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.