Biomimetic Metal–Organic Framework Combats Biofilm-Associated Infections via Hyperthermia-Enhanced Bacterial Metabolic Interference and Autophagy-Promoted Adaptive Immunity

Robust bacterial metabolism and the immunosuppression on peripheral immune cells cause biofilm-associated infections (BAIs) extremely refractory to be eradicated via antibiotics alone. Herein, hierarchical mesoporous UiO-66 metal–organic framework is decorated with selenite, polypyrrole, and macrophage membrane (MM) to develop a biomimetic nanosphere (USPM). Following the recruitment of USPM to the biofilm microenvironment (BME) via the pathogen-targeting ability derived from MM. The BME-responsive USPM can precisely release selenite to penetrate the loosened biofilm in synergy with near-infrared-induced mild photothermal therapy (mPTT). Selenite can quickly react with reducing substances to generate hydrogen selenide (H 2 Se) inside the biofilm. H 2 Se can competitively inhibit bacterial metabolic processes and disrupt biofilm metabolic homeostasis by cascade amplification effects. Furthermore, H 2 Se inside the biofilm further sensitizes photothermia to exert a precise local photothermal effect. Outside the biofilm, USPM can simultaneously promote the phagocytosis and autophagy of macrophages to kill and decompose the phagocytosed bacteria. Finally, the well-decomposed bacterial antigens in macrophages can be presented to antigen-presenting cells to arouse adaptive immune responses and enhance anti-biofilm effectiveness further. Such powerful mPTT-enhanced bacterial metabolic disruption and macrophagic autophagy-promoted adaptive immune activation suggest an alternative therapeutic strategy to cure refractory BAIs.