Sequential Physical Disruption and Metabolic Interference via a Photothermal Nanozyme Integrated Platform for Eradicating Biofilm Associated Infections and Promoting Tissue Regeneration

ABSTRACT Biofilm‐associated infections (BAIs) present a formidable clinical challenge due to the physical protection of extracellular polymeric substances (EPS) and the immunosuppressive microenvironment caused by excessive reactive oxygen species (ROS). Herein, a sequential “physical disruption‐metabolic interference‐immune repair” strategy is proposed using a platinum‐modified gallium‐doped Prussian blue nanoplatform (Pt@GaPB). It is verified that the robust photothermal effect of Pt@GaPB physically dismantles the EPS barrier, then the subsequently released gallium ions competitively disrupt bacterial iron homeostasis and metabolism, inhibiting DNA synthesis to precisely eradicate escaping planktonic MRSA, as confirmed by multi‐omics. Specifically, the platform's enzyme‐mimicking antioxidant activity scavenges ROS to remodel the macrophage niche, reactivating intracellular bactericidal functions for dual extracellular‐intracellular sterilization. In vivo studies confirm that this sequential strategy not only eradicates recalcitrant biofilms, but also accelerates skin and bone tissue regeneration. This work provides a potent, multimodal solution for overcoming the therapeutic hurdles of chronic BAIs.