Abstract Biofilm‐associated infections pose complex challenges that require addressing the multifaceted requirements of biofilm disruption, bacterial killing, and immunomodulation. In this study, microenvironment‐adaptive metallo‐polymeric nanodecoys (MPNs) are synthesized through one‐pot subcomponent coordination in aqueous solution, effectively eradicating bacterial biofilms and modulating immune response. Within the acidic microenvironment of biofilms, the positively charged MPNs demonstrated the ability to interact with and eliminate bacteria while facilitating a Fenton‐like reaction for efficient eradication of bacterial biofilms. As the local microenvironment shifted from a neutral to a basic state during subsequent tissue healing processes, the MPNs adaptively harness the multiple properties to bind pathogen‐associated molecular patterns, scavenge reactive oxygen species, thereby modulating the immune response, alleviating inflammation, and promoting tissue healing. This study presents an efficient strategy for preparing enzyme‐mimicking materials that closely resemble natural metalloenzymes, and the MPNs offer an efficient alternative to current antibiotic treatments for biofilm‐associated infections.

Microenvironment‐Adaptive Metallo‐Polymeric Nanodecoys via Subcomponent Coordination for Bacterial Biofilm Eradication and Immunomodulation