Chemical Strategies for the Detection and Elimination of Senescent Cells.

ConspectusCellular senescence can be defined as an irreversible stopping of cell proliferation that arises in response to various stress signals. Cellular senescence is involved in diverse physiological and pathological processes in different tissues, exerting effects on processes as differentiated as embryogenesis, tissue repair and remodeling, cancer, aging, and tissue fibrosis. In addition, the development of some pathologies, aging, cancer, and other age-related diseases has been related to senescent cell accumulation. Due to the complexity of the senescence phenotype, targeting senescent cells is not trivial, is challenging, and is especially relevant for in vivo detection in age-related diseases and tissue samples. Despite the elimination of senescent cells (senolysis) using specific drugs (senolytics) that have been shown to be effective in numerous preclinical disease models, the clinical translation is still limited due to the off-target effects of current senolytics and associated toxicities. Therefore, the development of new chemical strategies aimed at detecting and eliminating senescent cells for the prevention and selective treatment of senescence-associated diseases is of great interest. Such strategies not only will contribute to a deeper understanding of this rapidly evolving field but also will delineate and inspire new possibilities for future research.In this Account, we report our recent research in the development of new chemical approaches for the detection and elimination of senescent cells based on new probes, nanoparticles, and prodrugs. The designed systems take advantage of the over-representation in senescent cells of certain biomarkers such as ß-galactosidase and lipofuscin. One- and two-photon probes, for higher tissue penetration, have been developed. Moreover, we also present a renal clearable fluorogenic probe for the in vivo detection of the ß-galactosidase activity, allowing for correlation with the senescent burden in living animals. Moreover, as an alternative to molecular-based probes, we also developed nanoparticles for senescence detection. Besides, we describe advances in new therapeutic agents to selectively eradicate senescent cells using ß-galactosidase activity-sensitive gated nanoparticles loaded with cytotoxic or senolytic agents or new prodrugs aiming to increase the selectivity and reduction of off-target toxicities of current drugs. Moreover, new advances therapies have been applied in vitro and in vivo. Studies with the probes, nanoparticles, and prodrugs have been applied in several in vitro and in vivo models of cancer, fibrosis, aging, and drug-induced cardiotoxicity in which senescence plays an important role. We discuss the benefits of these chemical strategies toward the development of more specific and sophisticated probes, nanoparticles, and prodrugs targeting senescent cells.

Remarkable enhancement of cinnamaldehyde antimicrobial activity encapsulated in capped mesoporous nanoparticles: A new "nanokiller" approach in the era of antimicrobial resistance.

Combating antimicrobial resistance is one of the biggest health challenges because of the ineffectiveness of standard biocide treatments. This challenge could be approached using natural products, which have demonstrated powerful therapeutics against multidrug-resistant microbes. In the present work, a nanodevice consisting of mesoporous silica nanoparticles loaded with an essential oil component (cinnamaldehyde) and functionalized with the polypeptide ε-poly-l-lysine is developed and used as an antimicrobial agent. In the presence of the corresponding stimuli (i.e., exogenous proteolytic enzymes from bacteria or fungi), the polypeptide is hydrolyzed, and the cinnamaldehyde delivery is enhanced. The nanodevice's release mechanism and efficacy are evaluated in vitro against the pathogenic microorganisms Escherichia coli, Staphylococcus aureus, and Candida albicans. The results demonstrate that the new device increases the delivery of the cinnamaldehyde via a biocontrolled uncapping mechanism triggered by proteolytic enzymes. Moreover, the nanodevice notably improves the antimicrobial efficacy of cinnamaldehyde when compared to the free compound, ca. 52-fold for E. coli, ca. 60-fold for S. aureus, and ca. 7-fold for C. albicans. The enhancement of the antimicrobial activity of the essential oil component is attributed to the decrease of its volatility due to its encapsulation in the porous silica matrix and the increase of its local concentration when released due to the presence of microorganisms.

Water-Soluble Molecular Cages for Biological Applications.

The field of molecular cages has attracted increasing interest in relation to the development of biological applications, as evidenced by the remarkable examples published in recent years. Two key factors have contributed to this achievement: First, the remarkable and adjustable host-guest chemical properties of molecular cages make them highly suitable for biological applications. This allows encapsulating therapeutic molecules to improve their properties. Second, significant advances have been made in synthetic methods to create water-soluble molecular cages. Achieving the necessary water solubility is a significant challenge, which in most cases requires specific chemical groups to overcome the inherent hydrophobic nature of the molecular cages which feature the organic components of the cage. This can be achieved by either incorporating water-solubilizing groups with negative/positive charges, polyethylene glycol chains, etc.; or by introducing charges directly into the cage structure itself. These synthetic strategies allow preparing water-soluble molecular cages for diverse biological applications, including cages' anticancer activity, anticancer drug delivery, photodynamic therapy, and molecular recognition of biological molecules. In the review we describe selected examples that show the main concepts to achieve water solubility in molecular cages and some selected recent biological applications.

A navitoclax-loaded nanodevice targeting matrix metalloproteinase-3 for the selective elimination of senescent cells.

Cellular senescence is implicated in the occurrence and progression of multiple age-related disorders. In this context, the selective elimination of senescent cells, senolysis, has emerged as an effective therapeutic strategy. However, the heterogeneous senescent phenotype hinders the discovery of a universal and robust senescence biomarker that limits the effective of senolytic with off-target toxic effects. Therefore, the development of more selective strategies represents a promising approach to increase the specificity of senolytic therapy. In this study, we have developed an innovative nanodevice for the selective elimination of senescent cells (SCs) based on the specific enzymatic activity of the senescent secretome. The results revealed that when senescence is induced in proliferating WI-38 by ionizing radiation (IR), the cells secrete high levels of matrix metalloproteinase-3 (MMP-3). Based on this result, mesoporous silica nanoparticles (MSNs) were loaded with the senolytic navitoclax (Nav) and coated with a specific peptide which is substrate of MMP-3 (NPs(Nav)@MMP-3). Studies in cells confirmed the preferential release of cargo in IR-induced senescent cells compared to proliferating cells, depending on MMP-3 levels. Moreover, treatment with NPs(Nav)@MMP-3 induced a selective decrease in the viability of SCs as well as a protective effect on non-proliferating cells. These results demonstrate the potential use of NPs to develop enhanced senolytic therapies based on specific enzymatic activity in the senescent microenvironment, with potential clinical relevance. STATEMENT OF SIGNIFICANCE: The common ß-galactosidase activity has been exploited to develop nanoparticles for the selective elimination of senescent cells. However, the identification of new senescent biomarkers is a key factor for the development of improved strategies. In this scenario, we report for the first time the development of NPs targeting senescent cells based on specific enzymatic activity of the senescent secretome. We report a navitoclax-loaded nanodevice responsive to the matrix metalloproteinase-3 (MMP-3) associated with the senescent phenotype. Our nanosystem achieves the selective release of navitoclax in an MMP-3-dependent manner while limiting off-target effects on non-senescent cells. This opens the possibility of using nanoparticles able to detect an altered senescent environment and selectively release its content, thus enhancing the efficacy of senolytic therapies.

Toxicological Profiling and Long-Term Effects of Bare, PEGylated- and Galacto-Oligosaccharide-Functionalized Mesoporous Silica Nanoparticles.

Mesoporous silica nanoparticles (MSNs) are amongst the most used nanoparticles in biomedicine. However, the potentially toxic effects of MSNs have not yet been fully evaluated, being a controversial matter in research. In this study, bare MSNs, PEGylated MSNs (MSNs-PEG), and galacto-oligosaccharide-functionalized MSNs (MSNs-GAL) are synthesized and characterized to assess their genotoxicity and transforming ability on human lung epithelial BEAS-2B cells in short- (48 h) and long-term (8 weeks) exposure scenarios. Initial short-term treatments show a dose-dependent increase in genotoxicity for MSNs-PEG-treated cells but not oxidative DNA damage for MSNs, MSNs-PEG, or for MSNs-GAL. In addition, after 8 weeks of continuous exposure, neither induced genotoxic nor oxidative DNA is observed. Nevertheless, long-term treatment with MSNs-PEG and MSNs-GAL, but not bare MSNs, induces cell transformation features, as evidenced by the cell's enhanced ability to grow independently of anchorage, to migrate, and to invade. Further, the secretome from cells treated with MSNs and MSNs-GAL, but not MSNs-PEG, shows certain tumor-promoting abilities, increasing the number and size of HeLa cell colonies formed in the indirect soft-agar assay. These results show that MSNs, specifically the functionalized ones, provoke some measurable adverse effects linked to tumorigenesis. These effects are in the order of other nanomaterials, such as carbon nanotubes or cerium dioxide nanoparticles, but they are lower than those provoked by some approved drugs, such as doxorubicin or dexamethasone.

Intranasal administration of molecular-gated mesoporous nanoparticles to increase ponatinib delivery to the brain.

Background: Glioblastoma is the most common and lethal brain cancer. New treatments are needed. However, the presence of the blood-brain barrier is limiting the development of new treatments directed toward the brain, as it restricts the access and distribution of drugs to the CNS. Materials & methods: In this work, two different nanoparticles (i.e., mesoporous silica nanoparticles and magnetic mesoporous silica nanoparticles) loaded with ponatinib were prepared. Results & conclusion: Both particles were characterized and tested in vitro and in vivo, proving that they are not toxic for blood-brain barrier cells and they increase the amount of drug reaching the brain when administered intranasally in comparison with the results obtained for the free drug.

This article presents a couple of promising nanoparticles for the treatment of brain cancer. This research is interesting because the brain and spinal cord are protected by a membrane that prevents toxic substances from reaching them but also hinders the access of drugs. One type of particle has a magnet in its core, so it can be driven with another external magnet until it reaches target; the other type does not have a magnet but has a small size, which would allow it to cross the membrane mentioned above. These particles have been proven to be able to kill cancer cells and to reach the brain after been administered through the nose in a better way than the free drug.

Delivery of miR-200c-3p Using Tumor-Targeted Mesoporous Silica Nanoparticles for Breast Cancer Therapy.

Despite advances in breast cancer treatment, it remains the leading cause of cancer-related death in women worldwide. In this context, microRNAs have emerged as potential therapeutic targets but still present some limitations for in vivo applications. Particularly, miR-200c-3p is a well-known tumor suppressor microRNA that inhibits tumor progression and metastasis in breast cancer through downregulating ZEB1 and ZEB2. Based on the above, we describe the design and validation of a nanodevice using mesoporous silica nanoparticles for miR-200c-3p delivery for breast cancer treatment. We demonstrate the biocompatibility of the synthesized nanodevices as well as their ability to escape from endosomes/lysosomes and inhibit tumorigenesis, invasion, migration, and proliferation of tumor cells in vitro. Moreover, tumor targeting and effective delivery of miR-200c-3p from the nanoparticles in vivo are confirmed in an orthotopic breast cancer mouse model, and the therapeutic efficacy is also evidenced by a decrease in tumor size and lung metastasis, while showing no signs of toxicity. Overall, our results provide evidence that miR-200c-3p-loaded nanoparticles are a potential strategy for breast cancer therapy and a safe and effective system for tumor-targeted delivery of microRNAs.

Targeted Delivery of the Pan-Inflammasome Inhibitor MM01 as an Alternative Approach to Acute Lung Injury Therapy.

Acute lung injury (ALI) is a severe pulmonary disorder responsible for high percentage of mortality and morbidity in intensive care unit patients. Current treatments are ineffective, so the development of efficient and specific therapies is an unmet medical need. The activation of NLPR3 inflammasome during ALI produces the release of proinflammatory factors and pyroptosis, a proinflammatory form of cell death that contributes to lung damage spreading. Herein, it is demonstrated that modulating inflammasome activation through inhibition of ASC oligomerization by the recently described MM01 compound can be an alternative pharmacotherapy against ALI. Besides, the added efficacy of using a drug delivery nanosystem designed to target the inflamed lungs is determined. The MM01 drug is incorporated into mesoporous silica nanoparticles capped with a peptide (TNFR-MM01-MSNs) to target tumor necrosis factor receptor-1 (TNFR-1) to proinflammatory macrophages. The prepared nanoparticles can deliver the cargo in a controlled manner after the preferential uptake by proinflammatory macrophages and exhibit anti-inflammatory activity. Finally, the therapeutic effect of MM01 free or nanoparticulated to inhibit inflammatory response and lung injury is successfully demonstrated in lipopolysaccharide-mouse model of ALI. The results suggest the potential of pan-inflammasome inhibitors as candidates for ALI therapy and the use of nanoparticles for targeted lung delivery.

Human Papilloma Virus DNA Detection in Clinical Samples Using Fluorogenic Probes Based on Oligonucleotide Gated Nanoporous Anodic Alumina Films.

In this work, fluorogenic probes based on oligonucleotide capped nanoporous anodic alumina films are developed for specific and sensitive detection of human papilloma virus (HPV) DNA. The probe consists of anodic alumina nanoporous films loaded with the fluorophore rhodamine B (RhB) and capped with oligonucleotides bearing specific base sequences complementary to genetic material of different high-risk (hr) HPV types. Synthesis protocol is optimized for scale up production of sensors with high reproducibility. The sensors' surfaces are characterized by scanning electron microscopy (HR-FESEM) and atomic force microscopy (AFM) and their atomic composition is determined by energy dispersive X-ray spectroscopy (EDXS). Oligonucleotide molecules onto nanoporous films block the pores and avoid diffusion of RhB to the liquid phase. Pore opening is produced when specific DNA of HPV is present in the medium, resulting in RhB delivery, that is detected by fluorescence measurements. The sensing assay is optimized for reliable fluorescence signal reading. Nine different sensors are synthesized for specific detection of 14 different hr-HPV types in clinical samples with very high sensitivity (100%) and high selectivity (93-100%), allowing rapid screening of virus infections with very high negative predictive values (100%).

Development of New Targeted Nanotherapy Combined with Magneto-Fluorescent Nanoparticles against Colorectal Cancer.

The need for non-invasive therapies capable of conserving drug efficiency and stability while having specific targetability against colorectal cancer (CRC), has made nanoparticles preferable vehicles and principal building blocks for the development of complex and multi-action anti-tumoral approaches. For that purpose, we herein report the production of a combinatory anti-tumoral nanotherapy using the production of a new targeting towards CRC lines. To do so, Magneto-fluorescent NANO3 nanoparticles were used as nanocarriers for a combination of the drugs doxorubicin (DOX) and ofloxacin (OFLO). NANO3 nanoparticles' surface was modified with two different targeting agents, a newly synthesized (anti-CA IX acetazolamide derivative (AZM-SH)) and a commercially available (anti-epidermal growth factor receptor (EGFR), Cetuximab). The cytotoxicity revealed that only DOX-containing nanosystems showed significant and even competitive cytotoxicity when compared to that of free DOX. Interestingly, surface modification with AZM-SH promoted an increased cellular uptake in the HCT116 cell line, surpassing even those functionalized with Cetuximab. The results show that the new target has high potential to be used as a nanotherapy agent for CRC cells, surpassing commercial targets. As a proof-of-concept, an oral administration form of NANO3 systems was successfully combined with Eudragit® enteric coating and studied under extreme conditions.

High-Capacity Mesoporous Silica Nanocarriers of siRNA for Applications in Retinal Delivery.

The main cause of subretinal neovascularisation in wet age-related macular degeneration (AMD) is an abnormal expression in the retinal pigment epithelium (RPE) of the vascular endothelial growth factor (VEGF). Current approaches for the treatment of AMD present considerable issues that could be overcome by encapsulating anti-VEGF drugs in suitable nanocarriers, thus providing better penetration, higher retention times, and sustained release. In this work, the ability of large pore mesoporous silica nanoparticles (LP-MSNs) to transport and protect nucleic acid molecules is exploited to develop an innovative LP-MSN-based nanosystem for the topical administration of anti-VEGF siRNA molecules to RPE cells. siRNA is loaded into LP-MSN mesopores, while the external surface of the nanodevices is functionalised with polyethylenimine (PEI) chains that allow the controlled release of siRNA and promote endosomal escape to facilitate cytosolic delivery of the cargo. The successful results obtained for VEGF silencing in ARPE-19 RPE cells demonstrate that the designed nanodevice is suitable as an siRNA transporter.

Finite Element Models of Gold Nanoparticles and Their Suspensions for Photothermal Effect Calculation.

(1) Background: The ability of metal nanoparticles to carry other molecules and their electromagnetic interactions can be used for localized drug release or to heat malignant tissue, as in the case of photothermal treatments. Plasmonics can be used to calculate their absorption and electric field enhancement, which can be further used to predict the outcome of photothermal experiments. In this study, we model the nanoparticle geometry in a Finite Element Model calculus environment to calculate the effects that occur as a response to placing it in an optical, electromagnetic field, and also a model of the experimental procedure to measure the temperature rise while irradiating a suspension of nanoparticles. (2) Methods: Finite Element Method numerical models using the COMSOL interface for geometry and mesh generation and iterative solving discretized Maxwell's equations; (3) Results: Absorption and scattering cross-section spectrums were obtained for NanoRods and NanoStars, also varying their geometry as a parameter, along with electric field enhancement in their surroundings; temperature curves were calculated and measured as an outcome of the irradiation of different concentration suspensions; (4) Conclusions: The results obtained are comparable with the bibliography and experimental measurements.

Combination of palbociclib with navitoclax based-therapies enhances in vivo antitumoral activity in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer with a poor prognosis and limited effective therapeutic options. Induction of senescence, arrest of cell proliferation, has been explored as an effective method to limit tumor progression in metastatic breast cancer. However, relapses occur in some patients, possibly as a result of the accumulation of senescent tumor cells in the body after treatment, which promote metastasis. In this study, we explored the combination of senescence induction and the subsequent removal of senescent cells (senolysis) as an alternative approach to improve outcomes in TNBC patients. We demonstrate that a combination treatment, using the senescence-inducer palbociclib and the senolytic agent navitoclax, delays tumor growth and reduces metastases in a mouse xenograft model of aggressive human TNBC (hTNBC). Furthermore, considering the off-target effects and toxicity derived from the use of navitoclax, we propose a strategy aimed at minimizing the associated side effects. We use a galacto-conjugated navitoclax (nav-Gal) as a senolytic prodrug that can preferentially be activated by ß-galactosidase overexpressed in senescent cells. Concomitant treatment with palbociclib and nav-Gal in vivo results in the eradication of senescent hTNBC cells with consequent reduction of tumor growth, while reducing the cytotoxicity of navitoclax. Taken together, our results support the efficacy of combination therapy of senescence-induction with senolysis for hTNBC, as well as the development of a targeted approach as an effective and safer therapeutic opportunity.

ß-Galactosidase-Activatable Nile Blue-Based NIR Senoprobe for the Real-Time Detection of Cellular Senescence.

Cellular senescence is a stable cell cycle arrest in response to stress or other damage stimuli to maintain tissue homeostasis. However, the accumulation of senescent cells can lead to the progression of various senescence-related disorders. In this paper, we describe the development of a ß-galactosidase-activatable near-infrared (NIR) senoprobe, NBGal, for the detection of senescent cells based on the use of the FDA-approved Nile blue (NB) fluorophore. NBGal was validated in chemotherapeutic-induced senescence cancer models in vitro using SK-Mel 103 and 4T1 cell lines. In vivo monitoring of cellular senescence was evaluated in orthotopic triple-negative breast cancer-bearing mice treated with palbociclib to induce senescence. In all cases, NBGal exhibited a selective tracking of senescent cells mainly ascribed to the overexpressed ß-galactosidase enzyme responsible for hydrolyzing the NBGal probe generating the highly emissive NB fluorophore. In this way, NBGal has proven to be a qualitative, rapid, and minimally invasive probe that allows the direct detection of senescent cells in vivo.

Lipofuscin labeling through biorthogonal strain-promoted azide-alkyne cycloaddition for the detection of senescent cells.

A new method for senescent cell detection is described, which is based on lipofuscin labeling with a fluorescent reporter through a biorthogonal strain-promoted azide-alkyne cycloaddition. The sensing protocol involves a first step where the interaction of lipofuscin with a Sudan Black B derivative containing an azide moiety (SBB-N3 ) is carried out. In the final step, the azide moiety reacts with a fluorophore containing a cyclooctene ring (BODIPY). The efficacy of this two-step protocol is assessed in senescent melanoma SK-MEL-103 cells, senescent triple-negative breast cancer MDA-MB-231 cells and senescent WI-38 fibroblasts. In all cases, a clear fluorescence pattern was observed in senescent cells, compared to proliferative cells, only when the SBB-N3 -BODIPY probe was formed. Our results provide an alternative tool for the detection of senescent cells, based on an in situ bio-orthogonal reaction for lipofuscin labeling.

Tailored cancer therapy by magnetic nanoparticle hyperthermia: A virtual scenario simulation method.

BACKGROUND AND OBJECTIVE: Hyperthermia is a cancer treatment aiming to induce cell death by directly warming cancerous tissues above 40 °C. This technique can be applied both individually and together with other cancer therapies. The main challenge for researchers and medics is to heat only tumoral cells avoiding global or localized heating of sane tissues. The objective in this study is to provide a realistic virtual scenario to develop an optimized multi-site injection plan for tailored magnetic nanoparticle-mediated hyperthermia applications. METHODS: A three-dimensional model of a cat's back was tested in three different simulation scenarios, showing the impact of magnetic nanoparticles in each specific environment configuration. RESULTS: As a result of this study. This simulation method can, minimising the affection to healthy tissue. CONCLUSIONS: This virtual method will help real and personalized therapy planning and tailor the dose and distribution of magnetic nanoparticles for an enhanced hyperthermia cancer treatment.

Magneto-Fluorescent Mesoporous Nanocarriers for the Dual-Delivery of Ofloxacin and Doxorubicin to Tackle Opportunistic Bacterial Infections in Colorectal Cancer.

Cancer-related opportunistic bacterial infections are one major barrier for successful clinical therapies, often correlated to the production of genotoxic factors and higher cancer incidence. Although dual anticancer and antimicrobial therapies are a growing therapeutic fashion, they still fall short when it comes to specific delivery and local action in in vivo systems. Nanoparticles are seen as potential therapeutic vectors, be it by means of their intrinsic antibacterial properties and effective delivery capacity, or by means of their repeatedly reported modulation and maneuverability. Herein we report on the production of a biocompatible, antimicrobial magneto-fluorescent nanosystem (NANO3) for the delivery of a dual doxorubicin-ofloxacin formulation against cancer-related bacterial infections. The drug delivery capacity, rendered by its mesoporous silica matrix, is confirmed by the high loading capacity and stimuli-driven release of both drugs, with preference for tumor-like acidic media. The pH-dependent emission of its surface fluorescent SiQDs, provides an insight into NANO3 surface behavior and pore availability, with the SiQDs working as pore gates. Hyperthermia induces heat generation to febrile temperatures, doubling drug release. NANO3-loaded systems demonstrate significant antimicrobial activity, specifically after the application of hyperthermia conditions. NANO3 structure and antimicrobial properties confirm their potential use in a future dual anticancer and antimicrobial therapeutical vector, due to their drug loading capacity and their surface availability for further modification with bioactive, targeting species.

Enhancement of photoactivity and cellular uptake of (Bu4N)2[Mo6I8(CH3COO)6] complex by loading on porous MCM-41 support. Photodynamic studies as an anticancer agent.

The incorporation by ionic assembly of the hexanuclear molybdenum cluster (Bu4N)2[Mo6I8(CH3CO2)6] (1) in amino-decorated mesoporous silica nanoparticles MCM-41, has yielded the new molybdenum-based hybrid photosensitizer 1@MCM-41. The new photoactive material presents a high porosity, due to the intrinsic high specific surface area of MCM-41 nanoparticles (989 m2 g-1) which is responsible for the good dispersion of the hexamolybdenum clusters on the nanoparticles surface, as observed by STEM analysis. The hybrid photosensitizer can generate efficiently singlet oxygen, which was demonstrated by using the benchmark photooxygenation reaction of 9,10-anthracenediyl-bis(methylene)dimalonic acid (ABDA) in water. The photodynamic therapy activity has been tested using LED light as an irradiation source (λirr ~ 400-700 nm; 15.6 mW/cm2). The results show a good activity of the hybrid photosensitizer against human cervical cancer (HeLa) cells, reducing up to 70 % their viability after 20 min of irradiation, whereas low cytotoxicity is detected in the darkness. The main finding of this research is that the incorporation of molybdenum complexes at porous MCM-41 supports enhances their photoactivity and improves cellular uptake, compared to free clusters.

An enzyme-controlled mesoporous nanomachine for triple-responsive delivery.

The construction of a novel enzyme-controlled nanomachine with multiple release mechanisms for on-command delivery is described. This nanodevice was assembled by modifying mesoporous silica nanoparticles with 2-(benzo[d]thiazol-2-yl)phenyl 4-aminobenzoate moieties, and further capped with ß-cyclodextrin-modified glucose oxidase neoglycoenzyme. The device released the encapsulated payload in the presence of H2O2 and acidic media. The use of glucose as an input chemical signal also triggered cargo release through the enzymatic production of gluconic acid and hydrogen peroxide, and the subsequent disruption of the gating mechanism at the mesoporous surface. The nanodevice was successfully employed for the enzyme-controlled release of doxorubicin in HeLa cancer cells.