Biofilm microenvironment-activated multimodal therapy nanoplatform for effective anti-bacterial treatment and wound healing.

Antimicrobial drug development faces challenges from bacterial resistance, biofilms, and excessive inflammation. Here, we design an intelligent nanoplatform utilizing mesoporous silica nanoparticles doped with copper ions for loading copper sulfide (DM/Cu 2+ -CuS). The mesoporous silica doped with tetrasulfide bonds responds to the biofilm microenvironment (BME), releasing Cu 2+ ions, CuS along with hydrogen sulfide (H 2 S) gas. The release of hydrogen sulfide within 72 h reached 793.5 µM, significantly higher than that observed with conventional small molecule donors. H 2 S induces macrophages polarization towards the M2 phenotype, reducing inflammation and synergistically accelerating endothelial cell proliferation and migration with Cu 2+ ions. In addition, H 2 S disrupts extracellular DNA within biofilms, synergistically photothermal enhanced peroxidase-like activity of CuS to effectively eradicate biofilms. Remarkably, DM-mediated consumption of endogenous glutathione enhances the anti-biofilm activity of H 2 S and improves oxygen species (ROS) destruction efficiency. The combination of photothermal therapy (PTT), chemodynamic therapy (CDT), and gas treatment achieves sterilization rates of 99.3 % and 99.6 % against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), respectively, in vitro under 808 nm laser irradiation. Additionally, in vivo experiments demonstrate a significant biosafety and antibacterial potential. In summary, the H 2 S donor developed in this study exhibits enhanced biocompatibility and controlled release properties. By integrating BME-responsive gas therapy with antibacterial ions, PTT and CDT, a synergistic multimodal strategy is proposed to offer new therapeutic approaches for wound healing. STATEMENT OF SIGNIFICANCE: The advanced DMOS/Cu 2+ -CuS (DMCC) multimodal therapeutic nanoplatform has been developed for the treatment of drug-resistant bacterial wound infections and has exhibited enhanced therapeutic efficacy through the synergistic effects of photothermal therapy, chemodynamic therapy, Cu 2+ ions, and H 2 S. The DMCC exhibited exceptional biocompatibility and could release CuS, Cu 2+ , and H 2 S in response to elevated concentrations of glutathione within the biofilm microenvironment. H 2 S effectively disrupted the biofilm structure. Meanwhile, peroxidase activity of CuS combined with GSH-mediated reduction of Cu 2+ to Cu + generated abundant hydroxyl radicals under acidic conditions, leading to efficient eradication of pathogenic bacteria. Furthermore, both H 2 S and Cu 2+ could modulate M2 macrophages polarization and regulate immune microenvironment dynamics. These strategies collectively provided a novel approach for developing antibacterial nanomedical platforms.