A pH‐Responsive, Surface Charge‐Switchable Nanosystem with Enhanced Biofilm Penetration for Synergistic Photodynamic and Antibiotic Therapy of Diabetic Wounds

Abstract Chronic wounds, particularly those associated with diabetes, pose a significant clinical challenge due to their tendency to develop biofilms that resist conventional antibiotic treatments. To address this issue, a novel therapeutic strategy utilizing pH‐responsive nanoparticles loaded with aggregation‐induced emission photosensitizers and natural saturated fatty acids (AIE/LA@HMONs−PyB) for effective biofilm penetration and disruption is proposed. Under physiological conditions, AIE/LA@HMONs−PyB are negatively charged. Upon accumulation at infected sites, however, the pyridine betaine group on the surface of AIE/LA@HMONs−PyB enables rapid protonation and charge reversal in the acidic biofilm microenvironment, thereby enhancing their ability to penetrate the biofilm. Upon light irradiation, these nanoparticles generate reactive oxygen species that effectively disrupt the biofilm structure. This process enables the synergistic action of ciprofloxacin at a lower concentration, achieving an exceptional in vitro antibacterial efficiency of 99.99% against methicillin‐resistant Staphylococcus aureus (S. aureus) biofilms. Furthermore, in an in vivo diabetic wound model, this synergistic therapy accelerates wound healing by reducing inflammation, promoting angiogenesis, and enhancing collagen regeneration. The enhanced penetration strategy significantly improves the therapeutic efficacy of this combined approach, offering great promise for advancing chronic wound healing and enhancing patient outcomes.