Microenvironment‐Responsive Cu‐MOF Nanoplatform Activates Disulfiram for Synergistic Bacterial Killing and Enhanced Infected Wound Healing

Abstract Drug‐resistant bacterial infections pose a significant threat to global health, creating an urgent need for new antimicrobial agents. Reusing approved drugs has gained attention as a strategy to address this issue. In this study, a nano antibacterial platform (DSF@HKUST‐1@Dex) that responds to the infection microenvironment is proposed. This platform releases disulfiram (DSF), binds to copper ions in the mildly acidic conditions of infected areas, converting DSF from nontoxic to toxic in situ, thereby inducing bacterial death and enhancing copper ion absorption. Noncatalytic treatment is also initiated for a synergistic antibacterial effect. Excessive copper ions disrupt bacterial metabolism, inhibit the Tricarboxylic acid (TCA) cycle, reduce ATP levels, and induce cuproptosis‐like death, significantly enhancing antibacterial efficacy. In a bacterial wound infection model, the platform exhibited excellent antibacterial activity, promoting wound healing and reducing inflammation. Proteomic analysis showed that the platform selectively targeted bacterial peptidoglycan, disrupted the bacterial cell wall, impacted energy metabolism, and inhibited bacterial growth. In conclusion, this nanoplatform offers a promising strategy for treating drug‐resistant infections by repurposing old drugs, converting them to toxic forms, and providing a novel antimicrobial approach.