Smart controlled-release nanopesticides based on metal-organic frameworks.

The practical utilization rates of conventional pesticide formulations by target organisms are very low, which results in the pollution of ecological environments and the formation of pesticide residues in agricultural products. Water-based nanopesticide formulations could become alternative and effective formulations to eventually resolve the main issues of conventional pesticide formulations. In this feature article, we describe the design concept of smart (stimuli-responsive) controlled-release nanopesticides, which are created toward hierarchical targets (pests, pathogens, and foliage) in response to multidimensional stimuli from physiological and environmental factors (such as sunlight) of target organisms and plants, for achieving enhanced insecticidal and fungicidal efficacies. The pore sizes and functionalities of metal-organic frameworks (MOFs) can be fine-tuned through the choice of metal-containing units and organic ligands. Tailor-made MOF nanoparticles with large microporous or mesoporous sizes, as well as good biocompatibility and high thermal, mechanical, and chemical durabilities, are used to load pesticides within these pores followed by coating of plant polyphenols and natural polymers for stimuli-responsive controlled pesticide release. This feature article highlights our works on smart controlled-release MOF-based nanopesticides and also includes related works from other laboratories. The future challenges and promising prospects of smart controlled-release MOF-based nanopesticides are also discussed.

Smart, degradable, and eco-friendly carboxymethyl cellulose-CaII hydrogel-like networks gated MIL-101(FeIII) nanoherbicides for paraquat delivery.

Nanopesticides have been selected as one of the top 10 chemical innovations for enhancing the efficacy and safety of agrochemicals. Herein, smart, degradable, and eco-friendly metal-organic framework MIL-101(FeIII) nanoherbicides coated with carboxymethyl cellulose-CaII (CMC-CaII) cross-linking hydrogel-like networks are synthesized via a simple strategy. The coating of the CMC-CaII hydrogel-like gatekeepers is oriented by the coordination unsaturated FeIII clusters on the surfaces of the MIL-101(FeIII) nanocarriers to form a dense film network to prevent paraquat (PQ) leakage. Based on the stimuli factors (acid/basic pH, GSH, phosphates, and EDTA) of physiological and natural environments of target plants, the nanoherbicides are combined with five stimuli-responsive properties to attain the various controlled release of packaged PQ by the disassembly of the gatekeepers and/or the degradation of the MOF skeleton structure. More importantly, based on the stimuli-responsive controlled release mechanisms, the eco-friendly nanocarriers are ultimately degraded against bioaccumulation in plants or soil. The coating of natural CMC could promote the spreading of PQ owing to improvement of wettability for aqueous droplets of nanoherbicides on hydrophobic foliage. The PQ trapped in nanocarriers can effectively prevent PQ degradation, which showed that cumulative degradation rate is ca. 2.6 times lower than that of technical PQ under UV irradiation. The prepared nanoherbicides loaded with PQ show good control efficacy against weeds by controlling the release of PQ; good safety on seed germination (germination rate 97.32-99.67 %), seedling emergence (emergence rate 95.53-99.67 %), and are beneficial for the growth of wheat seedling (increase rate of plant height 1.89-6.97 % and 0.54-5.67 % after 7 and 15 days of seedling emergence, respectively) in the greenhouse; good biosafety for honeybees (Apis mellifera L.), which shows that lethal rates were 2.04 and 2.55 times lower than technical PQ for incubation 24 and 48 h, respectively. The nanoherbicides have potential applications in the field for PQ green agriculture.

Silane-Functionalized Metal-Organic Frameworks for Stimuli-Responsive Drug Delivery Systems: A New Universal Strategy.

A new universal strategy for silane functionalization of metal-organic frameworks (MOFs) was developed. It was demonstrated that silanes were coupled both with terminal hydroxyl (OH) groups and with bridging OH groups of metal-oxo clusters of MOFs through condensation reactions between the silanols of hydrolyzed silanes and the terminal/bridging OH groups to form metal-O-Si bonds. A wide variety of functionalization of MOFs with conventional silanes can be realized by combining synthesis reactions in the solution phase and chemical modifications on the surface. Multivalent supramolecular nanovalves based on the host-guest chemistry of cyclodextrin polymer (CDP) and benzimidazole stalks silanized on the nanoscale MOF (NMOF) surface were successfully constructed. The CDP-valved NMOFs showed the excellent performance of low pH- and α-amylase-responsive controlled drug release. In vitro and in vivo results demonstrated that the CDP-valved NMOFs had a significant inhibitory effect on tumor growth and almost no damage/toxicity to normal tissues. The silanization strategy is universal and opens up a new way for the functionalization of MOFs, which are endowed with a wide variety of applications spanning gas storage, chemical sensing, adsorption and separation, heterogeneous catalysis, and drug delivery.

Ultrathin Porous Nitrogen-Doped Carbon-Coated CuSe Heterostructures for Combination Cancer Therapy of Photothermal Therapy, Photocatalytic Therapy, and Logic-Gated Chemotherapy.

The construction of nanoplatforms for the multimodal cancer therapy still remains an enormous challenge. Ultrathin porous nitrogen-doped carbon coated stoichiometric copper selenide heterostructures (CuSe/NC) are prepared using a facile and green one-pot hydrothermal method. Interestingly, CuSe/NC itself can achieve both photothermal therapy (PTT) and photocatalytic therapy (PCT) under irradiation of a single near-infrared (NIR) light (808 nm), which is convenient and safe for clinical applications. Importantly, the triple-enhanced NIR light-activated PCT, including O2-independent free radicals, Fenton-like reaction, and glutathione (GSH) depletion, breaks through the limitations of hypoxia and overexpressed GSH in cancer cells. Furthermore, CuSe/NC is loaded with doxorubicin (DOX) via metal coordination and then decorates with DNA to construct the CuSe/NC-DOX-DNA nanoplatform. Surprisingly, the facile nanoplatform has an advanced biocomputing capability of an "AND" Boolean logic gate with the smart "AND" logic controlled release of DOX upon combined stimuli of pH and GSH for precise cancer chemotherapy. The synergistic mechanism of proton-mediated ligand exchange between DOX and GSH is proposed for the "AND" logic controlled drug release from CuSe/NC-DOX-DNA. In vitro and in vivo studies demonstrate that CuSe/NC-DOX-DNA has excellent anticancer efficacy and negligible toxicity. This innovative nanoplatform with multienhanced anticancer efficacy provides a paradigm for combination cancer therapy of PTT, PCT, and chemotherapy.

Pillararene-Based Supramolecular Vesicles for Stimuli-Responsive Drug Delivery.

Supramolecular vesicles (SMVs) self-assembled from the supra-amphiphiles, consisting of two scaffolds linked together through noncovalent interactions, can realize stimuli-responsive controlled release of encapsulated drugs for enhanced therapeutic efficacy and minimized side effect of drugs. Pillararenes (PAs), an emerging kind of macrocyclic hosts in 2008, are easy to modify with a variety of functionalities. SMVs from PAs and specific guests mainly based on the host-guest interactions have attracted increasing attention because of their drug delivery and controlled drug release. A great progress in the construction and stimuli-responsive drug delivery of the PA-based SMVs has been made since the first work was reported in 2012. This review summarizes the major achievements of the PA-based SMVs for stimuli-responsive drug delivery over the past 5 years, including the microstructures of SMVs, multiple stimuli-responsive SMVs, prodrug SMVs from prodrug PAs and guests, bola-type SMVs, multifunctional SMVs, glucose-responsive SMVs for insulin delivery, novel SMVs from responsive PAs, thermo-responsive SMVs, and ternary SMVs, for chemotherapy, photothermal therapy, photodynamic therapy, and other biological applications. The future challenges and research directions of PA-based SMVs are also outlined from the points of views of the fundamental research, biological applications, and clinical applications of PA-based SMVs.

Protein-Gated Upconversion Nanoparticle-Embedded Mesoporous Silica Nanovehicles via Diselenide Linkages for Drug Release Tracking in Real Time and Tumor Chemotherapy.

Two novel stimuli-responsive drug delivery systems (DDSs) were successfully created from bovine serum albumin- or myoglobin-gated upconversion nanoparticle-embedded mesoporous silica nanovehicles (UCNP@mSiO2) via diselenide (Se-Se)-containing linkages. More importantly, multiple roles of each scaffold of the nanovehicles were achieved. The controlled release of the encapsulated drug doxorubicin (DOX) within the mesopores was activated by triple stimuli (acidic pH, glutathione, or H2O2) of tumor microenvironments, owing to the conformation/surface charge changes in proteins or the reductive/oxidative cleavages of the Se-Se bonds. Upon release of DOX, the Förster resonance energy transfer between the UCNP cores and encapsulated DOX was eliminated, resulting in an increase in ratiometric upconversion luminescence for DOX release tracking in real time. The two protein-gated DDSs showed some differences in the drug release performances, relevant to structures and properties of the protein nanogates. The introduction of the Se-Se linkages not only increased the versatility of reductive/oxidative cleavages but also showed less cytotoxicity to all cell lines. The DOX-loaded protein-gated nanovehicles showed the inhibitory effect on tumor growth in tumor-bearing mice and negligible damage/toxicity to the normal tissues. The constructed nanovehicles in a spatiotemporally controlled manner have fascinating prospects in targeted drug delivery for cancer chemotherapy.

Cyclodextrin polymer-valved MoS2-embedded mesoporous silica nanopesticides toward hierarchical targets via multidimensional stimuli of biological and natural environments.

Targeted delivery of pesticides towards pests and pathogens can significantly improve the bioavailability and efficacy of pesticides and minimize the impact on the environment. Cyclodextrin polymer (CDP)-valved, benzimidazole functionalized, MoS2-embedded mesoporous silica (MoS2@MSN@CDP) nanopesticides were constructed toward hierarchical biological targets of pests, pathogens, and foliage. The splash and bounce of the aqueous droplets containing MoS2@MSN@CDP nanoparticles in the presence of Aersosol OT on superhydrophobic surfaces were well inhibited available for excellent wetting to prevent pesticides from losing to the environment. The multivalent supramolecular nanovalves between CDP and the functionalized benzimidazole moieties could be activated for the controlled release of pesticides in the cases of low pH and α-amylase. It is the first time to report the foliage-triggered controlled release of pesticides, owing to the competitive binding of epicuticular wax components to CDP. Furthermore, thermogenic MoS2 cores triggered the controlled release of pesticides under irradiation of near infrared light. The fungicidal efficacies of the stimuli-responsive nanopesticides against pathogenic fungi Rhizoctonia solani and Fusarium graminearum were demonstrated. It is clear that the smart nanopesticides could realize the controlled release of pesticides toward hierarchical biological targets for enhanced pesticide bioavailability and efficacy via the multidimensional stimuli of pH, α-amylase, epicuticular waxes, and sunlight.

Facile, Smart, and Degradable Metal-Organic Framework Nanopesticides Gated with FeIII-Tannic Acid Networks in Response to Seven Biological and Environmental Stimuli.

Nanopesticides were selected as one of the top 10 emerging technologies in chemistry that will change our world in 2019. Facile, smart, and degradable metal-organic framework MIL-101(FeIII) nanopesticides gated with FeIII-tannic acid (TA) networks are created using a universal strategy. The capping of the FeIII-TA network gatekeepers is instinctively oriented by the coordinatively unsaturated FeIII sites on the surfaces of the MIL-101(FeIII) nanocarriers; thus, their combination is perfectly matched. This is the first example that one smart gated nanoparticle is integrated with seven stimuli-responsive performances to meet the diverse controlled release of encapsulated cargos by the disassembly of the gatekeepers and/or the degradation of the nanocarriers. More importantly, each of the seven stimuli (acidic/alkaline pH, H2O2, glutathione, phosphates, ethylenediaminetetraacetate, and near-infrared light of sunlight) is closely related to the biological and natural environments of crops, and the biocompatible nanocarriers are eventually degraded against bioaccumulation even if the nanopesticides enter crops. These mechanisms of the stimuli-responsive controlled release are identified and clearly elaborated. It is found that the natural polyphenol can improve the wettability of aqueous droplets of nanopesticides on model hydrophobic foliage for pesticide adhesion and retention. The nanopesticides encapsulated with the fungicide tebuconazole show high fungicidal activities against pathogenic fungi Rhizoctonia solani (rice sheath blight) and Fusarium graminearum (wheat head blight); good safety on seed germination, seedling emergence, and plant height of wheat by seed dressing; and satisfactory control efficacy in wheat powdery mildew caused by Blumeria graminis in the greenhouse. The nanopesticides have potential applications in the field for high quality and yield of agricultural production.

User-safe and efficient chitosan-gated porous carbon nanopesticides and nanoherbicides.

Nanopesticides are selected as one of ten chemical innovations that will change our world. Carboxylated porous carbon nanoparticles (PCNs) were used to encapsulate water-insoluble pesticides and subsequently capped with chitosan (CS) to prepare the CS-gated PCN (PCN@CS) nanopesticides for the controlled release of pesticides in response to acidic pH and elevated temperature with good fungicidal efficacy. To resolve the issue of gastrointestinal absorption of PQ upon ingestion of PQ formulation, it is an innovative strategy to select the carboxylated PCNs as the paraquat (PQ) nanocarriers to inhibit PQ release in the gastrointestinal tract from the origin. The PQ-loaded PCN@CS nanoherbicides showed very low cytotoxicity to human normal cells and high survival rate in mice because the strong π-π interactions between the electron-deficient PQ and the electron-rich PCNs almost inhibited the release of PQ at both acidic and alkaline pH values. The controlled release of PQ from the nanoherbicides was realized at elevated temperatures owing to the weakening of the strong π-π interactions, aiming to eliminate weeds via the photothermal effect of PCNs under natural sunlight. The user-safe PCN-based PQ formulation can inhibit PQ release in the gastrointestinal tract and keep the PQ herbicidal efficacy in the practical application.

DNA-targeted formation and catalytic reactions of DNAzymes for label-free ratiometric electrochemiluminescence biosensing.

A label-free ratiometric electrochemiluminescence (ECL) sensing strategy for the sensitive detection of target DNA (T-DNA) was proposed on the basis of G-quadruplex/hemin-regulated ECL emissions of CdS quantum dots (QDs) and luminol with their common coreactant of H2O2. The ECL biosensor was constructed through stepwise assemblies of CdS QDs and hairpin DNA (H-DNA) on a glassy carbon electrode, and subsequent introduction of T-DNA resulted in the development of G-quadruplex/hemin DNAzymes via the specific recognition of T-DNA and H-DNA in the presence of hemin and K+ ions. The formed DNAzymes not only prompted the catalytic oxidation of hydroquinone followed by deposition of insoluble oxidation oligomers on the electrode surface to attenuate the cathodic ECL emission of CdS QDs but also triggered the catalytic oxidation of luminol to enhance the anodic ECL emission. The label-free ratiometric ECL biosensor for the detection of T-DNA showed a wide response range from 1 to 10,000 fM (10-15 M) with a low detection limit of 0.2 fM and exhibited excellent selectivity against mismatched base sequences. This work provides a reliable and sensitive sensing platform for the detection of targets in analytical community by means of rational design of DNA sequences.

Creation of glycoprotein imprinted self-assembled monolayers with dynamic boronate recognition sites and imprinted cavities for selective glycoprotein recognition.

Glycoproteins are involved in the pathogenesis and development of many diseases and are used as biomarkers for disease diagnosis. It is highly desirable to develop highly sensitive and selective methods for the detection of glycoproteins without the use of antibodies. Imprinting of proteins represents one of the most challenging tasks. Glycoprotein imprinted self-assembled monolayers (SAMs) were created, for the first time, from an oligo(ethylene glycol) (OEG) terminated 1,2-dithiolane derivative linked through an alkyl chain incorporated with two amide groups (DHAP) and combined functional thiols of p-mercaptophenylboronic acid (PMBA) and p-aminothiophenol (PATP) in aqueous media, without the use of polymerization initiators. Combined action of PMBA and PATP was essential for the development of boronate recognition sites for glycoproteins at the physiological pH, attributed to the water molecule-mediated Lewis acid-base interactions between the electron-deficient PMBA and the electron-rich PATP. DHAP played key roles not only in cementation of imprinted cavities by means of double hydrogen bond networks through the amide groups but also in resistance to nonspecific protein binding by terminal OEG moieties, as well as hydrogen bond binding sites from the amide groups exposed to imprinted cavities. The created glycoprotein imprinted SAMs showed excellent recognition selectivity of target glycoproteins. The strategy for tailor-made glycoprotein imprinted SAMs explores a new avenue to the creation of intelligent biomaterials and fabrication of chemosensors.

Dual Enhanced Electrochemiluminescence of Aminated Au@SiO2/CdS Quantum Dot Superstructures: Electromagnetic Field Enhancement and Chemical Enhancement.

This paper reports dual enhanced electrochemiluminescence (ECL) of CdS quantum dot (QD)-decorated aminated Au@SiO2 core/shell (Au@SiO2-NH2/CdS) superstructures. A maximum ECL emission of the Au@SiO2-NH2/CdS superstructures (Au core, ca. 55 nm) with a silica shell of 38 nm was 35-fold stronger than that of the counterparts (containing neither Au cores nor amino groups) with H2O2 as a coreactant. The fold of ECL enhancement is the largest, and the optical path of maximum ECL enhancement is the longest reported so far. The larger the Au cores in the superstructures, the stronger the ECL emission of CdS QDs was. Two types of ECL enhancement mechanisms were clearly proposed for the dual enhanced ECL of the Au@SiO2-NH2/CdS superstructures. One was the electromagnetic field enhancement induced by localized surface plasmon resonance of Au cores, and the other was the chemical enhancement from amino groups modified on the silica surface involved in the ECL process in the assistance of H2O2. It is the first time to put forward the new concept of chemical enhanced ECL that was directly related to the participation of other chemicals, which caused a decrease in the difference in the redox potential between emitters and coreactants for the increase of their redox currents. The constructed ECL platform was demonstrated to have promising applications in highly sensitive detection of glutathione (GSH), and the response mechanism of GSH was also explored.

Phosphonated Pillar[5]arene-Valved Mesoporous Silica Drug Delivery Systems.

To explore the diversity and promising applications of pillararene-based molecular machines, phosphonated pillar[5]arenes (PPA[5]) were synthesized to construct novel supramolecular nanovalves for the first time, based on mesoporous silica nanoparticles (MSNs) functionalized with choline and pyridinium moieties, respectively. PPA[5] encircled the choline or pyridinium stalks to construct supramolecular nanovalves for encapsulation of drugs within the MSN pores. PPA[5] showed a high binding affinity for the quaternary ammonium stalks through the host-guest interactions primarily via ion pairing between the phosphonate and quaternary ammonium moieties, in comparison with carboxylated pillar[5]arene (CPA[5]), to minimize premature drug release. The specific ion pairing between the phosphonate and quaternary ammonium moieties was elaborated for the first time to construct supramolecular nanovalves. The supramolecular nanovalves were activated by low pH, Zn2+ coordination, and competitive agents for controlled drug release, and release efficiency and antitumor efficacy were further enhanced when gold nanorod (GNR)-embedded MSNs (GNR@MSNs) were used instead under illumination of near-infrared (NIR) light, attributed to the synergistic effect of photothermo-chemotherapy. The constructed PPA[5]-valved GNR@MSN delivery system has promising applications in tumor photothermo-chemotherapy.

Supramolecular Vesicles Coassembled from Disulfide-Linked Benzimidazolium Amphiphiles and Carboxylate-Substituted Pillar[6]arenes that Are Responsive to Five Stimuli.

Novel supramolecular vesicles based on host-guest systems were coassembled from carboxylate-substituted pillar[6]arene (CPA[6]) and disulfide-linked benzimidazolium amphiphiles, and the microstructures of the CPA-based supramolecular vesicles were clearly elaborated. The supramolecular vesicles showed controlled drug release in response to five stimuli, with glutathione, pH, CO2 , Zn2+ ions, and hexanediamine, leading to cleavage of the disulfide bonds, protonation of the carboxylate groups, metal chelation, and competitive binding. This is the first case of a smart pillararene-based supramolecular vesicle being integrated with five stimuli-responsive functions to meet the diverse requirements of controlled drug release. Importantly, each of the five stimuli is closely related to microenvironments of tumors and diseases of the human body. The smart stimuli-responsive supramolecular vesicles have promising applications in drug therapy of tumors and relevant diseases.

Electrocatalytic oxidation of nitrite using metal-free nitrogen-doped reduced graphene oxide nanosheets for sensitive detection.

Nitrite can become poisonous to animals and human beings as it can lead to generation of carcinogenic N-nitrosamines. Metal-free nitrogen-doped reduced graphene oxide (NrGO) exhibited a good electrocatalytic activity toward oxidation of nitrite with the relatively low oxidation potential of 0.68V (v.s. saturated calomel electrode), thus, a facile electrochemical sensor based on metal-free NrGO was fabricated for sensitive detection of nitrite for the first time. The novel sensor showed a wide linear concentration range from 0.5 to 5000µM and a low detection limit of 0.2µM at the signal-to-noise ratio of 3 with good selectivity, stability, and reproducibility. This fabricated sensor was used for the determination of nitrite in pickled garlic and river water. These results demonstrate that the facile metal-free NrGO-modified electrochemical sensor has promising applications for the determination of nitrite in food and environment.

Sensitive Glycoprotein Sandwich Assays by the Synergistic Effect of In Situ Generation of Raman Probes and Plasmonic Coupling of Ag Core-Au Satellite Nanostructures.

Sensitive surface-enhanced Raman scattering (SERS) assays of glycoproteins have been proposed using p-aminothiophenol (PATP)-embedded Ag core-Au satellite nanostructures modified with p-mercaptophenylboronic acid (PMBA) and the self-assembled monolayer of PMBA on a smooth gold-coated wafer. The apparent Raman probe PATP on the surfaces of the Ag cores underwent a photodimerization to generate 4,4'-dimercaptoazobenzene (DMAB) in situ upon excitation of laser, and the in situ generated DMAB acted as the actual Raman probe with considerably strong SERS signals, which was further enhanced by the plasmonic coupling of the Ag core-Au satellite nanostructures due to the synergistic effect. The sandwich assays of glycoproteins showed high sensitivity and excellent selectivity against nonglycoproteins. The Ag core-Au satellite SERS nanostructures can be used for highly sensitive SERS assays of other analytes.

Carbon Nanodot-Decorated Ag@SiO2 Nanoparticles for Fluorescence and Surface-Enhanced Raman Scattering Immunoassays.

A novel immunoassay protocol was demonstrated by the combination of fluorescent carbon nanodots (CNDs) and Ag@SiO2 surface-enhanced Raman scattering (SERS) tag nanoparticles into ensembles for a bifunctional nanoplatform. The CND-decorated Ag@SiO2 nanoparticles were constructed for sensitive fluorescence and SERS immunoassays. The silica shell thickness and amount of Ag@SiO2 nanoparticles were optimized for availability of strong fluorescence emission. The considerably large Raman scattering cross section of in situ-generated actual Raman reporter, 4,4'-dimercaptoazobenzene, from the apparent reporter p-aminothiophenol modified on the surfaces of Ag nanoparticles upon illumination of laser compensated for the reduction of SERS signals resulting from silica coating to a great degree. The antibody-modified bifunctional nanoparticles were captured by antibody-modified quartz slides in the presence of antigens in the sandwich structures for fluorescence and SERS immunoassays. The bifunctional nanoparticles could be used not only as bimodal probes for biodetection but also as bimodal tracers for bioimaging.

Combination drug release of smart cyclodextrin-gated mesoporous silica nanovehicles.

An integrated γ-cyclodextrin-gated mesoporous silica delivery system via dual dynamic covalent bonds was constructed with dual drug loading for simultaneous and cascade release in targeted combination drug therapy.

Facile and sensitive glucose sandwich assay using in situ-generated Raman reporters.

A facile and sensitive glucose sandwich assay using surface-enhanced Raman scattering (SERS) has been developed through the use of the self-assembled p-mercaptophenylboronic acid (PMBA) monolayer on a smooth gold-coated slide and the SERS tags of Ag nanoparticles (AgNPs) modified with p-aminothiophenol (PATP) and PMBA. The photocoupling product 4,4'-dimercaptoazobenzene (DMAB), generated in situ from PATP on the AgNP surface during the SERS measurement, possessed considerably intense characteristic SERS peaks and acted as the actual Raman reporter, which improved the sensitivity of glucose detection devoid of interference of other biomolecules. The facile sandwich assay showed a high selectivity of glucose over fructose and galactose. This facile, sensitive, and selective SERS-based glucose sandwich assay can be developed into a diagnostic tool for determination of glucose levels.

pH- and redox-triggered synergistic controlled release of a ZnO-gated hollow mesoporous silica drug delivery system.

Hollow mesoporous silica spheres (HMSS) have a hierarchical mesoporous structure composed of a hollow cavity and mesoporous shell available for high capacity drug storage. The covalent attachment of ZnO quantum dots (QDs) to the HMSS outer surface as gatekeepers via disulfide-conjugated two amide linkages encapsulated the anticancer drugs doxorubicin (DOX) within the HMSS cavities and pores, and minimized premature release of the drug. The controlled release of the drug from the ZnO-gated HMSS delivery system was realized by the dissolution of ZnO QDs upon a decrease in pH and cleavage of the disulfide bonds, which indicates that the pH- and redox-responsive controlled release of the drugs could be synergically stimulated by tumor cells with weakly acidic environments and high-expressed glutathione. The constructed ZnO-gated HMSS delivery system has promising applications in site-specific drug release for tumor chemotherapy.