Mesoporous Catalytic‐Adsorptive Nanoregulator Orchestrates Biofilm eDNA/LPS Disassembly and TLR9/TLR4 Immune Reprogramming to Resolve Diabetic Foot Infections

ABSTRACT Chronic diabetic foot infections are severely hindered by tough biofilms and a self‐fueling hyperinflammatory microenvironment, primarily orchestrated by the synergistic interplay between extracellular DNA (eDNA) and lipopolysaccharides (LPS) which facilitates the assembly of impenetrable biofilm architectures while inducing cross‐inflammatory activation through the TLR4/9 axis. Conventional therapies often fail to resolve these “dual traps” of structural resistance and immunological interference. Herein, we developed a multifunctional mesoporous nano‐regulator composed of Colistin (CT) and m‐aminophenol formaldehyde (mAPF) framework, hence termed CT/mAPF to implement a “triad‐strategy”: biofilm disruption, bacterial eradication, and debris neutralization. The CT/mAPF nano‐regulator achieves potent bactericidal activity (99.99%) and initiates ROS‐mediated oxidative fragmentation of eDNA to destroy the biofilm scaffold. Crucially, the platform effectively neutralizes LPS and degrades eDNA, leading to the simultaneous silencing of TLR4 and TLR9 signaling pathways. This dual‐targeting approach weakens the eDNA/LPS‐mediated synergistic inflammatory response, and suppresses pro‐inflammatory cytokines ( IL‐6 , IL‐1β , TNF‐α ). In diabetic mouse models, CT/mAPF significantly accelerated bacterial clearance and wound closure through enhanced angiogenesis and collagen maturation. This integrated strategy resolves the cycle of chronic infection and inflammation, offering a robust strategy for Gram‐negative bacteria‐infected diabetic wound management.