Biofilm Microenvironment‐Responsive Self‐Assembly Nanoreactors for All‐Stage Biofilm Associated Infection through Bacterial Cuproptosis‐like Death and Macrophage Re‐Rousing

Abstract Bacterial biofilm‐associated infections (BAIs) are the leading cause of prosthetic implant failure. The dense biofilm structure prevents antibiotic penetration, while the highly acidic and H2O2‐rich biofilm microenvironment (BME) dampens the immunological response of antimicrobial macrophages. Conventional treatments that fail to consistently suppress escaping planktonic bacteria from biofilm result in refractory recolonization, allowing BAIs to persist. Herein, a BME‐responsive copper‐doped polyoxometalate clusters (Cu‐POM) combination with mild photothermal therapy (PTT) and macrophage immune re‐rousing for BAI eradication at all stages is proposed. The self‐assembly of Cu‐POM in BME converts endogenous H2O2 to toxic ·OH through chemodynamic therapy (CDT) and generates a mild PTT effect to induce bacterial metabolic exuberance, resulting in loosening the membrane structure of the bacteria, enhancing copper transporter activity and increasing intracellular Cu‐POM flux. Metabolomics reveals that intracellular Cu‐POM overload restricts the TCA cycle and peroxide accumulation, promoting bacterial cuproptosis‐like death. CDT re‐rousing macrophages scavenge planktonic bacteria escaping biofilm disintegration through enhanced chemotaxis and phagocytosis. Overall, BME‐responsive Cu‐POM promotes bacterial cuproptosis‐like death via metabolic interference, while also re‐rousing macrophage immune response for further planktonic bacteria elimination, resulting in all‐stage BAI clearance and providing a new reference for future clinical application.