Smart Nanosilver Strikes Twice: Precision Bacteria Killing Meets Autophagy‐Boosted Healing for Infected Wounds

Abstract Effective management of infected chronic wounds requires innovative strategies that combine precise antibacterial action with microenvironment reprogramming. Here, a pH‐responsive core‐shell nanosilver platform (PST/Ag) is reported that exploits structural disparities between bacterial and mammalian cells to achieve dual therapeutic effects. The PST/Ag selectively adheres to bacterial membranes and rapidly releases Ag ⁺ via pH‐responsive dissolution in the acidic infection niche, achieving multimodal bactericidal effects while mitigating resistance risks. Crucially, PST/Ag minimizes off‐target toxicity through disparity‐driven cellular trafficking: reduced endocytosis in skin cells confines Ag ⁺ release within lysosomal compartments, where Ag ⁺ is dynamically reduced to secondary nanoparticles, ensuring sustained sub‐toxic Ag ⁺ flux. This controlled release triggers a Hormesis effect—low‐dose Ag ⁺ activates protective autophagy, synergizing with polyserotonin shell‐derived metabolites to enhance fibroblast migration, angiogenesis, and extracellular matrix remodeling. In murine‐infected wound and rabbit wound models, PST/Ag outperforms conventional silver nanoparticles by concurrently eradicating bacteria, accelerating re‐epithelialization, and preventing scar formation. This “defense‐regulation” dual modality—precision antibacterial coupled with microenvironment reprogramming—redefines nanosilver‐based wound management paradigms, offering a translatable solution for complex tissue repair.