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 (H2Se) inside the biofilm. H2Se can competitively inhibit bacterial metabolic processes and disrupt biofilm metabolic homeostasis by cascade amplification effects. Furthermore, H2Se 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. Fabrication of USPM for treating BAIs via bacterial metabolic interference and autophagy-promoted immunity is presented. USPM releases selenite into the biofilm under acidity. Selenite reacts with reducing substances to yield H2Se, which exerts a disruptive effect on bacterial metabolic homeostasis. Furthermore, H2Se sensitizes photothermia within the biofilm. USPM stimulates M1 polarization and autophagic activation of macrophages and promotes the release of pro-inflammatory cytokines.image