Temperature-responsive hydrogel delivery of antimicrobial peptide engineered watermelon-derived extracellular...

Infected wounds present major clinical challenges due to excessive bacterial colonization, sustained inflammation, and impaired tissue repair. To address these barriers, we developed a temperature-responsive hydrogel delivery system incorporating watermelon-derived extracellular vesicles (wEV), antimicrobial peptide-engineered for the topical treatment of infected wounds. wEVs contained terpenoids, flavonoids, alkaloids, and proteins with intrinsic anti-inflammatory and pro-regenerative activity. To enhance stability and antibacterial potency, antimicrobial peptides (AMP) were conjugated to wEVs via mussel derivatives, producing wEV-AMP. These were embedded in a temperature-responsive Pluronic F127/chitosan hydrogel that gels at 37 °C for wound coverage and controlled release. In vitro, PF127/CS+wEV-AMP inhibited > 95 % of Staphylococcus aureus and Escherichia coli, suppressed biofilms, reduced inflammatory cytokines, and enhanced fibroblast migration. In infected rat wounds, healing rate reached ∼60 % by day 5 and nearly complete closure by day 14, with greater collagen deposition and M2 macrophage polarization. This multifunctional hydrogel integrates antimicrobial, immunomodulatory, and regenerative effects, offering strong potential for infectious wound treatment.