Injectable Thermosensitive Hydrogel Synergizes Antibacterial Action with Microenvironment Remodeling in Infected Diabetic Wounds

Abstract

Chronic wounds represent substantial clinical challenges due to their intricate pathophysiology, characterized by persistent infection, sustained inflammation, and compromised tissue regeneration. To overcome these obstacles, we developed an injectable thermosensitive hydrogel system (MR-NPs-Gels), incorporating engineered PLGA nanoparticles (MR-NPs) for the co-delivery of mupirocin, a first-line antibacterial agent, and l-arginine, a nitric oxide (NO) precursor. The MR-NPs-Gels exhibited favorable injectability, tissue adaptability, and ideal rheological properties. MR-NPs penetrated deep into tissues to exert antibacterial effects, while l-arginine released from them generated NO to exert anti-inflammatory and pro-angiogenic effects. In diabetic wound models, MR-NPs-Gels achieved a 77.39 ± 1.19% wound closure rate and more than 80% reduction in bacterial colony counts by day 9. Compared with commercial mupirocin ointment, this hydrogel significantly downregulated pro-inflammatory cytokines IL-6 and TNF-α, while upregulating angiogenic markers VEGF and CD31. Collectively, the co-delivery of mupirocin and l-arginine within MR-NPs-Gels enhances bacterial clearance and remodels the wound microenvironment synergistically, offering a promising topical therapeutic strategy for infected chronic wounds.