Enriched mesoporous bioactive glass scaffolds as bone substitutes in critical diaphyseal bone defects in rabbits.

In the field of orthopedic surgery, there is an increasing need for the development of bone replacement materials for the treatment of bone defects. One of the main focuses of biomaterials engineering are advanced bioceramics like mesoporous bioactive glasses (MBG´s). The present study compared the new bone formation after 12 weeks of implantation of MBG scaffolds with composition 82,5SiO2-10CaO-5P2O5-x 2.5SrO alone (MBGA), enriched with osteostatin, an osteoinductive peptide, (MBGO) or enriched with bone marrow aspirate (MBGB) in a long bone critical defect in radius bone of adult New Zealand rabbits. New bone formation from the MBG scaffold groups was compared to the gold standard defect filled with iliac crest autograft and to the unfilled defect. Radiographic follow-up was performed at 2, 6, and 12 weeks, and microCT and histologic examination were performed at 12 weeks. X-Ray study showed the highest bone formation scores in the group with the defect filled with autograft, followed by the MBGB group, in addition, the microCT study showed that bone within defect scores (BV/TV) were higher in the MBGO group. This difference could be explained by the higher density of newly formed bone in the osteostatin enriched MBG scaffold group. Therefore, MBG scaffold alone and enriched with osteostatin or bone marrow aspirate increase bone formation compared to defect unfilled, being higher in the osteostatin group. The present results showed the potential to treat critical bone defects by combining MBGs with osteogenic peptides such as osteostatin, with good prospects for translation into clinical practice. STATEMENT OF SIGNIFICANCE: Treatment of bone defects without the capacity for self-repair is a global problem in the field of Orthopedic Surgery, as evidenced by the fact that in the U.S alone it affects approximately 100,000 patients per year. The gold standard of treatment in these cases is the autograft, but its use has limitations both in the amount of graft to be obtained and in the morbidity produced in the donor site. In the field of materials engineering, there is a growing interest in the development of a bone substitute equivalent. Mesoporous bioactive glass (MBG´s) scaffolds with three-dimensional architecture have shown great potential for use as a bone substitutes. The osteostatin-enriched Sr-MBG used in this long bone defect in rabbit radius bone in vivo study showed an increase in bone formation close to autograft, which makes us think that it may be an option to consider as bone substitute.

Mechanistic insights into the antitumoral potential and in vivo antiproliferative efficacy of a silver-based core@shell nanosystem.

This study delves into the biomolecular mechanisms underlying the antitumoral efficacy of a hybrid nanosystem, comprised of a silver core@shell (Ag@MSNs) functionalized with transferrin (Tf). Employing a SILAC proteomics strategy, we identified over 150 de-regulated proteins following exposure to the nanosystem. These proteins play pivotal roles in diverse cellular processes, including mitochondrial fission, calcium homeostasis, endoplasmic reticulum (ER) stress, oxidative stress response, migration, invasion, protein synthesis, RNA maturation, chemoresistance, and cellular proliferation. Rigorous validation of key findings substantiates that the nanosystem elicits its antitumoral effects by activating mitochondrial fission, leading to disruptions in calcium homeostasis, as corroborated by RT-qPCR and flow cytometry analyses. Additionally, induction of ER stress was validated through western blotting of ER stress markers. The cytotoxic action of the nanosystem was further affirmed through the generation of cytosolic and mitochondrial reactive oxygen species (ROS). Finally, in vivo experiments using a chicken embryo model not only confirmed the antitumoral capacity of the nanosystem, but also demonstrated its efficacy in reducing cellular proliferation. These comprehensive findings endorse the potential of the designed Ag@MSNs-Tf nanosystem as a groundbreaking chemotherapeutic agent, shedding light on its multifaceted mechanisms and in vivo applicability.

Osteogenic Potential of a Biomaterial Enriched with Osteostatin and Mesenchymal Stem Cells in Osteoporotic Rabbits.

Mesoporous bioactive glasses (MBGs) of the SiO2-CaO-P2O5 system are biocompatible materials with a quick and effective in vitro and in vivo bioactive response. MBGs can be enhanced by including therapeutically active ions in their composition, by hosting osteogenic molecules within their mesopores, or by decorating their surfaces with mesenchymal stem cells (MSCs). In previous studies, our group showed that MBGs, ZnO-enriched and loaded with the osteogenic peptide osteostatin (OST), and MSCs exhibited osteogenic features under in vitro conditions. The aim of the present study was to evaluate bone repair capability after large bone defect treatment in distal femur osteoporotic rabbits using MBGs (76%SiO2-15%CaO-5%P2O5-4%ZnO (mol-%)) before and after loading with OST and MSCs from a donor rabbit. MSCs presence and/or OST in scaffolds significantly improved bone repair capacity at 6 and 12 weeks, as confirmed by variations observed in trabecular and cortical bone parameters obtained by micro-CT as well as histological analysis results. A greater effect was observed when OST and MSCs were combined. These findings may indicate the great potential for treating critical bone defects by combining MBGs with MSCs and osteogenic peptides such as OST, with good prospects for translation to clinical practice.

Bioinspired extracellular vesicle-coated silica nanoparticles as selective delivery systems.

In recent years, there has been a breakthrough in the integration of artificial nanoplatforms with natural biomaterials for the development of more efficient drug delivery systems. The formulation of bioinspired nanosystems, combining the benefits of synthetic nanoparticles with the natural features of biological materials, provides an efficient strategy to improve nanoparticle circulation time, biocompatibility and specificity toward targeted tissues. Among others biological materials, extracellular vesicles (EVs), membranous structures secreted by many types of cells composed by a protein rich lipid bilayer, have shown a great potential as drug delivery systems themselves and in combination with artificial nanoparticles. The reason for such interest relays on their natural properties, such as overcoming several biological barriers or migration towards specific tissues. Here, we propose the use of mesoporous silica nanoparticles (MSNs) as efficient and versatile nanocarriers in combination with tumor derived extracellular vesicles (EVs) for the development of selective drug delivery systems. The hybrid nanosystems demonstrated selective cellular internalization in parent cells, indicating that the EV targeting capabilities were efficiently transferred to MSNs by the developed coating strategy. As a result, EVs-coated MSNs provided an enhanced and selective intracellular accumulation of doxorubicin and a specific cytotoxic activity against targeted cancer cells, revealing these hybrid nanosystems as promising candidates for the development of targeted treatments.

Large-scale production of superparamagnetic iron oxide nanoparticles by flame spray pyrolysis: In vitro biological evaluation for biomedical applications.

Despite the large number of synthesis methodologies described for superparamagnetic iron oxide nanoparticles (SPIONs), the search for their large-scale production for their widespread use in biomedical applications remains a mayor challenge. Flame Spray Pyrolysis (FSP) could be the solution to solve this limitation, since it allows the fabrication of metal oxide nanoparticles with high production yield and low manufacture costs. However, to our knowledge, to date such fabrication method has not been upgraded for biomedical purposes. Herein, SPIONs have been fabricated by FSP and their surface has been treated to be subsequently coated with dimercaptosuccinic acid (DMSA) to enhance their colloidal stability in aqueous media. The final material presents high quality in terms of nanoparticle size, homogeneous size distribution, long-term colloidal stability and magnetic properties. A thorough in vitro validation has been performed with peripheral blood cells and mesenchymal stem cells (hBM-MSCs). Specifically, hemocompatibility studies show that these functionalized FSP-SPIONs-DMSA nanoparticles do not cause platelet aggregation or impair basal monocyte function. Moreover, in vitro biocompatibility assays show a dose-dependent cellular uptake while maintaining high cell viability values and cell cycle progression without causing cellular oxidative stress. Taken together, the results suggest that the FSP-SPIONs-DMSA optimized in this work could be a worthy alternative with the benefit of a large-scale production aimed at industrialization for biomedical applications.

Nanodevices based on mesoporous glass nanoparticles enhanced with zinc and curcumin to fight infection and regenerate bone.

Nanotechnology-based approaches are emerging as promising strategies to treat different bone pathologies such as infection, osteoporosis or cancer. To this end, several types of nanoparticles are being investigated, including those based on mesoporous bioactive glasses (MGN) which exhibit exceptional structural and textural properties and whose biological behaviour can be improved by including therapeutic ions in their composition and loading them with biologically active substances. In this study, the bone regeneration capacity and antibacterial properties of MGNs in the SiO2-CaO-P2O5 system were evaluated before and after being supplemented with 2.5% or 4% ZnO and loaded with curcumin. in vitro studies with preosteoblastic cells and mesenchymal stem cells allowed determining the biocompatible MGNs concentrations range. Moreover, the bactericidal effect of MGNs with zinc and curcumin against S. aureus was demonstrated, as a significant reduction of bacterial growth was detected in both planktonic and sessile states and the degradation of a pre-formed bacterial biofilm in the presence of the nanoparticles also occurred. Finally, MC3T3-E1 preosteoblastic cells and S. aureus were co-cultured to investigate competitive colonisation between bacteria and cells in the presence of the MGNs. Preferential colonisation and survival of osteoblasts and effective inhibition of both bacterial adhesion and biofilm formation of S. aureus in the co-culture system were detected. Our study demonstrated the synergistic antibacterial effect of zinc ions combined with curcumin and the enhancement of the bone regeneration characteristics of MGNs containing zinc and curcumin to obtain systems capable of simultaneously promoting bone regeneration and controlling infection. STATEMENT OF SIGNIFICANCE: In search of a new approach to regenerate bone and fight infections, a nanodevice based on mesoporous SiO2-CaO-P2O5 glass nanoparticles enriched with Zn2+ ions and loaded with curcumin was designed. This study demonstrates the synergistic effect of the simultaneous presence of zinc ions and curcumin in the nanoparticles that significantly reduces the bacterial growth in planktonic state and is capable to degrade pre-formed S. aureus biofilms whereas the nanosystem exhibits a cytocompatible behaviour in the presence of preosteoblasts and mesenchymal stem cells. Based on these results, the designed nanocarrier represents a promising alternative for the treatment of acute and chronic infections in bone tissues, while avoiding the significant current problem of bacterial resistance to antibiotics.

Integrated transcriptomics and metabolomics analysis reveals the biomolecular mechanisms associated to the antitumoral potential of a novel silver-based core@shell nanosystem.

A combination of omics techniques (transcriptomics and metabolomics) has been used to elucidate the mechanisms responsible for the antitumor action of a nanosystem based on a Ag core coated with mesoporous silica on which transferrin has been anchored as a targeting ligand against tumor cells (Ag@MSNs-Tf). Transcriptomics analysis has been carried out by gene microarrays and RT-qPCR, while high-resolution mass spectrometry has been used for metabolomics. This multi-omics strategy has enabled the discovery of the effect of this nanosystem on different key molecular pathways including the glycolysis, the pentose phosphate pathway, the oxidative phosphorylation and the synthesis of fatty acids, among others.

Biomimetic camouflaged nanoparticles with selective cellular internalization and migration competences.

In the last few years, nanotechnology has revolutionized the potential treatment of different diseases. However, the use of nanoparticles for drug delivery might be limited by their immune clearance, poor biocompatibility and systemic immunotoxicity. Hypotheses for overcoming rejection from the body and increasing their biocompatibility include coating nanoparticles with cell membranes. Additionally, source cell-specific targeting has been reported when coating nanoparticles with tumor cells membranes. Here we show that coating mesoporous silica nanoparticles with membranes derived from preosteoblastic cells could be employed to develop potential treatments of certain bone diseases. These nanoparticles were selected because of their well-established drug delivery features. On the other hand MC3T3-E1 cells were selected because of their systemic migration capabilities towards bone defects. The coating process was here optimized ensuring their drug loading and delivery features. More importantly, our results demonstrated how camouflaged nanocarriers presented cellular selectivity and migration capability towards the preosteoblastic source cells, which might constitute the inspiration for future bone disease treatments. STATEMENT OF SIGNIFICANCE: This work presents a new nanoparticle formulation for drug delivery able to selectively target certain cells. This approach is based on Mesoporous Silica Nanoparticles coated with cell membranes to overcome the potential rejection from the body and increase their biocompatibility prolonging their circulation time. We have employed membranes derived from preosteoblastic cells for the potential treatment of certain bone diseases. Those cells have shown systemic migration capabilities towards bone defects. The coating process was optimized and their appropriate drug loading and releasing abilities were confirmed. The important novelty of this work is that the camouflaged nanocarriers presented cellular selectivity and migration capability towards the preosteoblastic source cells, which might constitute the inspiration for future bone disease treatments.

Achievements in Mesoporous Bioactive Glasses for Biomedical Applications.

Nowadays, mesoporous bioactive glasses (MBGs) are envisaged as promising candidates in the field of bioceramics for bone tissue regeneration. This is ascribed to their singular chemical composition, structural and textural properties and easy-to-functionalize surface, giving rise to accelerated bioactive responses and capacity for local drug delivery. Since their discovery at the beginning of the 21st century, pioneering research efforts focused on the design and fabrication of MBGs with optimal compositional, textural and structural properties to elicit superior bioactive behavior. The current trends conceive MBGs as multitherapy systems for the treatment of bone-related pathologies, emphasizing the need of fine-tuning surface functionalization. Herein, we focus on the recent developments in MBGs for biomedical applications. First, the role of MBGs in the design and fabrication of three-dimensional scaffolds that fulfil the highly demanding requirements for bone tissue engineering is outlined. The different approaches for developing multifunctional MBGs are overviewed, including the incorporation of therapeutic ions in the glass composition and the surface functionalization with zwitterionic moieties to prevent bacterial adhesion. The bourgeoning scientific literature on MBGs as local delivery systems of diverse therapeutic cargoes (osteogenic/antiosteoporotic, angiogenic, antibacterial, anti-inflammatory and antitumor agents) is addressed. Finally, the current challenges and future directions for the clinical translation of MBGs are discussed.

Characterization of a Mesoporous Silica Nanoparticle Formulation Loaded with Mitomycin C Lipidic Prodrug (MLP) and In Vitro Comparison with a Clinical-Stage Liposomal Formulation of MLP.

Nanomedicines have revolutionized the treatment of certain types of cancer, as is the case of doxil, liposomal formulation with doxorubicin encapsulated, in the treatment of certain types of ovarian cancer, AIDS-related Kaposi sarcoma, and multiple myeloma. These nanomedicines can improve the performance of conventional chemotherapeutic treatments, with fewer side effects and better efficiency against cancer. Although liposomes have been used in some formulations, different nanocarriers with better features in terms of stability and adsorption capabilities are being explored. Among the available nanoparticles in the field, mesoporous silica nanoparticles (MSNP) have attracted great attention as drug delivery platforms for the treatment of different diseases. Here, a novel formulation based on MSNP loaded with a potent antitumor prodrug that works in vitro as well as in a clinically evaluated liposomal formulation has been developed. This novel formulation shows excellent prodrug encapsulation efficiency and effective release of the anticancer drug only under certain stimuli typical of tumor environments. This behavior is of capital importance for translating this nanocarrier to the clinic in the near future.

Superparamagnetic Iron Oxide Nanoparticles Decorated Mesoporous Silica Nanosystem for Combined Antibiofilm Therapy.

A crucial challenge to face in the treatment of biofilm-associated infection is the ability of bacteria to develop resistance to traditional antimicrobial therapies based on the administration of antibiotics alone. This study aims to apply magnetic hyperthermia together with controlled antibiotic delivery from a unique magnetic-responsive nanocarrier for a combination therapy against biofilm. The design of the nanosystem is based on antibiotic-loaded mesoporous silica nanoparticles (MSNs) externally functionalized with a thermo-responsive polymer capping layer, and decorated in the outermost surface with superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs are able to generate heat upon application of an alternating magnetic field (AMF), reaching the temperature needed to induce a change in the polymer conformation from linear to globular, therefore triggering pore uncapping and the antibiotic cargo release. The microbiological assays indicated that exposure of E. coli biofilms to 200 µg/mL of the nanosystem and the application of an AMF (202 kHz, 30 mT) decreased the number of viable bacteria by 4 log10 units compared with the control. The results of the present study show that combined hyperthermia and antibiotic treatment is a promising approach for the effective management of biofilm-associated infections.

Incorporation of Superparamagnetic Iron Oxide Nanoparticles into Collagen Formulation for 3D Electrospun Scaffolds.

Nowadays, there is an ever-increasing interest in the development of systems able to guide and influence cell activities for bone regeneration. In this context, we have explored for the first time the combination of type-I collagen and superparamagnetic iron oxide nanoparticles (SPIONs) to design magnetic and biocompatible electrospun scaffolds. For this purpose, SPIONs with a size of 12 nm were obtained by thermal decomposition and transferred to an aqueous medium via ligand exchange with dimercaptosuccinic acid (DMSA). The SPIONs were subsequently incorporated into type-I collagen solutions to prove the processability of the resulting hybrid formulation by means of electrospinning. The optimized method led to the fabrication of nanostructured scaffolds composed of randomly oriented collagen fibers ranging between 100 and 200 nm, where SPIONs resulted distributed and embedded into the collagen fibers. The SPIONs-containing electrospun structures proved to preserve the magnetic properties of the nanoparticles alone, making these matrices excellent candidates to explore the magnetic stimuli for biomedical applications. Furthermore, the biological assessment of these collagen scaffolds confirmed high viability, adhesion, and proliferation of both pre-osteoblastic MC3T3-E1 cells and human bone marrow-derived mesenchymal stem cells (hBM-MSCs).

Bacteria-Assisted Transport of Nanomaterials to Improve Drug Delivery in Cancer Therapy.

Currently, the design of nanomaterials for the treatment of different pathologies is presenting a major impact on biomedical research. Thanks to this, nanoparticles represent a successful strategy for the delivery of high amounts of drugs for the treatment of cancer. Different nanosystems have been designed to combat this pathology. However, the poor penetration of these nanomaterials into the tumor tissue prevents the drug from entering the inner regions of the tumor. Some bacterial strains have self-propulsion and guiding capacity thanks to their flagella. They also have a preference to accumulate in certain tumor regions due to the presence of different chemo-attractants factors. Bioconjugation reactions allow the binding of nanoparticles in living systems, such as cells or bacteria, in a simple way. Therefore, bacteria are being used as a transport vehicle for nanoparticles, facilitating their penetration and the subsequent release of the drug inside the tumor. This review would summarize the literature on the anchoring methods of diverse nanosystems in bacteria and, interestingly, their advantages and possible applications in cancer therapy.

Redox-Responsive Mesoporous Silica Nanoparticles for Cancer Treatment: Recent Updates.

Mesoporous silica nanoparticles have been widely applied as carriers for cancer treatment. Among the different types of stimuli-responsive drug delivery systems, those sensitive to redox stimuli have attracted much attention. Their relevance arises from the high concentration of reductive species that are found within the cells, compared to bloodstream, which leads to the drug release taking place only inside cells. This review is intended to provide a comprehensive overview of the most recent trends in the design of redox-responsive mesoporous silica nanoparticles. First, a general description of the biological rationale of this stimulus is presented. Then, the different types of gatekeepers that are able to open the pore entrances only upon application of reductive conditions will be introduced. In this sense, we will distinguish among those targeted and those non-targeted toward cancer cells. Finally, a new family of bridged silica nanoparticles able to degrade their structure upon application of this type of stimulus will be presented.

Janus-Type Mesoporous Silica Nanoparticles for Sequential Tumoral Cell and Mitochondria Targeting.

The development of nanoparticles has provided a powerful weapon in the fight against cancer due to the discovery of their selective accumulation in tumoral tissues, known as enhanced permeation and retention (EPR) effect (Peer et al, Nat Nanotechnol 2:751-760, 2007). Tumoral tissues require afastformation of blood vessels to sustain this rapid growth.

Transcriptome Analysis Identifies Novel Mechanisms Associated with the Antitumor Effect of Chitosan-Stabilized Selenium Nanoparticles.

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 ß-galactosidase activity.

Designing Mesoporous Silica Nanoparticles to Overcome Biological Barriers by Incorporating Targeting and Endosomal Escape.

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.

Endostatin Genetically Engineered Placental Mesenchymal Stromal Cells Carrying Doxorubicin-Loaded Mesoporous Silica Nanoparticles for Combined Chemo- and Antiangiogenic Therapy.

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.

Evaluation of the penetration process of fluorescent collagenase nanocapsules in a 3D collagen gel.

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 degradation 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 matrix. 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.

Emerging Strategies in Anticancer Combination Therapy Employing Silica-Based Nanosystems.

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.