Active-Oxygen-Species-Modulated Nanocatalytic Therapy Of Bacterial Infection And Tumor

Cancer and bacterial infections are currently the serious diseases threatening human lives.The most recent concept of nanocatalytic medicine,by modulating the reactive oxygen species（ROS）production and other chemical reactions under the catalysis of nanomaterials,achieves efficient and specific treatment of diseases.However,both cancer cells and bacteria possess complete antioxidant systems to resist external oxidative stress,so as to maintain the redox homeostasis.When nanodrugs produce ROS to attack the target receptor,tumor cells and bacteria could respond to increase antioxidant levels to scavenge excess ROS,seriously deteriorating the ROS killing effect in the nanocatalytic bacterial infection and tumor therapeutics.Hence,enhancing the ROS generation by nanomaterial itself or therapeutic microenvironment will be beneficial in elevating the ROS-based therapeutic efficacy,which is of great research significance for the development of effective nanocatalytic ROS treatment.By focusing on the ROS modulation required by the microenvironment of disease lesions,we have constructed three types of ROS-enhancing functional nanomedicine to achieve effective antibacterial and anti-tumor treatments.The related research results are as follows:（1）Self-catalytic ferrous regeneration strategies for the highly effective bacterial infection treatment.Fenton reaction modulation is the key of ROS-based therapy,in which,however,Fe³⁺turning into Fe²⁺is the rate-limiting step severely affecting the ROS-induced antibacterial application.Hence,Fe Se₂nanosheets are constructed to maintain the Fe²⁺regeneration during Fenton reaction for highly efficient ROS production,further promoting bacteria killing.When Fe²⁺reacts with H₂O₂producing Fe³⁺and·OH,Se^2-is able to reduce Fe³⁺back to Fe²⁺,thereby sustaining the effective Fenton reaction.In addition,Se species can combine with H⁺to form H₂Se,which further reacts with O₂producing O₂^·-.Thus the self-catalysis-produced Fe²⁺/O₂^·-and Fenton-generated·OH of Fe Se₂NSs will cooperatively break the oxidative threshold of bacteria,resulting in irreversible bacterial death with membrane destroy,lipid peroxidation and glutathione（GSH）depletions.The antibacterial potential of Fe Se₂accelerates bacteria-infected wound healing process.The oxidative stress modulated by Fe²⁺regeneration provides an accelerated while sustainable ROS enhancement strategy for broad-spectrum nonantibiotic bacterial disinfection.（2）GSH consumption-synergized ROS enhancement for ferroptosis-like tumor therapy.The highly expressed antioxidant GSH in cancer cells severely inhibits the ROS production.Based on this,we constructed cobalt molybdate-phosphomolybdate composite nanosheets（CPMNSs）to enhance ROS production via GSH consumption.Mo⁶⁺in CPMNSs reacts with GSH to effectively deplete GSH,and meanwhile,Mo⁵⁺ion generated by Mo⁶⁺reduction in polyoxometalate structure catalyzes H₂O₂decomposition to ¹O₂via Russell mechanism.In addition,the redox reaction between Mo⁶⁺and GSH triggers CPMNSs degradation and accelerates Co ion releasing,intensifying the·OH production by a Fenton-like reaction.GSH depletion not only deactivates GPX4,but also promotes ¹O₂/·OH generation,accumulating lipid peroxide.Both cells and tumors results demonstrate the potent cancer ferroptosis therapy by CPMNSs.Such a ferroptosis-like design in nanocatalytic medicine broads the research methods in cancer therapeutic regimen.（3）GSH regeneration inhibition-synergized ROS production for ferroptotic tumor therapy.When GSH is consumed,glutathione reductase will catalyze the oxidized GSSG accept the electrons from nicotinamide adenine dinucleotide phosphate（NADPH）to convert back to GSH,restoring the antioxidant capacity.Herein,a Pt-MIL-101（Fe）-based nanocatalytic medicine is proposed to catalyze NADPH oxidation and the following cascade reactions to produce·OH and prevent GSH regeneration,thus promoting the ferroptotic death of cancer cells.In the cascade reaction process,Pt-MIL-101 catalyzes the O₂^·-generation from O₂by mimicking NADPH oxidase（NOX）to accept electron from NADPH.Then,Pt-MIL-101 further catalyzes O₂^·-disproportionation to H₂O₂by mimicking superoxide dismutase.The generated H₂O₂acts as reaction substrate reacts with Fe³⁺/Fe²⁺in MIL-101 structure center producing toxic·OH.The NADPH depletion by the NOX mimic largely prevents the GSH regeneration and de-activates GPX4,inhibiting lipid peroxide reduction.And cascade reaction-promoted·OH/O₂^·-generation accelerates lipid peroxide production.The developed cascade NADPH-depleted strategy double-guarantees lipid peroxide accumulation,facilitating tumor ferroptosis occurrence.