Due to the emergence of drug resistance in bacteria and biofilm protection, achieving a satisfactory therapeutic effect for bacteria‐infected open wounds with conventional measures is problematic. Here, a photothermal cascade nano‐reactor (CPNC@GOx‐Fe2+) is constructed through a supramolecular strategy through hydrogen bonding and coordination interactions between chitosan‐modified palladium nano‐cube (CPNC), glucose oxidase (GOx), and ferrous iron (Fe2+). CPNC@GOx‐Fe2+ exhibits excellent photothermal effects and powers the GOx‐assisted cascade reaction to generate hydroxyl radicals, enabling photothermal and chemodynamic combination therapy against bacteria and biofilms. Further proteomics, metabolomics, and all‐atom simulation results indicate that the damage of the hydroxyl radical to the function and structure of the cell membrane and the thermal effect enhance the fluidity and inhomogeneity of the bacterial cell membrane, resulting in the synergistic antibacterial effect. In the biofilm‐associated tooth extraction wound model, the hydroxyl radical generated from the cascade reaction process can initiate the radical polymerization process to form a hydrogel in situ for wound protection. In vivo experiments confirm that synergistic antibacterial and wound protection can accelerate the healing of infected tooth‐extraction wounds without affecting the oral commensal microbiota. This study provides a way to propose a multifunctional supramolecular system for the treatment of open wound infection.

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