A triple-enhanced chemodynamic approach based on glucosepowered hybrid nanoreactors for effective bacteria killing

Rapid evolution of multidrug resistance in bacterial pathogens is outpacing the development of new antibiotics,and chemodynamic therapy(CDT)provides an excellent alternative.However,achieving highly efficient CDT is still a great challenge,since the pH in the infection site is close to neutral and the supply of H_(2)O_(2)is inadequate.We herein constructed the antibacterial nanoreactors.Indocyanine green(ICG)and glucose oxidase(GOx)were incorporated into homologous zeolitic imidazolate framework-8(ZIF-8)nanoparticles coating with metal polyphenol network(MPN)composed by Fe^(3+)and tannic acid(TA).The well-designed nanoreactors could simultaneously break the pH and H_(2)O_(2)limitations,and generate hyperthermia under irradiation,thus realizing a triple-enhanced CDT for high-efficiency sterilization.Furthermore,the nanoreactors could combine CDT with photothermal therapy(PTT)and photodynamic therapy(PDT),which not only improved the bactericidal efficiency and broadened the antibacterial spectrum,but also alleviated the antibiotics resistance issues.Remarkably,the proposed nanoreactors achieved a robust in vitro bacterial killing against Gram-positive methicillin-resistant Staphylococcus aureus(MRSA)and Gram-negative Pseudomonas aeruginosa.The nanoreactors achieved an 99.7%MRSA reduction in an MRSA-induced murine abscess model accompanied with negligible toxicity.Overall,this study provides a promising strategy for multiple-enhanced CDT and multimodal combined therapy for pathogenic infections.

Mesoporous silica nanoparticles for drug and gene delivery

Mesoporous silica nanoparticles(MSNs) are attracting increasing interest for potential biomedical applications. With tailored mesoporous structure, huge surface area and pore volume,selective surface functionality, as well as morphology control, MSNs exhibit high loading capacity for therapeutic agents and controlled release properties if modified with stimuli-responsive groups, polymers or proteins. In this review article, the applications of MSNs in pharmaceutics to improve drug bioavailability, reduce drug toxicity, and deliver with cellular targetability are summarized. Particularly,the exciting progress in the development of MSNs-based effective delivery systems for poorly soluble drugs, anticancer agents, and therapeutic genes are highlighted.

“Pincer movement”:Reversing cisplatin resistance based on simultaneous glutathione depletion and glutathione S-transferases inhibition by redox-responsive degradable organosilica hybrid nanoparticles

The therapeutic efficacy of cisplatin has been restricted by drug resistance of cancers.Intracellular glutathione(GSH)detoxification of cisplatin under the catalysis of glutathione S-transferases(GST)plays important roles in the development of cisplatin resistance.Herein,a strategy of“pincer movement”based on simultaneous GSH depletion and GST inhibition is proposed to enhance cisplatin-based chemotherapy.Specifically,a redox-responsive nanomedicine based on disulfide-bridged degradable organosilica hybrid nanoparticles is developed and loaded with cisplatin and ethacrynic acid(EA),a GST inhibitor.Responding to high level of intracellular GSH,the hybrid nanoparticles can be gradually degraded due to the break of disulfide bonds,which further promotes drug release.Meanwhile,the disulfide-mediated GSH depletion and EA-induced GST inhibition cooperatively prevent cellular detoxification of cisplatin and reverse drug resistance.Moreover,the nanomedicine is integrated into microneedles for intralesional drug delivery against cisplatin-resistant melanoma.The in vivo results show that the nanomedicine-loaded microneedles can achieve significant GSH depletion,GST inhibition,and consequent tumor growth suppression.Overall,this research provides a promising strategy for the construction of new-type nanomedicines to overcome cisplatin resistance,which extends the biomedical application of organosilica hybrid nanomaterials and enables more efficient chemotherapy against drug-resistant cancers.

A homogenous nanoporous pulmonary drug delivery system based on metal-organic frameworks with fine aerosolization performance and good compatibility

Pulmonary drug delivery has attracted increasing attention in biomedicine,and porous particles can effectively enhance the aerosolization performance and bioavailability of drugs.However,the existing methods for preparing porous particles using porogens have several drawbacks,such as the inhomogeneous and uncontrollable pores,drug leakage,and high risk of fragmentation.In this study,a series of cyclodextrin-based metal-organic framework(CD-MOF)particles containing homogenous nanopores were delicately engineered without porogens.Compared with commercial inhalation carrier,CDMOF showed excellent aerosolization performance because of the homogenous nanoporous structure.The great biocompatibility of CD-MOF in pulmonary delivery was also confirmed by a series of experiments,including cytotoxicity assay,hemolysis ratio test,lung function evaluation,in vivo lung injury markers measurement,and histological analysis.The results of ex vivo fluorescence imaging showed the high deposition rate of CD-MOF in lungs.Therefore,all results demonstrated that CD-MOF was a promising carrier for pulmonary drug delivery.This study may throw light on the nanoporous particles for effective pulmonary administration.

Tailored core-shell dual metal-eorganic frameworks as a versatile nanomotor for effective synergistic antitumor therapy

Malignant tumor has become an urgent threat to global public healthcare.Because of the heterogeneity of tumor,single therapy presents great limitations while synergistic therapy is arousing much attention,which shows desperate need of intelligent carrier for co-delivery.A core-shell dual metaleorganic frameworks(MOFs)system was delicately designed in this study,which not only possessed the unique properties of both materials,but also provided two individual specific functional zones for co-drug delivery.Photosensitizer indocyanine green(ICG)and chemotherapeutic agent doxorubicin(DOX)were stepwisely encapsulated into the nanopores of MIL-88 core and ZIF-8 shell to construct a synergistic photothermal/photodynamic/chemotherapy nanoplatform.Except for efficient drug delivery,the MIL-88 could be functioned as a nanomotor to convert the excessive hydrogen peroxide at tumor microenvironment into adequate oxygen for photodynamic therapy.The DOX release from MIL-88-ICG@ZIF-8-DOX nanoparticles was triggered at tumor acidic microenvironment and further accelerated by near-infrared(NIR)light irradiation.The in vivo antitumor study showed superior synergistic antitumor effect by concentrating the nanoparticles into dissolving microneedles as compared to intravenous and intratumoral injection of nanoparticles,with a significantly higher inhibition rate.It is anticipated that the multi-model synergistic system based on dual-MOFs was promising for further biomedical application.