Chemodynamic Synergistic Light-driven Therapy For Antibacterial Research Based On Metallo-nanoenzymes

Bacterial infections have become a major threat to global public health.With the emergence of antibiotic resistance,there is an urgent need to develop non-antibiotic dependent pathways and methods for effective antimicrobial resistance.The emergence of novel antimicrobial materials with chemodynamic,photothermal,and photodynamic activities provides new ideas to address drug-resistant bacteria.In the first part of this thesis,we constructed iron phosphate-hydrogel(FePO₄-HG)system with positive charge and macroporous structure based on chemodynamic antimicrobial therapy.FePO₄-HG showed different enzyme-like catalytic activities in chemodynamics,exhibited peroxidase-like(POD)activity in acidic microenvironment of bacterial infection,could catalyze the conversion of trace amounts of H₂O₂ into toxic hydroxyl radicals(·OH),showing superoxide dismutase-peroxidase(SOD-CAT)-like synergistic catalysis in normal tissues under neutral or weakly alkaline conditions,protecting them from damage by exogenous H₂O₂ as well as·OH.In addition,the positive charge and macroporous structure of FePO₄-HG can trap bacteria,enhance the interaction with bacteria,and effectively kill bacteria within the range of·OH destruction.FePO₄-HG showed excellent bactericidal ability against methicillin-resistant Staphylococcus aureus(MRSA)and ampicillin-resistant Escherichia coli(AREC),with antibacterial rates of 98.2%and 96.1%,respectively.Characterization experiments showed that the FePO₄-HG+H₂O₂ system could effectively disrupt the formation of bacterial biofilm and promote the oxidation process of glutathione(GSH),accelerating bacterial death without developing drug resistance,good hemocompatibility and low cytotoxicity.By establishing a mouse wound infection model,it was found that FePO₄-HG+H₂O₂ system could effectively treat MRSA-infected wounds and accelerate wound healing with no inflammation and no tissue adhesion.Therefore,FePO₄-HG as a novel chemodynamic antibacterial material can effectively treat bacterial infections and overcome bacterial drug resistance.In the second part of this thesis,we constructed the ZIF-Mn system based on chemodynamic synergistic photothermal antimicrobial therapy through the coordination of Metal-Organic Frameworks(MOF)with manganese atoms.The ZIF-Mn system exhibits photothermal activity due to high temperature calcination treatment,and the ZIF-Mn system exhibits chemodynamic activity due to doping with manganese,which has a photothermal synergistic chemodynamic antimicrobial ability based on the modulation of near-infrared(808 nm)radiation.In addition to the cell membrane disruption by superheat and further bactericidal by ROS generated by POD-like and oxidase-like(OXD)activity,ZIF-Mn also possesses SOD-like activity to protect normal tissues from ROS.The positive charge of ZIF-Mn allows adsorption of bacteria to kill them within the range of ROS destruction,and its high specific surface area structure ensures more catalytic active sites to produce ROS with high quantum yields.Property experiments showed that the ZIF-Mn system has low cytotoxicity,no drug resistance generation,and good blood compatibility.In vitro antimicrobial studies showed that the ZIF-Mn+H₂O₂ system showed high antibacterial rates of 98.8%and 97.3%against MRSA and AREC,respectively.By establishing a mouse wound infection model,it was found that the ZIF-Mn+H₂O₂ system could effectively treat MRSA-infected wounds with accelerated wound healing,no inflammation and no tissue adhesion.Therefore,ZIF-Mn as a novel chemodynamic synergistic photothermal antimicrobial material can effectively treat microbial infections and overcome drug resistance.In the third part of this thesis,we prepared Zr-MOF based on chemodynamic synergistic photothermal as well as photodynamic antimicrobial therapies and loaded MoS₂ by amidation reaction to obtain nanocomposites UiO-66-NH-CO-MoS₂(UNMS NCs).Under laser irradiation in the near infrared(808 nm),the·OH generated by the POD-like activity based on MoS₂ with photothermal activity,and the ~1O₂ and·OH generated by the photodynamic activity of the UNMS NCs system exhibited synergistic bactericidal effects.The positive charge of the UNMS NCs could trap bacteria,enhance the interaction with them,and kill them effectively within the ROS destruction range.In vitro antibacterial activity experiments showed that UNMS NCs exhibited good antibacterial activity in a wide p H(3-7)range,with antibacterial rates as high as 98.8%and 97.2%for MRSA and AREC,respectively,with no resistance generation and low cytotoxicity.Superheat generated by UNMS NCs under NIR light radiation could accelerate the oxidation process of GSH,further leading to bacterial death.By establishing a mouse wound infection model,it was found that the UNMS NCs+H₂O₂system could effectively treat MRSA-infected wounds and accelerate wound healing with no inflammation and no tissue adhesion.UNMS NCs,as a novel chemodynamic synergistic photothermal and photodynamic antibacterial material,has great potential in treating bacterial infections and overcoming bacterial drug resistance.The above three parts are dedicated to the construction of antimicrobial materials based on chemodynamic synergistic photodynamic therapy,which provide a theoretical basis and research foundation for clinical treatment of bacterial infections and solving drug resistance problems.