to transport cytotoxic drugs to deep areas of solid tumors and once there, to be engulfed by tumoral cells causing their destruction. This system is based on mesoporous silica nanocarriers encapsulated within supported lipid bilayers (SLBs). The SLB avoids premature release of the housed drug while providing high colloidal stability and an easy to functionalize surface. The tumor penetration property is provided by attachment of engineered polymeric nanocapsules that transport and controllably unveil and release the proteolytic enzymes that in turn digest the extracellular matrix, facilitating the nanocarrier diffusion through the matrix. Additionally, targeting properties were endowed by conjugating an antibody specific to the investigated tumoral cells to enhance binding, internalization, and drug delivery. This multifunctional design improves the therapeutic efficacy of the transported drug as a consequence of its more homogeneous distribution throughout the tumoral tissue.

Chem. Mater. 2018, 30, 112−120



The use of therapeutic proteins plays a fundamental role in the treatment of numerous diseases. The low physico-chemical stability of proteins in physiological conditions put their function at risk in the human body until they reach their target. Moreover, several proteins are unable to cross the cell membrane. All these facts strongly hinder their therapeutic effect. Nanomedicine has emerged as a powerful tool which can provide solutions to solve these limitations and improve the efficacy of treatments based on protein administration. This review discusses the advantages and limitations of different types of strategies employed for protein delivery, such as PEGylation, transport within liposomes or inorganic nanoparticles or their in situ encapsulation.

Molecules 2018, 23, 1008



Mesoporous silica nanoparticles have been reported as suitable drug carriers, but their successful delivery to target tissues following systemic administration remains a challenge. In the present work, ultrasound-induced inertial cavitation was evaluated as a mechanism to promote their extravasation in a flow-through tissue-mimicking agarose phantom. Two different ultrasound frequencies, 0.5 or 1.6 MHz, with pressures in the range 0.5–4 MPa were used to drive cavitation activity which was detected in real time. The optimal ultrasound conditions identified were employed to deliver dye-loaded nanoparticles as a model for drug-loaded nanocarriers, with the level of extravasation evaluated by fluorescence microscopy. The same nanoparticles were then co-injected with submicrometric polymeric cavitation nuclei as a means to promote cavitation activity and decrease the required in-situ acoustic pressure required to attain extravasation. The overall cavitation energy and penetration of the combination was compared to mesoporous silica nanoparticles alone. The results of the present work suggest that combining mesoporous silica nanocarriers and submcrometric cavitation nuclei may help enhance the extravasation of the nanocarrier, thus enabling subsequent sustained drug release to happen from those particles already embedded in the tumour tissue.

Chemical Engineering Journal 340 (2018) 2–8


Self-immolative chemistry is based on the cascade of disassembling reactions triggered by the adequate stimulation and leading to the sequential release of the smaller constituent elements. This review will focus on the possibilities that this type of chemistry offers to nanomedicine research, which is an area where the stimuli responsive behavior is always targeted. There are some examples on the use of self-immolative chemistry for prodrugs or nanoparticles for drug delivery, but there is still an exciting land of opportunities waiting to be explored. This review aims at revising what has been done so far, but, most importantly, it aims at inspiring new research of self-immolative chemistry on nanomedicine.

Chemical Engineering Journal 340 (2018) 24–31


In this study, we present an innovation in the tumor treatment in vivo mediated by magnetic mesoporous silica nanoparticles. This device was built with iron oxide magnetic nanoparticles embedded in a mesoporous silica matrix and coated with an engineered thermoresponsive polymer. The magnetic nanoparticles act as internal heating sources under an alternating magnetic field (AMF) that increase the temperature of the surroundings, provoking the polymer transition and consequently the release of a drug trapped inside the silica pores. By a synergic effect between the intracellular hyperthermia and chemotherapy triggered by AMF application, significant tumor growth inhibition was achieved in 48 h after treatment. Furthermore, the small magnetic loading used in the experiments indicates that the treatment is carried out without a global temperature rise of the tissue, which avoids the problem of the necessity to employ large amounts of magnetic cores, as is common in current magnetic hyperthermia.

ACS Appl. Mater. Interfaces 2018, 10, 12518−12525


The implementation of nanoparticles as nanomedicines requires sophisticated surface modifications to reduce the immune response and enhance recognition abilities. Mesoporous silica nanoparticles present extraordinary host–guest abilities and facile surface functionalization. These two factors make them ideal candidates for the development of novel drug-delivery systems, at the expense of increasing structural complexity. With this idea in mind, a system composed of triggerable and tunable silica nanoparticles was developed for application as drug-delivery nanocarriers. Diels–Alder cycloaddition adducts were chosen as thermal-responsive units that permitted the binding of gold nanocaps able to block the pores and allow the incorporation of targeting fragments. The capping efficiency was tested under different thermal conditions to give outstanding efficiencies within the physiological range and mild temperatures,as well as enhanced release under pulsing heating cycles, which showed the best release profiles.

Chem. Eur. J. 2018, 24, 6992 – 7001


Nanographene oxide (nGO)-mediated hyperthermia has been increasingly investigated as a localized, minimally invasive anticancer therapeutic approach. Near InfraRed (NIR) light irradiation for inducing hyperthermia is particularly attractive, because biological systems mostly lack chromophores that absorb in this spectral window, facilitating the selective heating and destruction of cells which have internalized the NIR absorbingnanomaterials. However, little is known about biological effects accompanying nGO-mediated hyperthermia at cellular and molecular levels. In this work, well-characterized pegylated nGO sheets with a hydrodynamic size of 300 nm were incubated with human Saos-2 osteosarcoma cells for 24 h and their internalization verified by flow cytometry and confocal microscopy. No effect on cell viability was observed after nGO uptake by Saos-2 cells. However, a proliferation delay was observed due to the presence of nGO sheets in the cytoplasm. 1 H NMR metabolomics was employed to screen for changes in the metabolic profile of cells, as this could help to improve understanding of cellular responses to nanomaterials and provide new endpoint markers of effect. Cells internalizing nGO sheets showed noticeable changes in several metabolites compared to control cells, including decreased levels of several amino acids, taurine and creatine and increased levels of phosphocholine and uridine/adenosine nucleotides. After NIR irradiation, cells showed decreases in glutamate and uridine nucleotides, together with increases in glycerophosphocholine and adenosine monophosphate. Overall, this study has shown that the cellular metabolome sensitively responded to nGO exposure and nGO-mediated hyperthermia and that NMR metabolomics is a powerful tool to investigate treatment responses

Materials Science & Engineering C 91 (2018) 340–348


The development of nanomachines able to operate at the nanoscale, performing complex tasks such as drug delivery, precision surgery, or cell detection, constitutes one of the most important challenges in nanotechnology. The principles that rule the nanoscale are completely different from the ones which govern the macroscopic world and, therefore, the collaboration of scientists with expertise in different fields is required for the effective fabrication of these tiny machines. In this review, the most recent advances carried out in the synthesis and application of nanomachines for diagnosis applications will be presented in order to provide a picture of their potential in the detection of important biomolecules or pathogens in a selective and controlled manner.

Int. J. Mol. Sci. 2018, 19, 1579


A mesoporous bioactive glass (MBG) of molar composition 75SiO2-20CaO-5P2O5 (MBG-75S) has been synthetized as a potential bioceramic for bone regeneration purposes. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), nitrogen adsorption studies and transmission electron microscopy (TEM) demonstrated that MBG-75S possess a highly ordered mesoporous structure with high surface area and porosity, which would explain the high ionic exchange rate (mainly calcium and silicon soluble species) with the surrounded media. MBG-75S showed high biocompatibility in contact with Saos-2 osteoblast-like cells. Concentrations up to 1 mg/ml did not lead to significant alterations on either morphology or cell cycle. Regarding the effects on osteoclasts, MBG-75S allowed the differentiation of RAW-264.7 macrophages into osteoclast-like cells but exhibiting a decreased resorptive activity. These results point out that MBG-75S does not inhibit osteoclastogenesis but reduces the osteoclast boneresorbing capability. Finally, in vitro studies focused on the innate immune response, evidenced that MBG-75S allows the proliferation of macrophages without inducing their polarization towards the M1 pro-inflammatory phenotype. This in vitro behavior is indicative that MBG-75S would just induce the required innate immune response without further inflammatory complications under in vivo conditions. The overall behavior respect to osteoblasts, osteoclasts and macrophages, makes this MBG a very interesting candidate for bone grafting applications in osteoporotic patients.

Journal of Colloid and Interface Science 528 (2018) 309–320

Melanoma is one of the most severe public health issues worldwide, not only because of the high number of cases but also for its poor prognosis in late stages. Therefore, early diagnosis and efficient treatment are key toward a future solution. However, melanoma is highly resistant to cytotoxicity in its metastatic form. In this context, a therapeutic strategy based on a targeted chemo-photothermal nanotransporter for cytotoxic compounds is proposed. This approach comprises the use of core–multishell gold nanorods, coated with mesoporous silica and further covered with a thermosensitive polymerwhich is vectorized for selective internalization in melanoma cells. The proposed nanoformulation is capable of releasing the transported cytotoxic compounds on demand, in response to near-IR irradiation, with high selec-tivity and efficacy against malignant cells, even at low concentrations, thereby providing a new tool against melanoma disease.
Part. Part. Syst. Charact.2018, 1800148

Nanocarriers for cancer therapy have been extensively studied, but there is still some research that must be addressed in order to achieve their safe application. In this field, hyperthermia thermal treatments mediated by the use of responsive nanomaterials are not different, and researchers have carried out many attempts to overcome their drawbacks due to the valuable potential of these techniques. Here, an overview is presented of nanodevices based on magnetic- and photoresponsive nanocrystals that respond to magnetic fields and/or near-infrared stimuli for cancer therapies. Special attention is given to the synergic effect that can be achieved with nanoscale heating in combination with chemotherapy through drug-delivery devices to effectively kill cancer cells. In this way, the nanoparticles act as heating sources or “hot spots,” which can trigger cellular responses in the absence of a global temperature rise, making the tumor cells more sensitive to chemotherapeutics. The fabrication of optical and magnetic drug-delivery devices, the heating mechanisms, and their applications in tumor treatment are also summarized

Small Methods2018, 1800007


Mesoporous silica nanoparticles (MSNs) were functionalized with amino groups (MSN-NH2) and thenwith hyaluronic acid, a biocompatible biopolymer which can be recognized by CD44 receptors in tumorcells, to obtain a targeting drug delivery system. To this purpose, three hyaluronic acid samples differ-ing for the molecular weight, namely HAS(8–15 kDa), HAM(30–50 kDa) and HAL(90–130 kDa), wereused. The MSN-HAS, MSN-HAM, and MSN-HALmaterials were characterized through zeta potential anddynamic light scattering measurements at pH = 7.4 and T = 37◦C to simulate physiological conditions.While zeta potential showed an increasing negative value with the increase of the HA chain length, ananomalous value of the hydrodynamic diameter was observed for MSN-HAL, which was smaller than thatof MSN-HASand MSN-HAMsamples. The cellular uptake of MSN-HA samples on HeLa cells at 37◦C wasstudied by optical and electron microscopy. HA chain length affected significantly the cellular uptakethat occurred at a higher extent for MSN-NH2and MSN-HASthan for MSN-HAMand MSN-HALsamples.Cellular uptake experiments carried out at 4◦C showed that the internalization process was inhibitedfor MSN-HA samples but not for MSN-NH2. This suggests the occurrence of two different mechanismsof internalization. For MSN-NH2the uptake is mainly driven by the attractive electrostatic interactionwith membrane phospholipids, while MSN-HA internalization involves CD44 receptors overexpressedin HeLa cells.

Colloids and Surfaces B: Biointerfaces 168 (2018) 50–59



In this work we present the synthesis, characterization and in vitro biological evaluation of PEGylated and actively-targeted ultrasound-responsive hybrid mesoporous silica nanoparticles. This work covers the development of the chemical strategies necessary to afford a modular nanocarrier starting from a proof-of-concept material presented in previous work. This functional ultrasound-responsive material can be adapted to different specific pathological conditions by carefully choosing the appropriate targeting moieties. The new ultrasound responsive material is able to target HeLa cells when conjugated with biotin or an RGD peptide. Ultrasound-responsive cytotoxicity towards cancer cells of doxorubicin-loaded nanoparticles is demonstrated in an in vitrocytotoxicity assay.

J. Mater. Chem. B, 2018, 6, 2785-2794


Calcium phosphate (CaP) based hybrid materials have been synthesized through a precipitation method in aqueous medium in the presence of the anionic surfactant sodium dodecylbenzene sulfonate (SDBS) as structure directing agent. Parameters of synthesis, such as Ca/P molar ratio, surfactant concentration and initial pH, have been investigated trying to get mesostructured CaP phases. A lamellar-like hybrid mesophase consisting in several wavy layers of apatite or apatitebrushite nanoplates was successfully obtained. Materials have been characterized by several physico-chemical techniques. A potential application of these lamellar calcium phosphate based hybrids can be as matrixes in drug delivery systems with the possibility of loading hydrophobic drugs in the organic interlayers. To evaluate their potential as biomaterials, the biocompatibility of two hybrids has been studied in vitro with human Saos-2 osteoblasts. Cell assays showed that, upon the appropriate synthesis and stabilization conditions, a biocompatible CaP and SDBS mesolamellar hybrid can be prepared.

ChemistrySelect 2018, 3, 6880 – 6891


Fibrosis is a common lesion in different pathologic diseases and defined by the excessive accumulation of collagen. Different approaches have been used to treat different conditions characterized by fibrosis. The FDA and EMA approved the use of collagenase to treat palmar fibromatosis (Dupuytren’s contracture). The EMA approved additionally its use in severe Peyronie’s disease, but it has been used off label in other conditions [1,2]. The approved treatment includes up to three (in palmar fibromatosis) or up to eight (in
penile fibromatosis) injections followed by finger extension or penile modeling procedures, typically causing severe pain. Frequent single injections are adequate to treat palmar fibromatosis [3]. The need to repeatedly inject doses of this enzyme can be due to the labile nature of collagenase, which exhibits a complete activity loss after a short period of time. This study presents a novel strategy to manage this enzyme based on the synthesis of polymeric nanocapsules that contain collagenase encapsulated within their matrix. These nanocapsules have been engineered for achieving a gradual release of the encapsulated enzyme for a longer time, which can be up to ten days. The efficacy of these nanocapsules has been tested in a murine model of local dermal fibrosis, and the results demonstrate a reduction in fibrosis greater than that with the injection of free enzyme; this type of treatment showed a significant improvement compared to conventional therapy of free collagenase.

Acta Biomaterialia 74 (2018) 430–438


In the last few years mesoporous silica nanoparticles (MSNs) have gained the attention of the nanomedicine research community, especially for the potential treatment of cancer. Although this topic has been reviewed before, periodic updates on such a hot topic are necessary due to the dynamic character of this field. The reasons that make MSNs so attractive for designing controlled drug delivery systems lie beneath their physico-chemical stability, easy functionalisation, low toxicity and their great loading capacity of many different types of therapeutic agents. The present brief overview tries to cover some of the recent findings on stimuli-responsive mesoporous silica nanocarriers together with the efforts to design targeted nanosystems using that platform. The versatility of those smart nanocarriers has promoted them as very promising candidates to be used in the clinic in the near future to overcome some of the pitfalls of conventional medicine.

Journal of Materials Science: Materials in Medicine (2018) 29:65


Mesoporous bioactive glasses (MBGs) in the system SiO2-CaO-P2O5-Ga2O3 have been synthesized by the evaporation induced self-assembly method and subsequent impregnation with Ga cations. Two different compositions have been prepared and the local environment of Ga(III) has been characterized using 29Si, 71Ga and 31P NMR analysis, demonstrating that Ga(III) is efficiently incorporated as both, network former (GaO4 units) and network modifier (GaO6 units). In vitro bioactivity tests evidenced that Ga-containing MBGs retain their capability for nucleation and growth of an apatite-like layer in contact with a simulated body fluid with ion concentrations nearly equal to those of human blood plasma. Finally, in vitro cell culture tests evidenced that Ga incorporation results in a selective effect on osteoblasts and osteoclasts. Indeed, the presence of this element enhances the early differentiation towards osteoblast phenotype while disturbing osteoclastogenesis. Considering these results, Ga-doped MBGs might be proposed as bone substitutes, especially in osteoporosis scenarios.

Acta Biomaterialia 76 (2018) 333–343


Mesoporous Bioactive Glasses (MBGs) are a family of bioceramics widely investigated for their putative clinical use as scaffolds for bone regeneration. Their outstanding textural properties allow for high bioactivity when compared with other bioactive materials. Moreover, their great pore volumes allow these glasses to be loaded with a wide range of biomolecules to stimulate new bone formation. In this study, an MBG with a composition, in mol%, of 80% SiO2–15% CaO–5% P2O5 (Blank, BL) was compared with two analogous glasses containing 4% and 5% of ZnO (4ZN and 5ZN) before and after impregnation with osteostatin, a C-terminal peptide from a parathyroid hormone-related protein (PTHrP107-111). Zn2+ ions were included in the glass for their bone growth stimulator properties, whereas osteostatin was added for its osteogenic properties. Glasses were characterized, and their cytocompatibility investigated, in pre-osteoblastic MC3T3-E1 cell cultures. The simultaneous additions of osteostatin and Zn2+ions provoked enhanced MC3T3-E1 cell viability and a higher differentiation capacity, compared with either raw BL or MBGs supplemented only with osteostatin or Zn2+. These in vitro results show that osteostatin enhances the osteogenic effect of Zn2+-enriched glasses, suggesting the potential of this combined approach in bone tissue engineering applications.

Nanomaterials 2018, 8, 592


Aminopropyl modified mesoporous SiO2 nanoparticles, MCM-41 type, have been synthesized by the co-condensation method from tetraethylorthosilicate (TEOS) and aminopropyltriethoxysilane (APTES). By means of modifying TEOS/APTES ratio we have carried out an in-depth characterization of the nanoparticles as a function of APTES content. Surface charge and nanoparticles morphology were strongly influenced by the amount of APTES and particles changed from hexagonal to bean-like morphology insofar APTES increased. Besides, the porous structure was also affected, showing a contraction of the lattice parameter and pore size, while increasing the wall thickness. These results bring about new insights about the nanoparticles formation during the cocondensation process. The model proposed herein considers that different interactions stablished between TEOS and APTES with the structure directing agent have consequences on pore size, wall thickness and particle morphology. Finally, APTES is an excellent linker to covalently attach active targeting agents such as folate groups. We have hypothesized that APTES could also play a role in the biological behavior of the nanoparticles. So, the internalization efficiency of the nanoparticles has been tested with cancerous LNCaP and non-cancerous preosteoblast-like MC3T3-E1 cells. The results indicate a cooperative effect between aminopropylsilane presence and folic acid, only for the cancerous LNCaP cell line.

Materials Chemistry and Physics 220 (2018) 260–269


Certain biomaterials are capable of inducing the secretion of Vascular Endothelial Growth Factor (VEGF) from cells exposed to their biochemical influence, which plays a vital role in stimulating angiogenesis. Looking for this capacity, in this study three porous glasses were synthesized and characterized. Glass compositions (in mol-%) were: 60SiO2–(36-2x)CaO–4P2O5–xCuO–xSrO with x=0, 1 or 2.5, respectively, for B60, CuSr-1 or CuSr-2.5 glasses. Cu2+ and Sr2+ ions were added because of the reported biological capabilities of Cu2+ as angiogenic stimulator and Sr2+ as osteogenic stimulator. The objective of this study was to determine the concentration of the glass particles that, being out of the cytotoxic range, could increase VEGF secretion. The viability of cultivated bone marrow stromal cells (ST-2) was assessed. The samples were examined with light microscopy (LM) after the histochemical staining for haematoxylin and eosin (HE). The biological activity of glasses was evaluated in terms of the influence of the Cu2+ and Sr2+ ions on the cells. The dissolution products of CuSr-1 and CuSr-2.5 produced the highest secretion of VEGF from ST-2 cells after 48 h of incubation. The combination of Cu2+ and Sr2+ lays the foundation for engineering a bioactive glass than can lead to vascularized, functional bone tissue when used in bone regeneration applications.

Journal of Non-Crystalline Solids 500 (2018) 217–224


 The poor penetration of drug nanocarriers within tumor tissues is one of the most critical factors which limit their effectiveness. Nanomedicine has developed different strategies in order to overcome this important hurdle. Some of these strategies are based on the degradation of the highly dense extracellular matrix (ECM) which is usually present in many solid tumors. In this sense, one of the most promising approaches consists in the nanoparticle decoration with proteolytic enzymes able to digest the ECM favoring its penetration. Other strategy is based on the capacity of ultrasounds to induce cavitation which propels the nanocarriers to deep areas into the tumor. Both strategies have demonstrated significant improvement in the penetration of nanocarriers in malignant tissues, enhancing their effectivity.

Material Sci & Eng Int J 2018, 2(1): 00028


 We report the use of bis-catecholic polymers as candidates for obtaining effective, tunable gatekeeping coatings for mesoporous silica nanoparticles (MSNs) intended for drug release applications. In monomers, catechol rings act as adhesive moieties and reactive sites for polymerization, together with middle linkers which may be chosen to tune the physicochemical properties of the resulting coating. Stable and low-toxicity coatings (pNDGA and pBHZ) were prepared from two biscatechols of different polarity (NDGA and BHZ) on MSN carriers previously loaded with rhodamine B (RhB) as a model payload, by means of a previously reported synthetic methodology and without any previous surface modification. Coating robustness and payload content were shown to depend significantly on the workup protocol. The release profiles in a model physiological PBS buffer of coated systems (RhB@MSN@pNDGA and RhB@MSN@pBHZ) showed marked differences in the “gatekeeping” behavior of each coating, which correlated qualitatively with the chemical nature of their respective linker moieties. While the uncoated system (RhB@MSN) lost its payload almost completely after 2 days, release from RhB@MSN@pNDGA was virtually negligible, likely due to the low polarity of the parent bis-catechol (NDGA). As opposed to these extremes, RhB@MSN@pBHZ presented the most promising behavior, showing an intermediate release of 50% of the payload in the same period of time.

ACS Appl. Mater. Interfaces 2018, 10, 7661−7669


Mesoporous nanospheres in the system SiO2-CaO (NanoMBGs) with a hollow core surrounded by a radial arrangement  of mesopores were characterized, labeled with FITC (FITC-NanoMBGs) and loaded with ipriflavone (NanoMBG-IPs) in order to evaluate their incorporation and their effects on both osteoblasts and osteoclasts simultaneously and maintaining the communication with each other in coculture. The influence of these nanospheres on macrophage polarization towards pro-inflammatory M1 or reparative M2 phenotypes was also evaluated in basal and stimulated conditions through the expression of CD80 (as M1 marker) and CD206 (as M2 marker) by flow cytometry and confocal microscopy. NanoMBGs did not induce the macrophage polarization towards the M1 pro-inflammatory phenotype, favoring the M2 reparative phenotype and increasing the macrophage response capability against stimuli as LPS and IL-4. NanoMBG-IPs induced a significant decrease of osteoclast proliferation and resorption activity after 7 days in coculture with osteoblasts, without affecting osteoblast proliferation and viability. Drug release test demonstrated that only a fraction of the payload is released by diffusion, whereas the rest of the drug remains within the hollow core after 7 days, thus ensuring the local long-term pharmacological treatment beyond the initial fast IP release. All these data ensure an appropriate immune response to these nanospheres and the potential application of NanoMBG-IPs as local drug delivery system in osteoporotic patients.

European Journal of Pharmaceutics and Biopharmaceutics 133 (2018) 258–268

An increase of bone diseases incidence has boosted the study of ceramic biomaterials as potential osteo-inductive scaffolds. In particular, mesoporous bioactive glasses have demonstrated to possess a broad application in the bone regeneration field, due their osteo-regenerative capa bility and their ability to release drugs from the mesoporous structure. These special features have been studied as an option to fight against bone infection, which is one of the most common problems regarding bone regeneration therapies. In this work, a mesoporous bioglass functionalized with polyamines and capped with adenosine triphosphate (ATP) as the molecular gate was developed for the controlled release of the antibiotic levofloxacin. Phosphate bonds of ATP were hydrolyzed in the presence of acid phosphatase (APase), the concentration of which is significantly increased in bone infection due to the activation of bone resorption processes. The solid was characterized and tested successfully against bacteria. The final gated solid induced bacterial death only in the presence of acid phosphatase. Additionally, it was demonstrated that the solid is not toxic against human cells. The double function of the prepared material as a drug delivery system and bone regeneration enhancer confirms the possible development of a new approach in the tissue engineering field, in which controlled release of therapeutic agents can be finely tuned and, at the same time, osteoinduction is favored
Chem. Eur. J. 2018 24 ,1–9

Despite the claim that encapsulation of drugs improves the therapeutic profile of free drugs, there are still important limitations in drug delivery. With respect to cancer treatment, two promising implementations are combination therapy and targeted devices, which are aimed at increasing the drug effect either by achieving higher cell death rates or by discriminating between cell populations. However, for the time being, the scope of combining both approaches is unknown. To advance this knowledge, a two-drug-delivery system with dual cell-organelle targeting based on mesoporous silica nanoparticles, which are known to be able to host drugs within their pores, has been designed. In vitro results show a synergistic effect and high efficacy, demonstrating that the combination of dual therapy and targeting could still advance the development of drug-delivery nanodevices against difficult-to-treat cancers.

Bioconjugate Chem. 2018, 29, 3677−3685


Zwitterionization of biomaterials has been heightened to a potent tool to develop biocompatible materials that are able to inhibit bacterial and non-specific proteins adhesion. This constitutes a major progress in the biomedical field. This manuscript overviews the main functionalization strategies that have been reported up to date to design and develop these advanced biomaterials. On this regard, the recent research efforts that were dedicated to provide their surface of zwitterionic nature are summarized by classifying biomaterials in two main groups. First, we centre on biomaterials in clinical use, concretely bioceramics, and metallic implants. Finally, we revise emerging nanostructured biomaterials, which are receiving growing attention due to their multifunctionality and versatility mainly in the local drug delivery and bone tissue regeneration scenarios.

Medicines 2018, 5, 125


Mesoporous silica materials (MSM) have a great surface area and a high pore volume,meaning that they consequently have a large loading capacity, and have been demonstrated to be unique candidates for the treatment of different pathologies, including bacterial infection. In this text, we review the multiple ways of action in which MSM can be used to fight bacterial infection, including early detection, drug release, targeting bacteria or biofilm, antifouling surfaces, and adjuvant capacity. This review focus mainly on those that act as a drug delivery system, and therefore that have an essential characteristic, which is their great loading capacity. Since MSM have advantages in all stages of combatting bacterial infection; its prevention, detection and finally in its treatment, we can venture to talk about them as the “nightmare of bacteria”.

Pharmaceutics 2018, 10, 279


In this work, we evaluate the tissue response and tolerance to a designed 3D porous scaffold composed of nanocrystalline carbonate-hydroxyapatite and agarose as a preliminary step in bone repair and regeneration. These scaffolds  were subcutaneously implanted into rats, which were sacrificed at different times. CD4þ, CD8þ and ED1þ cells were evaluated as measurements of inflammatory reaction and tolerance. We observed some inflammatory response early after subcutaneous implantation. The 3D interconnected porosity increased scaffold integration via the formation of granulation tissue and the generation of a fibrous capsule around the scaffold. The capsule is initially formed by collagen which progressively invades the scaffold, creating a network that supports the settlement of connective tissue and generating a compact structure. The timing of the appearance of CD4þ and CD8þ cell populations is in agreement with the resolved inflammatory response. The appearance of macrophage activity evidences a slow and gradual degradation activity. Degradation started with the agarose component of the scaffold, but the nano-apatite was kept intact for up to 30 days. Therefore, this apatite/agarose scaffold showed a high capacity for integration by a connective network that stabilizes the scaffold and results in slow nano-apatite degradation. The fundamental properties of the scaffold would provide mechanical support and facilitate bone mobilization, which is of great importance in the masticatory system or large bones.

J. Biomater. Appl.2018, Vol. 33(5) 741–752


Trojan-horse strategy for cancer therapy employing tumor-tropic mesenchymal stem cells transfected with a non-viral nanovector is here presented. In this sense, ultrasound-responsive mesoporous silica nanoparticles were coated with a polycation (using two different molecular weights), providing them with gene transfection capabilities that were evaluated using two different plasmids. First, the expression of Green Fluorescent Protein was analyzed in Decidua-derived Mesenchymal Stem Cells after incubation with the silica nanoparticles. The most successful nanoparticle was then employed to induce the expression of two suicide genes: cytosine deaminase and uracil phosphoribosyl transferase, which allow the
cells to convert a non-toxic pro-drug (5-fluorocytosine) into a toxic drug (5-Fluorouridine monophosphate). The effect of the production of the toxic final product was also evaluated in a cancer cell line (NMU cells) co-cultured with the transfected vehicle cells, Decidua-derived Mesenchymal Stem Cells.

Acta Biomaterialia 83 (2019) 372–378


The osteogenic and angiogenic responses to metal macroporous scaffolds coated with silicon substituted hydroxyapatite (SiHA) and decorated with vascular endothelial growth factor (VEGF) have been evaluated in vitro and in vivo. Ti6Al4V-ELI scaffolds were prepared by electron beam melting and subsequently
coated with Ca10(PO4)5.6(SiO4)0.4(OH)1.6 following a dip coating method. In vitro studies demonstrated that SiHA stimulates the proliferation of MC3T3-E1 pre-osteoblastic cells, whereas the adsorption of VEGF stimulates the proliferation of EC2 mature endothelial cells. In vivo studies were carried out in an osteoporotic sheep model, evidencing that only the simultaneous presence of both components led to a significant increase of new tissue formation in osteoporotic bone.

Acta Biomaterialia 83 (2019) 456–466


The design of drug delivery systems needs to consider biocompatibility and host body recognition for an adequate actuation. In this work, mesoporous silica nanoparticles (MSNs) surfaces were successfully modified with two silane molecules to provide mixed-charge brushes (-NH3 /-PO3 €) and well evaluated in terms of surface properties, low-fouling capability and cell uptake in comparison to PEGylated MSNs. The modification process consists in the simultaneous direct-grafting of hydrolysable short chain amino (aminopropyl silanetriol, APST) and phosphonate-based (trihydroxy-silyl-propyl-methyl-phospho nate, THSPMP) silane molecules able to provide a pseudo-zwitterionic nature under physiological pH conditions. Results confirmed that both mixed-charge pseudo-zwitterionic MSNs (ZMSN) and PEG-MSN display a significant reduction of serum protein adhesion and macrophages uptake with respect to pristine MSNs. In the case of ZMSNs, this reduction is up to a 70–90% for protein adsorption and c.a. 60% for cellular uptake. This pseudo-zwitterionic modification has been focused on the aim of local treatment of bacterial infections through the synergistic effect between the inherent antimicrobial effect of mixed-charge system and the levofloxacin antibiotic release profile. These findings open promising future expectations for the effective treatment of bacterial infections through the use of mixed-charge pseudo-zwitterionic MSNs furtive to macrophages and with antimicrobial properties.

Acta Biomaterialia 84 (2019) 317–327


3D porous scaffolds based on agarose and nanocrystalline apatite, two structural components that act as a temporary mineralized extracellular matrix, were prepared by the GELPOR3D method. This shaping technology allows the introduction of thermally-labile molecules within the scaffolds during the fabrication procedure. An angiogenic protein, Vascular Endothelial Growth Factor, and an antibiotic, cephalexin, loaded in mesoporous silica nanoparticles, were included to design multifunctional scaffolds for bone reconstruction. The dual release of both molecules showed a marked increase in the number of blood vessels on embryonic day 14 in chicken embryos grown ex ovo, while, at the same time providing an antibiotic local concentration capable of inhibiting Staphylococcus aureus bacterial growth. In this sense, different release patterns, monitored by UV-spectroscopy, could be tailored as a function of the cephalexin loading strategy, either releasing all the loaded cephalexin in the first 4 h or less than 50% after 24 h. The scaffold surface was characterized by a high hydrophilicity, with contact angles between 50 and 63, which enabled the adhesion and proliferation of preosteoblastic cells.

Acta Biomaterialia 86 (2019) 441–449


The rise and development of nanotechnology has enabled the creation of a wide number
of systems with new and advantageous features to treat cancer. However, in many cases, the lone
application of these new nanotherapeutics has proven not to be enough to achieve acceptable
therapeutic efficacies. Hence, to avoid these limitations, the scientific community has embarked on
the development of single formulations capable of combining functionalities. Among all possible
components, silica—either solid or mesoporous—has become of importance as connecting and
coating material for these new-generation therapeutic nanodevices. In the present review, the most recent examples of fully inorganic silica-based functional composites are visited, paying particular attention to those with potential biomedical applicability. Additionally, some highlights will be given with respect to their possible biosafety issues based on their chemical composition.

Int. J. Mol. Sci. 2019, 20, 929


Nanotechnology, which has already revolutionised many technological areas, is expected to transform life sciences. In this sense, nanomedicine could address some of the most important limitations of conventional medicine. In general, nanomedicine includes three major objectives: (1) trap and protect a great amount of therapeutic agents; (2) carry them to the specific site of disease avoiding any leakage; and (3) release on-demand high local concentrations of therapeutic agents. This feature article will make special emphasis on mesoporous silica nanoparticles that release their therapeutic cargo in response to ultrasound.

Chem. Commun., 2019, 55, 2731--2740


Theselectivedeliveryof therapeuticandimagingagentsto tumoralcellshas beenpostulatedas one of the mostimportantchallengesin the nanomedicinefield.Meta-iodo-benzilguanidine(MIBG)is widelyusedfor the diagnosisofneuroblastoma(NB)due to its strongaffinityfor the norepi-nephrinetransporter(NET),usuallyoverexpressedon themembraneof malignantcells.Herein,afamilyof novelY-shapedscaffoldshas beensynthesized, whichhave structuralanaloguesof MIBGcovalentlyattachedat eachend of the Y-structure.The cellularuptakecapacityof thesedouble-target-ing ligandshas beenevaluatedin vitroand in vivo,yieldingonespecificY-shapedstructurethat is ableto be engulfedby themalignantcells,and accumulatesin the tumoraltissue,atsignificantlyhigherlevelsthanthe structurecontainingonlyone singletargetingagent.ThisY-shapedligandcan provideapowerfultool for the currenttreatmentand diagnosisof thisdisease.



An approach for safely delivering AgNPs to cancer cells and the evaluation of the affected cellular mechanism are presented. The use of mesoporous silica nanoparticles (MSNs) as nanovehicles decorated with transferrin (Tf, targeting agent) provides a nanoplatform for the nucleation and immobilization of AgNPs (MSNs-Tf-AgNPs). We performed the physico-chemical characterization of the nanosystems and evaluated their therapeutic potential using bioanalytical strategies to estimate the efficiency of the targeting, the degree of cellular internalization in two cell lines with different TfR expression, and the cytotoxic effects of the delivered AgNPs. In addition, cellular localization of the nanosystems in cells has been evaluated by a transmission electron microscopy analysis of ultrathin sections of human hepatocarcinoma (HepG2) cells exposed to MSNs-Tf-AgNPs. The in vitro assays demonstrate that only the nanosystem functionalized with Tf is able to transport the AgNPs inside the cells which overexpress transferrin receptors. Therefore, this novel nanosystem is able to deliver AgNPs specifically to cancer cells overexpressing Tf receptors and offers the possibility of a targeted therapy using reduced doses of silver nanoparticles as cytotoxic agents. Then, a quantitative proteomic experiment validated through the analysis of gene expression has been performed to identify the molecular mechanisms of action associated with the chemotherapeutic potential of the MSNs-Tf-AgNP nanocarriers.

Nanoscale, 2019, 11, 4531–4545


In this paper we aim to analyse the behaviour of ZnO nanocrystals (ZnO NCs), prepared with a new synthetic approach and not embedded in any composite matrix, for bone implant applications in vitro. In particular, we have developed a novel, fast and reproducible microwave-assisted synthesis, to obtain highly-crystalline, round-shaped ZnO NCs of 20 nm in diameter as an extremely-stable colloidal solution in ethanol. The nanocrystals were also partially chemically functionalized by anchoring amino-propyl groups to the ZnO surface (ZnO–NH2 NCs). Thus, the role of both ZnO NC concentration and surface chemistry were tested in terms of biocompatibility towards pre-osteoblast cells, promotion of cell proliferation and differentiation, and also in terms of antimicrobial activity against Gram positive and negative bacteria, such as Escherichia coli and Staphylococcus aureus, respectively. The results suggest that ZnO–NH2 NCs is the most promising
candidate to solve infectious disease in bone implants and at the same time promote bone tissue proliferation, even at high concentrations. Although further investigations are needed to clarify the mechanism underlying the inhibition of biofilm formation and to investigate the role of the ZnO–NH2 NCs in in vivo assays, we demonstrated that fine and reproducible control over the chemical and structural parameters in ZnO nanomaterials can open up new horizons in the use of functionalized ZnO NCs as a highly biocompatible and osteoinductive nanoantibiotic agent for bone tissue engineering.

RSC Adv., 2019, 9, 11312–11321

There is an urgent need of biosynthetic bone grafts with enhanced osteogenic capacity. In this study, we describe the design of hierarchical meso -macroporous 3D-scaffolds based on mesopo ous bioactive glasses (MBGs), enriched with the peptide osteostatin and Zn 2+ ions, and their osteogenic effect on human mesenchymal stem cells (hMSCs) as a preclinical strategy in bone regeneration. The MBG compositions investigated were 80%SiO2–15%CaO–5%P2O5(in mol-%) Blank (BL), and two analogous glasses containing 4% ZnO (4ZN) and 5% ZnO (5ZN). By using additive fabrication techniques, scaffolds exhibiting hierarchical porosity: mesopores (around 4 nm), macropores (1–600lm) and big channels (1000l m), were prepared. These MBG scaffolds with or without osteostatin were evaluated in hMCSs cultures. Zinc promoted hMSCs colonization (both the surface and inside) of MBG scaffolds. Moreover, Zn 2+ ions and osteostatin together, but not independently, in the scaffolds were found to induce the osteoblast differentiation genes runt related transcription factor-2 (RUNX2) and alkaline phos- phatase (ALP) in hMSCs after 7 d of culture in the absence of an osteogenic differentiation-promoting medium. These results add credence to the combined use of zinc and osteostatin as an effective strategy for bone regeneration applications.
Acta Biomaterialia 89 (2019) 359–371

Since the second half of the 20th century, bioceramics are used for bone repair and regeneration. Inspired by bones and teeth, and aimed at mimicking their structure and composition, several artificial bioceramics were developed for biomedical applications. And nowadays, in the 21st century, with the increasing prominence of nanoscience and nanotechnology, certain bioceramics are being used to build smart drug delivery systems, among other applications. This minireview will mainly describe both tendencies through the research work carried out by the research team of María Vallet-Regí.

Pure Appl. Chem. 2019; 91(4): 687–706


Macroporous scaffolds made of a SiO2-CaO-P2O5mesoporous bioactive glass (MBG) ande-polycaprolactone (PCL) have been prepared by robocasting. These scaffolds showed an excellentin vitrobiocompatibility in contact with osteoblast like cells (Saos 2) and osteoclasts derived fromRAW 264.7 macrophages.In vivostudies were carried out by implantation into cavitary defects drilledin osteoporotic sheep. The scaffolds evidenced excellent bone regeneration properties, promoting newbone formation at both the peripheral and the inner parts of the scaffolds, thick trabeculae, high vascu-larization and high presence of osteoblasts and osteoclasts. In order to evaluate the effects of the localrelease of an antiosteoporotic drug, 1% (%wt) of zoledronic acid was incorporated to the scaffolds. Thescaffolds loaded with zoledronic acid induced apoptosis in Saos 2 cells, impeded osteoclast differentiationin a time dependent manner and inhibited bone healing, promoting an intense inflammatory response inosteoporotic sheep.

Acta Biomaterialia 90 (2019) 393–402


Osteoporosis is the most common disease involving bone degeneration. Current clinical treatments are not able to offer a satisfying curative effect, so the development of effective treatments is desired. Gene silencing through siRNA delivery has gained great attention as a potential treatment in bone diseases. SOST gene inhibits the Wnt signaling pathway reducing osteoblast differentiation. Consequently, silencing SOST genes with a specific siRNA could be a potential option to treat osteoporosis. Generally, siRNAs have a very short halflife and poor transfection capacity, so an effective carrier is needed. In particular, mesoporous silica nanoparticles (MSNs) have attracted great attention for intracellular delivery of nucleic acids. We took advantage of their high loading capacity to further load the pores with osteostatin, an osteogenic peptide. In this study, we developed a system based on MSNs coated with poly(ethylenimine), which can effectively deliver SOST siRNA and osteostatin inside cells, with the consequent augmentation of osteogenic markers with a synergistic effect. This established the potential utility of MSNs to co-deliver both biomolecules to promote bone formation, this being a potential alternative to treat osteoporosis.

ACS Nano 2019, 13, 5451−5464


 Introduction: Mesoporous silica nanoparticles (MSNs) are outstanding nanoplatforms for drug delivery. Herein, the most recent advances to turn MSN-based carriers into minimal side effect drug delivery agents are covered. Areas covered: This review summarizes the scientific advances dealing with MSNs for targeted and stimuli-responsive drug delivery since 2015. Delivery aspects to diseased tissues together with approaches to obtain smart MSNs able to respond to internal or external stimuli and their applications are here described. Special emphasis is done on the combination of two or more stimuli on the same nanoplatform and on combined drug therapy. Expert opinion: The use of MSNs in nanomedicine is a promising research field because they are outstanding platforms for treating different pathologies. This is possible thanks to their structural, chemical, physical and biological properties. However, there are certain issues that should be overcome to improve the suitability of MSNs for clinical applications. All materials must be properly characterized prior to their in vivo evaluation; furthermore, preclinical in vivo studies need to be standardized to demonstrate the MSNs clinical translation potential.

Expert Opin. Drug. Deliv.. 16 (4), 415-439     2019


The purpose of this work was the assembly of multicomponent nano-bioconjugates based on mesoporous silica nanoparticles (MSNs), proteins (bovine serum albumin, BSA, or lysozyme, LYZ), and gold nanoparticles (GNPs). These nanobioconjugates may find applications in nanomedicine as theranostic devices. Indeed, MSNs can act as drug carriers, proteins stabilize MSNs within the bloodstream, or may have therapeutic or targeting functions. Finally, GNPs can either be used as contrast agents for imaging or for photothermal therapy. Here, amino-functionalized MSNs (MSN−NH2) were synthesized and characterized through various techniques (small angle X-rays scattering TEM, N2 adsorption/desorption isotherms, and thermogravimetric analysis (TGA)). BSA or lysozyme were then grafted on the external surface of MSN−NH2 to obtain MSN−BSA and MSN−LYZ bioconjugates, respectively. Protein immobilization on MSNs surface was confirmed by Fourier transform infrared spectroscopy, ζ-potential measurements, and TGA, which also allowed the estimation of protein loading. The MSN−protein samples were then dispersed in a GNP solution to obtain MSN−protein−GNPs nano-bioconjugates. Transmission electron microscopy (TEM) analysis showed the occurrence of GNPs on the MSN−protein surface, whereas almost no GNPs occurred in the protein-free control samples. Fluorescence and Raman spectroscopies suggested that proteins−GNP interactions involve tryptophan residues.

ACS Omega 2019, 4, 11044−11052


The ability of bacteria to form biofilms hinders any conventional treatment for chronic infections and hasserious socio-economic implications. For this purpose, a nanocarrier capable of overcoming the barrier ofthe mucopolysaccharide matrix of the biofilm and releasing its loaded-antibiotic within this matrixwould be desirable. Herein, we developed a new nanosystem based on levofloxacin (LEVO)-loaded meso-porous silica nanoparticles (MSN) decorated with the lectin concanavalin A (ConA). The presence of ConApromotes the internalization of this nanosystem into the biofilm matrix, which increases the antimicro-bial efficacy of the antibiotic hosted within the mesopores. This nanodevice is envisioned as a promisingalternative to conventional treatments for infection by improving the antimicrobial efficacy and reducingside effects.

Acta Biomaterialia 96 (2019) 547–556


Based on an already tested laboratory procedure, a new magnetron sputtering methodology to simultaneously coat two-sides of large area implants (up to ~15 cm2) with Ti nanocolumns in industrial reactors has been developed. By analyzing the required growth conditions in a laboratory setup, a new geometry and methodology have been proposed and tested in a semi-industrial scale reactor. A bone plate (DePuy Synthes) and a pseudo-rectangular bone plate extracted from a patient were coated following the new methodology, obtaining that their osteoblast proliferation efficiency and antibacterial functionality were equivalent to the coatings grown in the laboratory reactor on small areas. In particular, two kinds of experiments were performed: Analysis of bacterial adhesion and biofilm formation, and osteoblasts–bacteria competitive in vitro growth scenarios. In all these cases, the coatings show an opposite behavior toward osteoblast and bacterial proliferation, demonstrating that the proposed methodology represents a valid approach for industrial production and practical application of nanostructured titanium coatings.

Nanomaterials 2019, 9, 1217; doi:10.3390/nano9091217


Both the prevalence of antibiotic resistance and the increased biofilm-associated infections
are boosting the demand for new advanced and more e ective treatment for such infections. In this sense, nanotechnology o ers a ground-breaking platform for addressing this challenge. This review shows the current progress in the field of antimicrobial inorganic-based nanomaterials and their activity against bacteria and bacterial biofilm. Herein, nanomaterials preventing the bacteria adhesion and nanomaterials treating the infection once formed are presented through a classification based on their functionality. To fight infection, nanoparticles with inherent antibacterial activity and nanoparticles acting as nanovehicles are described, emphasizing the design of the carrier nanosystems with properties targeting the bacteria and the biofilm.

Int. J. Mol. Sci. 2019, 20, 3806


A very small number of biomaterials investigated for bone regeneration were reported as able to prevent the oxidative stress. In this study beads based on alginate hydrogel and mesoporous glasses (MG) containing different amounts of cerium oxides (Ce3+/Ce4+) exhibiting antioxidant properties were investigated as a good approach to mimic the action of antioxidant enzymes in our organism. The effect of cerium contents on the bioactivity and biocompatibility of beads were investigated. Moreover, the potential capability of Ce-containing MG to prevent the oxidative stress caused by the activity of reactive oxygen species (ROS) was here investigated for the first time. The increment of cerium oxide from 1.2, to 3.6 and 5.3 mol% decreases the surface area and porosity of MG and increases the catalase mimetic activity after 168 h. Swelling tests in different cell culture media (D- and α-MEM) demonstrated the rehydration capability of beads. The presence of beads with the highest Ce-contents (3.6 and 5.3%) improved the proliferation of pre-osteoblastic cells MC3T3-C1 cells. However, the cell differentiation decreased when increased the cerium content. Lactate dehydrogenase assays showed beads are cytocompatible materials. Moreover, oxidative stress tests with H2O2 showed a better response related to cell viability and the elimination of oxidant species when increased cerium content. Beads of glasses with 1.2 and 3.6% of CeO2 are excellent candidates as bioactive scaffolds for bone regeneration capable of counteract the oxidative stress.

Materials Science & Engineering C 105 (2019) 109971



The poor delivery of nanoparticles to target cancer cells hinders their success in the clinical setting. In this work, an alternative target readily available for circulating nanoparticles has been selected to elimi- nate the need for nanoparticle penetration in the tissue: the tumor blood vessels. A tumor endothelium- targeted nanoparticle (employing an RGD-containing peptide) capable of co-delivering two anti-vascular drugs (one anti-angiogenic drug and one vascular disruption agent) is here presented. Furthermore, the nanodevice presents two additional anti-vascular capabilities upon activation by Near-Infrared light: pro- voking local hyperthermia (by gold nanorods in the system) and generating toxic reactive oxygen species (by the presence of a photosensitizer). RGD-targeting is shown to increase uptake by HUVEC cells, and while the nanoparticles are shown not to be toxic for these cells, upon Near-Infrared irradiation their almost complete killing is achieved. The combination of all four therapeutic modalities is then evalu- ated in an ex ovo fibrosarcoma xenograft model, which shows a significant reduction in the number of blood vessels irrigating the xenografts when the nanoparticles are present, as well as the destruction of the existing blood vessels upon irradiation. These results suggest that the combination of different anti- vascular therapeutic strategies in a single nanocarrier appears promising and should be further explored in the future.

Acta Biomaterialia 101 (2020) 459–468


Silicon-substituted hydroxyapatite (SiHA) macroporous scaffolds have been prepared by robocasting. In order to optimize their bone regeneration properties, we have manufactured these scaffolds presenting different microstructures: nanocrystalline and crystalline. Moreover, their surfaces have been decorated with vascular endothelial growth factor (VEGF) to evaluate the potential coupling between vasculariza- tion and bone regeneration. In vitro cell culture tests evidence that nanocrystalline SiHA hinders pre- osteblast proliferation, whereas the presence of VEGF enhances the biological functions of both endothe- lial cells and pre-osteoblasts. The bone regeneration capability has been evaluated using an osteoporotic sheep model. In vivo observations strongly correlate with in vitro cell culture tests. Those scaffolds made of nanocrystalline SiHA were colonized by fibrous tissue, promoted inflammatory response and fostered osteoclast recruitment. These observations discard nanocystalline SiHA as a suitable material for bone re- generation purposes. On the contrary, those scaffolds made of crystalline SiHA and decorated with VEGF exhibited bone regeneration properties, with high ossification degree, thicker trabeculae and higher pres- ence of osteoblasts and blood vessels. Considering these results, macroporous scaffolds made of SiHA and decorated with VEGF are suitable bone grafts for regeneration purposes, even in adverse pathological scenarios such as osteoporosis.

Acta Biomaterialia 101 (2020) 544–553



The treatment of bone fractures still represents a challenging clinical issue when complications due to impaired bone remodelling (i.e. osteoporosis) or infections occur. These clinical needs still require a radical improvement of the existing therapeutic approach through the design of advanced biomaterials combining the ability to promote bone regeneration with anti-adhesive properties able to minimise unspecific biomolecules adsorption and bacterial adhesion. Strontium-containing mesoporous bioactive glasses (Sr-MBG), which are able to exert a pro-osteogenic effect by releasing Sr2+ ions, have been successfully functionalised to provide mixed-charge (ANH3 /ACOO€) surface groups with anti-adhesive abilities.
Sr-MBG have been post-synthesis modified by co-grafting hydrolysable short chain silanes containing amino (aminopropylsilanetriol) and carboxylate (carboxyethylsilanetriol) moieties to achieve a zwitterionic zero-charge surface. The final system was then characterised in terms of textural-structural properties, bioactivity, cytotoxicity, pro-osteogenic and anti-adhesive capabilities.

Journal of Colloid and Interface Science 563 (2020) 92–103


In recent years, nanomedicine has emerged at the forefront of nanotechnology, generating great expectations in the biomedical field. Researchers are developing novel nanoparticles for both diagnostic applications using imaging technology and treatment purposes through drug delivery technologies. Among all the available nanoparticles, inorganic mesoporous silica nanoparticles are the newcomers to the field, contributing with their unique and superlative properties. A brief overview of the most recent progress in the synthesis of mesoporous silica nanoparticles and their use as drug delivery nanocarriers is provided. The latest trends in this type of nanoparticles and their use in modern medicine are discussed, highlighting the significant impact that this technology might have in the near future.

Adv. Funct. Mater.2020, 30, 1902634


Bone diseases, such as bone cancer, bone infection and osteoporosis, constitute a major issue for modern societies as a consequence of their progressive ageing. Even though these pathologies can be currently treated in the clinic, some of those treatments present drawbacks that may lead to severe complications. For instance, chemotherapy lacks great tumor tissue selectivity, afecting healthy and diseased tissues. In addition, the inappropriate use of antimicrobials is leading to the appearance of drug-resistant bacteria and persistent biofilms, rendering current antibiotics useless. Furthermore, current antiosteoporotic treatments present many side effects as a consequence of their poor bioavailability and the need to use higher doses. In view of the existing evidence, the encapsulation and selective delivery to the diseased tissues of the different therapeutic compounds
seem highly convenient. In this sense, silica-based mesoporous nanoparticles over great loading capacity within their pores, the possibility of modifying the surface to target the particles to the malignant areas and great biocompatibility. This manuscript is intended to be a comprehensive review of the available literature on complex bone diseases treated with silica-based mesoporous nanoparticles—the further development of which and eventual translation into the clinic could bring significant benefits for our future society.

Pharmaceutics 2020, 12, 83


Ultrasound has attracted much attention in recent years as an external stimulus capable of activating different types of nanomaterials for therapeutic application. One of the characteristics that makes ultrasound an especially appealing triggering stimulus for nanomedicine is its capacity to be non-invasively applied in a focused manner at deep regions of the body. Combining ultrasound with nanoparticles, different biological effects can be achieved. In this work, an overview of the four main types of inducible responses will be provided: inducing drug release, producing ultrasound-derived biological effects, modifying nanoparticle biodistribution and developing theranostic agents. Several examples of each one of these applications are presented here to illustrate the key concepts underlying recent developments in the discipline.

Bull. Chem. Soc. Jpn. 2020, 93, 220–229


Surface modification of orthopedic and dental implants has been demonstrated to be an effective strategy to accelerate bone healing at early implantation times. Among the different alternatives, coating implants with a layer of hydroxyapatite (HAp) is one of the most used techniques, due to its excellent biocompatibility and osteoconductive behavior. The composition and crystalline structure of HAp allow for numerous ionic substitutions that provide added value, such as antibiotic properties or osteoinduction. In this article, we will review and critically analyze the most important advances in the field of substituted hydroxyapatite coatings. In recent years substituted HAp coatings have been deposited not only on orthopedic prostheses and dental implants, but also on macroporous scaffolds, thus expanding their applications towards bone regeneration therapies. Besides, the capability of substituted HAps to immobilize proteins and growth factors by noncovalent interactions has opened new possibilities for preparing hybrid coatings that foster bone healing processes. Finally, the most important in vivo outcomes will be discussed to understand the prospects of substituted HAp coatings from a clinical point of view. 

J. Mater. Chem. B, 2020, 8, 1781--1800


One of the major concerns in the application of nanocarriers in oncology is their scarce penetration capacity in tumoral tissues. Living organisms
(cells and bacteria) present the capacity to navigate autonomously following chemical gradients being able to penetrate deeply into dense
tissues. Currently, the possibility to employ these organisms for the transportation of therapeutic agents or nanocarriers has received huge attention. Herein, a new approach to deliver drug-loaded nanoparticles achieving high penetration in tumoral matrices is presented. Escherichia coli bacteria wall is decorated with azide groups, whereas alkyne-strained groups are incorporated on the surface of mesoporous silica nanoparticles loaded with a potent cytotoxic compound, doxorubicin. Both functional
groups form stable triazole bonds by click-type reaction allowing the covalent grafting of nanoparticles on living bacteria. Both motility and penetration capacity are evaluated in a 3D tumoral matrix model composed by a dense collagen extracellular matrix containing human fibrosarcome cells. The results confirm that bacteria are able to transport the nanoparticles crossing a thick collagen layer being able to destroy almost 80% of the tumoral cells located underneath. These findings envision a powerful strategy in cancer treatment by allowing a homogeneous distribution of therapeutic agents in the malignancy.

Adv. Mater. Interfaces 2020, 7, 1901942


The enormous versatility of mesoporous silica nanoparticles permits the creation of a large number of nanotherapeutic systems for the treatment of cancer and many other pathologies. In addition to the controlled release of small drugs, these materials allow a broad number of molecules of a very di erent nature and sizes. In this review, we focus on biogenic species with therapeutic abilities (proteins, peptides, nucleic acids, and glycans), as well as how nanotechnology, in particular silica-based materials, can help in establishing new and more ecient routes for their administration. Indeed, since the applicability of those combinations of mesoporous silica with bio(macro)molecules goes beyond cancer treatment, we address a classification based on the type of therapeutic action. Likewise, as illustrative content, we highlight the most typical issues and problems found in the preparation of those hybrid nanotherapeutic materials.

Pharmaceutics 2020, 12, 432


Mesoporous silica nanoparticles have been broadly applied as drug delivery systems owing to their exquisite features, such as excellent textural properties or biocompatibility. However, there are various biological barriers that prevent their proper translation into the clinic, including: (1) lack of selectivity toward tumor tissues, (2) lack of selectivity for tumoral cells and (3) endosomal sequestration of the particles upon internalization. In addition, their open porous structure may lead to premature drug release, consequently affecting healthy tissues and decreasing the efficacy of the treatment. First, this review will provide a comprehensive and systematic overview of the different approximations that have been implemented into mesoporous silica nanoparticles to overcome each of such biological barriers. Afterward, the potential premature and non-specific drug release from these mesoporous nanocarriers will be addressed by introducing the concept of stimuliresponsive gatekeepers, which endow the particles with on-demand and localized drug delivery.

Nanomaterials 2020, 10, 916


Chronic bone infection is considered as one of the most problematic biofilm-related infections. Its recurrent and resistant nature, high morbidity, prolonged hospitalization, and costly medical care expenses have driven the efforts of the scientific community to develop new therapies to improve the standards used today. There is great debate on the management of this kind of infection in order to establish consistent and agreed guidelines in national health systems. The scientific research is oriented toward the design of anti-infective biomaterials both for prevention and cure. The properties of these materials must be adapted to achieve better anti-infective performance and good compatibility, which allow a good integration of the implant with the surrounding tissue. The objective of this review is to study in-depth the antibacterial biomaterials and the strategies underlying them. In this sense, this manuscript focuses on antimicrobial coatings, including the new technological advances on surface modification; scaffolding design including multifunctional scaffolds with both antimicrobial and bone regeneration properties; and nanocarriers based on mesoporous silica nanoparticles with advanced properties (targeting and stimuli-response capabilities).

Adv. Healthcare Mater. 2020, 2000310


Mesoporous silica nanoparticles have attracted much attention in recent years as drug and gene delivery systems for biomedical applications. Among their most beneficial features for biomedicine, we can highlight their biocompatibility and their outstanding textural properties, which provide a great loa ing capacity for many types of cargos. In the context of cancer nanomedicine, combination therapy and gene transfection/silencing have recently been highlighted as two of its most promising fields. In this review, we aim to provide an overview of the different small molecule drug‐nucleic acid co‐delivery combinations that have been developed using
mesoporous silica nanoparticles as carriers. By carefully selecting the   chemotherapeutic drug and nucleic acid cargos to be co‐delivered by mesoporous silica nanoparticles, different therapeutic goals can be achieved by overcoming resistance mechanisms, combining different cytotoxic mechanisms, or providing an additional antiangiogenic effect. The examples here presented highlight the great promise of this type of strategies for the development of future therapeutics.

Pharmaceutics 2020, 12, 526


Injectable therapeutic formulations locally releasing their cargo with tunable kinetics in response to external biochemical/physical cues are gaining interest in the scientific community, with the aim to overcome the cons of traditional administration routes. In this work, we proposed an alternative solution to this challenging goal by combining thermosensitive hydrogels based on custom-made amphiphilic poly(ether urethane)s (PEUs) and mesoporous silica nanoparticles coated with a self-immolative polymer sensitive to acid pH (MSN-CS-SIP). By exploiting PEU chemical versatility, Boc-protected amino groups were introduced as PEU building block (PEU-Boc), which were then subjected to a deprotection reaction to expose pendant primary amines along the polymer backbone (PEU-NH2, 3E18 -NH2/gPEU-NH2) with the aim to accelerate system response to external acid pH environment. Then, thermo-sensitive hydrogels were designed (15% w/v) showing fast gelation in physiological conditions (approximately 5 min), while no significant changes in gelation temperature and kinetics were induced by the Boc-deprotection. Conversely, free amines in PEU-NH2 effectively enhanced and
accelerated acid pH transfer (pH 5) through hydrogel thickness (PEU-Boc and PEUNH2
gels covered approximately 42 and 52% of the pH delta between their initial pH and
the pH of the surrounding buffer within 30 min incubation, respectively). MSN-CS-SIP
carrying a fluorescent cargo as model drug (MSN-CS-SIP-Ru) were then encapsulated
within the hydrogels with no significant effects on their thermo-sensitivity. Injectability
and in situ gelation at 37C were demonstrated ex vivo through sub-cutaneous injection in rodents. Moreover, MSN-CS-SIP-Ru-loaded gels turned out to be detectable through the skin by IVIS imaging. Cargo acid pH-triggered delivery from PEU-Boc and PEUNH2 gels was finally demonstrated through drug release tests in neutral and acid
pH environments (in acid pH environment approximately 2-fold higher cargo release).
Additionally, acid-triggered payload release from PEU-NH2 gels was significantly higher
compared to PEU-Boc systems at 3 and 4 days incubation. The herein designed
hybrid injectable formulations could thus represent a significant step forward in the
development of multi-stimuli sensitive drug carriers. Indeed, being able to adapt their
behavior in response to biochemical cues from the surrounding physio-pathological
environment, these formulations can effectively trigger the release of their payload
according to therapeutic needs.

Front Bioeng Biotech. 8, 384 2020


Tuberculosis (TB) remains the leading cause of death from a single infection agent worldwide. In recent years, the occurrence of TB cases caused by drug-resistant
strains has spread, and is expected to continue to grow. Therefore, the development of new alternative treatments to the use of antibiotics is highly important. In that sense, nanotechnology can play a very relevant role, due to the unique characteristics of nanoparticles. In fact, different types of nanoparticles have already been evaluated both as potential bactericides and as efficient drug delivery vehicles. In this work, the use of selenium nanoparticles (SeNPs) has been evaluated to inhibit the growth of two types of mycobacteria: Mycobacterium smegmatis (Msm) and Mycobacterium tuberculosis (Mtb). The results showed that SeNPs are able to inhibit the growth of both types of mycobacteria by damaging their cell envelope integrity. These results open a new opportunity for the use of this type of nanoparticles as antimycobacterial agents by themselves, or for the development of novel nanosystems that combine the action of these nanoparticles with other drugs.

Front Microbiol. 11, 800 2020


In this work, two types of mesoporous carbon particles with different morphology, size, and pore structure have been functionalized with a selfimmolative polymer sensitive to changes in pH and tested as drug nanocarriers. It is shown that their textural properties allow significantly higher loading capacity compared to typical mesoporous silica nanoparticles. I  vial release experiments of a model Ru dye at pH 7.4 and 5 confirm the pH-responsiveness of the hybrid systems, showing that only small amounts of the cargo are released at physiological pH, whereas at slightly acidic pH (e.g., that of lysosomes), self-immolation takes place and a significant amount of the cargo is released. Cytotoxicity studies using human osteosarcoma cells show that the hybrid nanocarriers are not cytotoxic by themselves but induce significant cell groth inhibition when loaded with a chemotherapeutic drug such as doxorubicin. In preparation of an in vivo application, in vial responsiveness of the hybrid system to short-term pH-triggering is confirmed. The consecutive in vivo study shows no substantial cargo release over a period of 96 h under physiological pH conditions. Short-term exposure to acidic pH releases an experimental fluorescent cargo during and continuously after the triggering period over 72 h.

ACS Appl. Mater. Interfaces 2020, 12, 14946−14957


Three-dimensional Mesoporous bioactive glasses (MBGs) scaffolds has been widely considered for bone regeneration purposes and additive manufacturing enables the fabrication of highly bioactive patient-specific constructs for bone defects. Commonly, this process is performed with the addition of polymeric binders that facilitate the printability of scaffolds. However, these additives cover the MBG particles resulting in the reduction of their osteogenic potential. The present work investigates a simple yet effective phosphate-buffered saline immersion method for achieving polyvinyl alcohol binder removal while enables the maintenance of the mesoporous structure of MBG 3D-printed scaffolds. This resulted in significantly modifying the surface of the scaffold via the spontaneous formation of a biomimetic mineralized layer which positively affected the physical and biological properties of the scaffold. The extensive surface remodeling induced by the deposition of the apatite-like layer lead to a 3-fold increase in surface area, a 5-fold increase in the roughness, and 4-fold increase in the hardness of the PBS-immersed scaffolds when compared to the as-printed counterpart. The biomimetic mineralization also occurred throughout the bulk of the scaffold connecting the MBGs particles and was responsible for the maintenance of structural integrity. In vitro assays using MC3T3-E1 pre-osteoblast like cells demonstrated a significant upregulation of osteogenic-related genes for the scaffolds previously immersed in PBS
when compared to the as-printed PVA-containing scaffolds. Although the pre-immersion scaffolds performed equally towards osteogenic cell differentiation, our data suggest that a short immersion in PBS of MBG scaffolds is beneficial for the osteogenic properties and might accelerate bone formation after implantation.

Materials Science & Engineering C 109 (2020) 110572


Nanomaterials have unique properties and characteristics derived fromtheir shape and small size that are not present in bulk materials. If size and shape are decisive, the synthesis method used, which determines the above parameters, is equally important. Among the di erent nanomaterial’s synthesis methods, we can find chemical methods (microemulsion, sol-gel, hydrothermal treatments, etc.), physical methods (evaporation-condensation, laser treatment, etc.) and biosynthesis. Among all
of them, the use of laser ablation that allows obtaining non-toxic nanomaterials (absence of foreign compounds) with a controlled 3D size, has emerged in recent years as a simple and versatile alternative for the synthesis of a wide variety of nanomaterials with numerous applications. This manuscript reviews the latest advances in the use of laser ablation for the synthesis of silicon-based nanomaterials,
highlighting its usefulness in the prevention of bacterial infection.

Nanomaterials 2020, 10, 1443


Bone regeneration is a clinical challenge which requires multiple approaches. Sometimes, it also includes the development of osteogenic and antibacterial biomaterials to treat the emergence of possible infec- tion processes arising from surgery. This study evaluates the antibacterial properties of gelatin-coated meso-macroporous scaffolds based on the bioactive glass 80%SiO 2 –15%CaO–5%P 2 O 5 (mol-%) before (BL- GE) and after being doped with 4% of ZnO (4ZN-GE) and loaded with both saturated and the minimal inhibitory concentrations of one of the antibiotics: levofloxacin (LEVO), vancomycin (VANCO), rifampicin (RIFAM) or gentamicin (GENTA). After physical-chemical characterization of materials, release studies of inorganic ions and antibiotics from the scaffolds were carried out. Moreover, molecular modelling allowed determining the electrostatic potential density maps and the hydrogen bonds of antibiotics and the glass matrix. Antibacterial in vitro studies (in planktonic, inhibition halos and biofilm destruction) with S. au- reus and E. coli as bacteria models showed a synergistic effect of zinc ions and antibiotics. The effect was especially noticeable in planktonic cultures of S. aureus with 4ZN-GE scaffolds loaded with VANCO, LEVO or RIFAM and in E. coli cultures with LEVO or GENTA. Moreover, S. aureus biofilms were completely destroyed by 4ZN-GE scaffolds loaded with VANCO, LEVO or RIFAM and the E. coli biofilm total destruc- tion was accomplished with 4ZN-GE scaffolds loaded with GENTA or LEVO. This approach could be an important step in the fight against microbial resistance and provide needed options for bone infection treatment.

Acta Biomaterialia 114 (2020) 395–406


Nanoparticles have become a powerful tool in oncology not only as carrier of the highly
toxic chemotherapeutic drugs but also as imaging contrast agents that provide valuable information about the state of the disease and its progression. The enhanced permeation and retention e ect for loaded nanocarriers in tumors allow substantial improvement of selectivity and safety of anticancer nanomedicines. Additionally, the possibility to design stimuli-responsive nanocarriers able to release their payload in response to specific stimuli provide an excellent control on the administered dosage. The aim of this review is not to present a comprehensive revision of the di erent theranostic mesoporous silica nanoparticles (MSN) which have been published in the recent years but just to describe a few selected examples to o er a panoramic view to the reader about the suitability and e ectiveness of these nanocarriers in the oncology field.

Pharmaceutics 2020, 12, 957


Mesoporous bioactive glasses (MBGs) are gaining increasing interest in the design of new biomaterials for bone defects treatment. An important research trend to enhance their biological behavior is the inclusion of moderate amounts of oxides with therapeutical action such as CuO. MBGs with composition (85-x) SiO2–10CaO–5P2O5–xCuO (x = 0, 2.5 or 5 mol-%) were synthesized, investigating the influence of the CuO
content and some synthesis parameters in their properties. Two series were developed; first one used HCl as catalyst and chlorides as CaO and CuO precursors, second one, used HNO3 and nitrates. MBGs of chlorides family exhibited calcium/copper phosphate nanoparticles between 10 and 20 nm in size. Nevertheless, CuO-containing MBGs of nitrates family showed metallic copper nanoparticles larger than 50 nm as well as quicker in vitro bioactive responses. Thus, MBGs of the nitrate series were coated by an apatite-like layer after 24 h soaked in simulated body fluid (SBF) a remarkably short period for a MBG containing 5% of CuO. A model, focused in the location of copper in the glass network, was proposed to relate nanostructure and in vitro behaviour. Moreover, after 24 h soaked in MEM or THB culture media, all the MBGs released therapeutic amounts of Ca2+ and Cu2+ ions. Because the quick bioactive response in SBF, the capacity to host biomolecules in their pores and to release therapeutic concentrations of Ca2+ and Cu2+ ions, MBGs of the nitrate families are proposed as excellent biomaterials
for bone regeneration.

Microporous and Mesoporous Materials 308 (2020) 110454


The synthesis of Mobil Composition of Matter 41 (MCM-41) mesoporous silica nanoparticles (MSNs) of controlled sizes and porous structure has been performed at laboratory and pilot plant scales. Firstly, the e ects of the main operating conditions (TEOS –Tetraethyl ortosilicate– addition rate, nanoparticle maturation time, temperature, and CTAB –Cetrimonium bromide– concentration) on the synthesis at laboratory scale (1 L round-bottom flask) were studied via a Taguchi experimental design. Subsequently, a profound one-by-one study of operating conditions was permitted to upscale the process without significant particle enlargement and pore deformation. To achieve this, the temperature was set to 60 C and the CTAB to TEOS molar ratio to 8. The final runs were performed at pilot plant scale (5 L cylindrical reactor with temperature and stirring speed control) to analyze stirring speed, type of impeller, TEOS addition rate, and nanoparticle maturation time e ects, confirming results at laboratory scale. Despite slight variations on the morphology of the nanoparticles, this methodology provided MSNs with adequate sizes and porosities for biomedical applications, regardless of the reactor/scale. The process was shown to be robust and reproducible using mild synthesis conditions (2 mLmin TEOS addition rate, 400 rpm stirred by a Rushton
turbine, 60 min maturation time, 60 CTAB, molar ratio TEOS/CTAB = 8), providing ca. 13 g of prismatic short mesoporous 100–200 nm nanorods with non-connected 3 nm parallel mesopores.

Int. J. Mol. Sci. 2020, 21, 7899



The use of 3D scaffolds based on mesoporous bioactive glasses (MBG) enhanced with therapeutic ions, biomolecules and cells is emerging as a strategy to improve bone healing. In this paper, the osteogenic capability of ZnO-enriched MBG scaffolds loaded or not with osteostatin (OST) and human mesenchymal stem cells (MSC) was evaluated after implantation in New Zealand rabbits. Cylindrical meso-macroporous scaffolds with composition (mol %) 82.2SiO2–10.3CaO–3.3P2O5–4.2ZnO (4ZN) were obtained by rapid prototyping and then, coated with gelatin for easy handling and potentiating the release of inorganic ions and OST. Bone defects (7.5mm diameter, 12mm depth) were drilled in the distal femoral epiphysis and filled with 4ZN, 4ZN+MSC, 4ZN+OST or 4ZN+MSC +OST materials to evaluate and compare their osteogenic features. Rabbits were sacrificed at 3 months extracting the distal third of bone specimens for necropsy, histological, and microtomography (μCT) evaluations. Systems investigated exhibited bone regeneration capability. Thus, trabecular bone volume density (BV/TV) values obtained from μCT showed that the good bone healing capability of 4ZN was significantly improved by the scaffolds coated with OST and MSC. Our findings in vivo suggest the interest of these MBG complete systems to improve bone repair in the clinical practice.

J. Mater. Sci. Mater. Med. (2020) 31:100



Mesoporous bioactive glass nanospheres (NanoMBGs) have high potential for clinical applications. However, the impact of these nanoparticles on the immune system needs to be addressed. In this study, the biocompatibility of SiO2-CaO NanoMBGs was evaluated on di erent mouse immune cells, including spleen cells subsets, bone marrow-derived dendritic cells (BMDCs), or cell lines like SR.D10 Th2 CD4+ lymphocytes and DC2.4 dendritic cells. Flow cytometry and confocal microscopy
show that the nanoparticles were rapidly and eciently taken up in vitro by T and B lymphocytes or by specialized antigen-presenting cells (APCs) like dendritic cells (DCs). Nanoparticles were not cytotoxic and had no e ect on cell viability or proliferation under T-cell (anti-CD3) or B cell (LPS) stimuli. Besides, NanoMBGs did not a ect the balance of spleen cell subsets, or the production of intracellular or secreted pro- and anti-inflammatory cytokines (TNF- , IFN- , IL-2, IL-6, IL-10) by activated T, B, and dendritic cells (DC), as determined by flow cytometry and ELISA. T cell activation
surface markers (CD25, CD69 and Induced Costimulator, ICOS) were not altered by NanoMBGs. Maturation of BMDCs or DC2.4 cells in vitro was not altered by NanoMBGs, as shown by expression of Major Histocompatibility Complex (MHC) and costimulatory molecules (CD40, CD80, CD86), or IL-6 secretion. The e ect of wortmannin and chlorpromazine indicate a role for phosphoinositide 3-kinase (PI3K), actin and clathrin-dependent pathways in NanoMBG internalization. We thus demonstrate that these NanoMBGs are both non-toxic and non-inflammagenic for murine lymphoid cells and myeloid DCs despite their ecient intake by the cells.

Int. J. Mol. Sci. 2020, 21, 8291



The rise of antibiotic resistance and the growing number of biofilm-related infections make bacterial infections a serious threat for global human health. Nanomedicine has entered into this scenario by bringing new alternatives to design and develop e ective antimicrobial nanoweapons to fight against bacterial infection. Among them, mesoporous silica nanoparticles (MSNs) exhibit unique characteristics that make them ideal nanocarriers to load, protect and transport antimicrobial cargoes to the target bacteria and/or biofilm, and release them in response to certain stimuli. The combination of infection-targeting and stimuli-responsive drug delivery capabilities aims to increase the specificity and ecacy of antimicrobial treatment and prevent undesirable side e ects, becoming a ground-breaking alternative to conventional antibiotic treatments. This review focuses on the scientific advances developed to date in MSNs for infection-targeted stimuli-responsive antimicrobials delivery. The targeting strategies for specific recognition of bacteria are detailed. Moreover, the possibility of incorporating anti-biofilm agents with MSNs aimed at promoting biofilm penetrability is overviewed. Finally, a comprehensive description of the di erent scientific approaches
for the design and development of smart MSNs able to release the antimicrobial payloads at the infection site in response to internal or external stimuli is provided.

Int. J. Mol. Sci. 2020, 21, 8605



Nanoparticles designed for diagnosing and treating di erent diseases have impacted the scientific research in biomedicine, and are expected to revolutionize the clinic in the near future through a new area called nanomedicine. In the last few years, a new approach in this field has emerged: the use of cell membranes for coating nanoparticles in an attempt to mimic the ability of cells to interface and interact with physiological environments. Although such functions have been replicated through synthetic techniques, many research groups are now employing naturally derived cell membranes to coat di erent types of nanoparticles in an attempt to improve their performance for a wide range of applications. This review summarizes the literature on nanoparticles coated with cell membranes and, more importantly, aims at inspiring and encouraging new developments to this technology in the biomedical area.

Biology 2020, 9, 406



In the search of a new biomaterial for the treatment of bone defects resulting from traumatic events, an osteoporosis scenario with bone fractures, tumor removal, congenital pathologies or implant revisions for infection, we developed 3D scaffolds based on mesoporous bioactive glasses (MBGs) (85−x)SiO2–5P2O5–10CaO–xSrO (x = 0, 2.5 and 5 mol.%). The scaffolds with meso-macroporosity were fabricated by pouring a suspension of MBG powders in polyvinyl alcohol (PVA) into a negative template of polylactic acid (PLA), followed by removal of the template by extraction at low temperature. SrO-containing MBGs exhibited excellent properties for bone substitution including ordered mesoporous structure, high textural properties, quick in vitro bioactive response in simulated body fluid (SBF) and the ability of releasing concentrations of strontium ions able to stimulate expression of early markers of osteoblastic differentiation. Moreover, the direct contact of MC3T3-E1 pre-osteoblastic cells with the scaffolds confirmed the cytocompatibility of the three compositions investigated. Nevertheless, the scaffold containing 2.5% of SrO induced the best cellular proliferation showing the potential of this scaffold as a candidate to be further investigated in vitro and in vivo, aiming to be clinically used for bone regeneration applications in non-load bearing sites.

Materials 2020, 13, 5526



The increasing emergence of new strains of Mycobacterium tuberculosis (Mtb) highly resistant to antibiotics constitute a public health issue, since tuberculosis still constitutes the primary cause of death in the world due to bacterial infection. Mtb has been shown to produce membrane-derived extracellular vesicles (EVs) containing proteins responsible for modulating the pathological immune response after infection. These natural vesicles were considered a promising alternative to the  development of novel vaccines. However, their use was compromised by the observed lack of reproducibility between preparations. In this work, with the aim of developing nanosystems mimicking the extracellular vesicles produced by Mtb, mesoporous silica nanoparticles (MSNs) have been used as nanocarriers of immunomodulatory and vesicle-associated proteins (Ag85B, LprG and LprA). These novel nanosystems have been designed and extensively characterized, demonstrating the e ectiveness of the covalent anchorage of the immunomodulatory proteins to the surface of the MSNs. The immunostimulatory capacity of the designed nanosystems has been demonstrated by measuring the levels of pro- (TNF) and anti-inflammatory (IL-10) cytokines in exposed macrophages. These results open a new possibility for the development of more complex nanosystems, including additional vesicle components or even antitubercular drugs, thus allowing for the combination of immunomodulatory and bactericidal e ects against Mtb.

Pharmaceutics 2020, 12, 1218



Current chemotherapy treatments lack great selectivity towards tumoral cells, which leads to nonspecific drug distribution and subsequent side e ects. In this regard, the use of nanoparticles able to encapsulate and release therapeutic agents has attracted growing attention. In this sense, mesoporous silica nanoparticles (MSNs) have been widely employed as drug carriers owing to their exquisite physico-chemical properties. Because MSNs present a surface full of silanol groups, they can be easily functionalized to endow the nanoparticles with many di erent functionalities, including the introduction of moieties with anity for the cell membrane or relevant compartments within the cell, thus increasing the ecacy of the treatments. This review manuscript will provide the state-of-the-art on MSNs functionalized for targeting subcellular compartments, focusing on the cytoplasm, the mitochondria, and the nucleus.

Int. J. Mol. Sci. 2020, 21, 9696



The incorporation and effects of hollow mesoporous nanospheres in the system SiO2–CaO (nanoMBGs) containing ipriflavone (IP), a synthetic isoflavone that prevents osteoporosis, were evaluated. Due to their superior porosity and capability to host drugs, these nanoparticles are designed as a potential alternative to conventional bioactive glasses for the treatment of periodontal defects. To identify the endocytic mechanisms by which these nanospheres are incorporated within the MC3T3-E1 cells, five inhibitors (cytochalasin B, cytochalasin D, chlorpromazine, genistein and wortmannin) were used before the addition of these nanoparticles labeled with fluorescein isothiocyanate (FITC–nanoMBGs). The results indicate that nanoMBGs enter the pre-osteoblasts mainly through clathrin-dependent mechanisms and in a lower proportion by macropinocytosis. The present study evidences the active incorporation of nanoMBG–IPs by MC3T3-E1 osteoprogenitor cells that stimulate their differentiation into mature osteoblast phenotype with increased alkaline phosphatase activity. The final aim of this study is to demonstrate the biocompatibility and osteogenic behavior of IP-loaded bioactive nanoparticles to be used for periodontal augmentation purposes and to shed light on internalization mechanisms that determine the incorporation of these nanoparticles into the cells.

Nanomaterials 2020, 10, 2573



Ultrasound has attracted much attention in recent years as an external stimulus capable of activating different types of nanomaterials for therapeutic application. One of the characteristics that makes ultrasound an especially appealing triggering stimulus for nanomedicine is its capacity to be non-invasively applied in a focused manner at deep regions of the body. Combining ultrasound with nanoparticles, different biological effects can be achieved. In this work, an overview of the four main types of inducible responses will be provided: inducing drug release, producing ultrasound-derived biological effects, modifying nanoparticle biodistribution and developing theranostic agents. Several examples of each one of these applications are presented here to illustrate the key concepts underlying recent developments in the discipline.

Bull. Chem. Soc. Jpn. 2020, 93, 220–229



In the process of synthesis of a new drug, as important as the drug itself is the formulation used, because the same compound can present a very different efficacy depending on how it is administered. In this work, we demonstrate how the antitumor capacity of a new octahedral organoruthenium complex, [Ru(ppy-CHO)(phen)2][PF6] is affected by its encapsulation in different types of mesoporous silica nanoparticles. The interactions between the Ru complex and the silica matrix and how these interactions are affected at two different pHs (7.4 and 5.4, mimicking physiological and endolysosomal acidic conditions, respectively) have been
studied. The encapsulation has also been shown to affect the induction of apoptosis and necrosis and progression of the cell cycle compared to the free drug. The encapsulation of the Ru complex in nanoparticles functionalized with amino groups produced very high anticancer activity in cancer cells in vitro, especially against U87 glioblastoma cells, favoring cellular internalization and significantly increasing the anticancer capacity of the initial non-encapsulated Ru complex.

Inorg. Chem. 2020, 59, 10275−10284



Infectious diseases hold third place in the top 10 causes of death worldwide and were responsible for more than 6.7 million deaths in 2016. Nanomedicine is a multidisciplinary field which is based on the application of nanotechnology for medical purposes and can be defined as the use of nanomaterials for diagnosis, monitoring, control, prevention, and treatment of diseases, including infectious diseases. One of the most used nanomaterials in nanomedicine are nanoparticles, particles with a nano-scale size that show highly tunable physical and optical properties, and the capacity to a wide library of compounds. This manuscript is intended to be a comprehensive review of the available recent literature on nanoparticles used for the prevention and treatment of human infectious diseases caused by different viruses, and bacteria from a clinical point of view by basing on original articles which talk about what has been made to date and excluding commercial products, but also by highlighting what has not been still made and some clinical concepts that must be considered for futures nanoparticles-based technologies applications.

Nanomaterials 2021, 11, 137



One of the major limitations of nanomedicine is the scarce penetration of nanoparticles in tumoral tissues. These constrains have been tried to be solved by different strategies, such as the employ of polyethyleneglycol (PEG) to avoid the opsonization or reducing the extracellular matrix (ECM) density. Our research group has developed some strategies to overcome these limitations such as the employ of pH-sensitive collagenase nanocapsules for the digestion of the collagen-rich extracellular matrix present in most of tumoral tissues. However, a deeper understanding of physicochemical kinetics involved in the nanocapsules degrada- tion process is needed to understand the nanocapsule framework degradation process produced during the penetration in the tissue. For this, in this work it has been employed a double-fluorescent labelling strategy of the polymeric enzyme nanocapsule as a crucial chemical tool which allowed the analysis of nanocapsules and free collagenase during the diffusion process throughout a tumour-like collagen ma- trix. This extrinsic label strategy provides far greater advantages for observing biological processes. For the detection of enzyme, collagenase has been labelled with fluorescein Isothiocyanate (FITC), whereas the nanocapsule surface was labelled with rhodamine Isothiocyanate (RITC). Thus, it has been possible to monitor the hydrolysis of nanocapsules and their diffusion throughout a thick 3D Collagen gel during the time, obtaining a detailed temporal evaluation of the pH-sensitive collagenase nanocapsule behaviour. These collagenase nanocapsules displayed a high enzymatic activity in low concentrations at acidic pH, and their efficiency to penetrate into tissue models pave the way to a wide range of possible nanomedical applications, especially in cancer therapy.

Acta Biomaterialia 121 (2021) 263–274



Mesoporous silica nanoparticles (MSNs) are promising drug nanocarriers for infection treatment. Many investigations have focused on evaluating the capacity of MSNs to encapsulate antibiotics and release them in a controlled fashion. However, little attention has been paid to determine the antibiotic doses released from these nanosystems that are effective against biofilm during the entire release time. Herein, we report a systematic and quantitative study of the direct effect of the antibiotic-cargo released from MSNs on Gram-positive and Gram-negative bacterial biofilms. Levofloxacin (LVX), gentamicin (GM) and rifampin (RIF) were separately loaded into pure-silica and amino-modified MSNs. This accounts for the versatility of these nanosystems since they were able to load and release different antibiotic molecules of diverse chemical nature. Biological activity curves of the released antibiotic were determined for both bacterial strains, which allowed to calculate the active doses that are effective against bacterial biofilms. Furthermore, in vitro biocompatibility assays on osteoblast-like cells were carried out at different periods of times. Albeit a slight decrease in cell viability was observed at the very initial stage, due to the initial burst antibiotic release, the biocompatibility of these nanosystems is evidenced since a recovery of cell viability was achieved after 72 h of assay. Biological activity curves for GM released from MSNs exhibited sustained patterns and antibiotic doses in the 2–6 μg/mL range up to 100 h, which were not enough to eradicate biofilm. In the case of LVX and RIF first-order kinetics featuring an initial burst effect followed by a sustained release above the minimum inhibitory concentration (MIC) up to 96 h were observed. Such doses reduced by 99.9% bacterial biofilm and remained active up to 72 h with no emergence of bacterial resistance. This pioneering research opens up promising expectations in the design of personalized MSNs-based nanotherapies to treat chronic bone infection.

Microporous and Mesoporous Materials 311 (2021) 110681



Combination therapies constitute a powerful tool for cancer treatment. By combining  drugs with different mechanisms of action, the limitations of each individual agent can be overcome, while increasing therapeutic benefit. Here, we propose employing tumor-migrating decidua-derived mesenchymal stromal cells as therapeutic agents combining antiangiogenic therapy and chemotherapy. First, a plasmid encoding the antiangiogenic protein endostatin was transfected into these cells by nucleofection, confirming its expression by ELISA and its biological effect in an ex ovo chick embryo model. Second, doxorubicin-loaded mesoporous silica nanoparticles were introduced into the cells, which would act as vehicles for the drug being released. The effect of the drug was evaluated in a coculture in vitro model with mammary cancer cells. Third, the combination of endostatin transfection and doxorubicin-nanoparticle loading was carried out with the decidua mesenchymal stromal cells. This final cell platform was shown to retain its tumor-migration capacity in vitro, and the combined in vitro therapeutic efficacy was confirmed through a 3D spheroid coculture model using both cancer and endothelial cells. The results presented here show great potential for the development of combination therapies based on genetically-engineered cells that can simultaneously act as cellular vehicles for drug-loaded nanoparticles.

Pharmaceutics 2021, 13, 244



Combination therapy has emerged as one of the most promising approaches for cancer treatment. However, beyond remotely-triggered therapies that require advanced infrastructures and optimization, new combination therapies based on internally triggered cell-killing effects have also demonstrated promising therapeutic profiles. In this revision, the focus is on self-triggered strategies able to improve the therapeutic effect of drug delivery nanosystems. As reviewed, ferroptosis, hypoxia, and immunotherapy show potency enough to treat satisfactorily tumors in vivo. However, the interest of combining those with chemotherapeutics, especially with carriers based on mesoporous silica, has provided a new generation of therapeutic nanomedicines with potential enough to achieve complete tumor remission in murine models.

Biotechnol. J. 2021, 16, 1900438



Selenium nanoparticles (SeNPs) have been receiving special attention in recent years due to their antioxidant capacity and antitumor properties. However, the mechanisms associated with these properties remain to be elucidated. For this reason, a global transcriptome analysis has been designed in this work and it was carried out using human hepatocarcinoma cells and chitosan‐ stabilized SeNPs (Ch‐SeNPs) to identify new targets and pathways related to the antitumor mechanisms associated with Ch‐SeNPs. The results obtained confirm the alteration of the cell cycle and the effect of Ch‐SeNPs on different tumor suppressors and other molecules involved in key mechanisms related to cancer progression. Furthermore, we demonstrated the antioxidant properties of these nanoparticles and their capacity to induce senescence, which was further confirmed through the measurement of β‐galactosidase activity.

Pharmaceutics 2021, 13, 356



Tuberculosis remains today a major public health issue with a total of 9 million new cases and 2 million deaths annually. The lack of an effective vaccine and the increasing emergence of new strains of Mycobacterium tuberculosis (Mtb) highly resistant to antibiotics, anticipate a complicated scenario in the near future. The use of nanoparticles features as an alternative to antibiotics in tackling this problem due to their potential effectiveness in resistant bacterial strains. In this context, silver nanoparticles have demonstrated high bactericidal efficacy, although their use is limited by their relatively high toxicity, which calls for the design of nanocarriers that allow silver based nanoparticles to be safely delivered to the target cells or tissues. In this work mesoporous silica nanoparticles are used as carriers of silver based nanoparticles as antimycobacterial agent against Mtb. Two different synthetic approaches have been used to afford, on the one hand, a 2D hexagonal mesoporous silica nanosystem which contains silver bromide nanoparticles distributed all through the silica network and, on the other hand, a core@shell nanosystem with metallic silver nanoparticles as core and mesoporous silica shell in a radial mesoporous rearrangement. Both materials have demonstrated good antimycobacterial capacity in in vitro test using Mtb, being lower the minimum inhibitory concentration for the nanosystem which contains silver bromide. Therefore, the interaction of this material with the mycobacterial cell has been studied by cryo-electron microscopy, establishing a direct connection between the antimycobactericidal effect observed and the damage induced in the cell envelope.

Colloids and Surfaces B: Biointerfaces 197 (2021) 111405



The several biological barriers that nanoparticles might encounter when administered to a patient constitute the major bottleneck of nanoparticle-mediated tumor drug delivery, preventing their successful translation into the clinic and reducing their therapeutic profile. In this work, mesoporous silica nanoparticles have been employed as a platform to engineer a versatile nanomedicine able to address such barriers, achieving (a) excessive premature drug release control, (b) accumulation in tumor tissues, (c) selective internalization in tumoral cells, and (d) endosomal escape. The nanoparticles have been decorated with a self-immolative redox-responsive linker to prevent excessive premature release, to which a versatile and polyvalent peptide that is able to recognize tumoral cells and induce the delivery of the nanoparticles to the cytoplasm via endosomal escape has been grafted. The excellent biological performance of the carrier has been demonstrated using 2D and 3D in vitro cell cultures and a tumor-bearing chicken embryo model, demonstrating in all cases high biocompatibility and cytotoxic effect, efficient endosomal escape and tumor penetration, and accumulation in tumors grown on the chorioallantoic membrane of chicken embryos.

ACS Appl. Mater. Interfaces 2021, 13, 8, 9656–9666



The use of nanoparticles for intracellular drug delivery could reduce the toxicity and side effects of the drug but, the uptake of these nanocarriers could induce adverse effects on cells and tissues after their incorporation. Macrophages play a central role in host defense and are responsible for in vivo nanoparticle trafficking. Assessment of their defense capacity against pathogenic micro-organisms after nanoparticle uptake, is necessary to prevent infections associated with nanoparticle therapies. In this study, the effects of hollow mesoporous SiO2-CaO nanospheres labeled with fluorescein isothiocyanate (FITC-NanoMBGs) on the function of peritoneal macrophages was assessed by measuring their ability to phagocytize Candida albicans expressing a red fluorescent protein. Two macrophage/fungus ratios (MOI 1 and MOI 5) were used and two experimental strategies were carried out: a) pretreatment of macrophages with FITC-NanoMBGs and subsequent fungal infection; b) competition assays after simultaneous addition of fungus and nanospheres. Macrophage pro-inflammatory phenotype markers (CD80 expression and interleukin 6 secretion) were also evaluated. Significant decreases of CD80+macrophage percentage and interleukin 6 secretion were observed after 30 min, indicating that the simultaneous incorporation of NanoMBG and fungus favors the macrophage non-inflammatory phenotype. The present study evidences that the uptake of these nanospheres in all the studied conditions does not alter the macrophage function. Moreover, intracellular FITC-NanoMBGs induce a transitory increase of the fungal phagocytosis by macrophages at MOI 1 and after a short time of interaction. In the competition assays, as the intracellular fungus quantity increased, the intracellular FITC-NanoMBG content decreased in a MOI- and time-dependent manner. These results have confirmed that macrophages clearly distinguish between inert material and the live yeast in a
dynamic intracellular incorporation. Furthermore, macrophage phagocytosis is a critical determinant to know their functional state and a valuable parameter to study the nanomaterial / macrophages / Candida albicans interface.

Int. Immunopharmacol. 94 (2021) 107457



Peyronie and Dupuytren are pathologies characterized by the appearance of localized fibrotic lesions in an organ. These disorders originate from an excessive production of collagen in the tissue provoking dysfunction and functional limitations to the patients. Local administration of collagenase is the most used treatment for these fibrotic-type diseases, but a high lability of the enzyme limits its therapeutic efficacy. Herein, we present a novel methodology for the preparation of collagenase nanocapsules without affecting its enzymatic activity and capable of releasing the enzyme in response to an ultraviolet A (UVA) light stimulus. Polymeric coating around collagenase was formed by free-radical polymerization of acrylamide-type monomers. Their degradation capacity under UVA irradiation was provided by incorporating a novel photocleavable acrylamide-type crosslinker within the polymeric framework. This property allowed collagenase release to be triggered in a controlled manner by employing an easily focused stimulus. Additionally, UVA irradiation presents considerable benefits by itself due to its capacity to induce collagenase production in situ. An expected synergistic effect of collagenase nanocapsules in conjunction with UVA effect may present a promising treatment for these fibrotic diseases.

Pharmaceutics 2021, 13(4), 499



Upon contact with a biological milieu, nanomaterials tend to interact with biomolecules
present in the media, especially proteins, leading to the formation of the so-called “protein corona”. As a result of these nanomaterial–protein interactions, the bio-identity of the nanomaterial is altered, which is translated into modifications of its behavior, fate, and pharmacological profile. For biomedical applications, it is fundamental to understand the biological behavior of nanomaterials prior to any clinical translation. For these reasons, during the last decade, numerous publications have
been focused on the investigation of the protein corona of many different types of nanomaterials. Interestingly, it has been demonstrated that the structure of the protein corona can be divided into hard and soft corona, depending on the affinity of the proteins for the nanoparticle surface. In the present document, we explore the differences between these two protein coronas, review the analysis techniques used for their assessment, and reflect on their relevance for medical purposes.

Nanomaterials 2021, 11, 888



Angiogenic biomaterials are designed to promote vascularization and tissue regeneration. Nanoparticles of bioactive materials loaded with drugs represent an interesting strategy to stimulate osteogenesis and angiogenesis and to inhibit bone resorption. In this work, porcine endothelial progenitor cells (EPCs), essential for blood vessel formation, were isolated and characterized to evaluate the in vitro effects of unloaded (NanoMBGs) and ipriflavone-loaded nanospheres (NanoMBG-IPs), which were designed to prevent osteoporosis. The expression of vascular endothelial growth factor
receptor 2 (VEGFR2) was studied in EPCs under different culture conditions: (a) treatment with NanoMBGs or NanoMBG-IPs, (b) culture with media from basal, M1, and M2 macrophages previously treated with NanoMBGs or NanoMBG-IPs, (c) coculture with macrophages in the presence of NanoMBGs or NanoMBG-IPs, and (d) coculture with M2d angiogenic macrophages. The endocytic mechanisms for nanosphere incorporation by EPCs were identified using six different endocytosis inhibitors. The results evidence the great potential of these nanomaterials to enhance VEGFR2
expression and angiogenesis, after intracellular incorporation by EPCs through clathrin-dependent endocytosis, phagocytosis, and caveolae-mediated uptake. The treatment of EPCs with basal, M1, and M2 macrophage culture media and EPC/macrophage coculture studies also confirmed the angiogenic effect of these nanospheres on EPCs, even in the presence of phagocytic cells.

Nanomaterials 2021, 11, 1102