A pH‐responsive charge‐reversal liposome with enhanced biofilm penetration for multimodal synergistic therapy of bacterial infections

Abstract Biofilm infections pose a significant clinical challenge largely due to the limited penetration of a variety of antibacterial agents, making traditional antibiotic therapies ineffective. In this study, we develop a pH‐responsive, charge‐reversal liposomal system (TPA‐ICN/LVF@Lipo‐PyB) loaded with the phototherapeutic agent TPA‐ICN and the antibiotic levofloxacin (LVF) for multimodal synergistic therapy of methicillin‐resistant Staphylococcus aureus (MRSA) biofilm infections. The surface‐grafted pyridine betaine group enables charge reversal of TPA‐ICN/LVF@Lipo‐PyB through rapid and efficient protonation to enhance its penetration capability in the acidic microenvironment of biofilms. Upon laser irradiation, the liposomal system exhibits both photodynamic and photothermal properties to inactivate bacteria within the biofilm. Simultaneously, the photothermal effect effectively disassembles the liposome due to the presence of thermosensitive phospholipids to trigger LVF release, ensuring the effective eradication of residual bacteria. Remarkably, the multimodal synergistic therapy demonstrates exceptional in vitro bacterial eradication, achieving a 99.99% reduction in MRSA biofilms. Furthermore, TPA‐ICN/LVF@Lipo‐PyB significantly accelerates the healing of MRSA‐infected wounds by reducing inflammation, promoting angiogenesis, and enhancing collagen regeneration. These outstanding therapeutic results highlight the potential of this approach for the safe and effective clinical management of wound infections.