ROS-responsive exosome–hydrogel dressing for synergistic antimicrobial and immunomodulatory therapy of infected diabetic wounds

IntroductionChronic diabetic wounds are frequently colonized by multidrug-resistant bacteria and are often trapped in persistent inflammation. However, few wound dressings can simultaneously eradicate infection and remodel the immune microenvironment to promote tissue repair.MethodsHere, we developed a reactive-oxygen-species (ROS)-responsive exosome-laden hydrogel that integrates on-demand antibacterial peptide release with immunoregulatory therapy. A ROS-cleavable antibacterial peptide (RA) was conjugated onto macrophage-derived exosomes via strain-promoted azide–alkyne cycloaddition to generate RAEXO. The physicochemical properties, cellular uptake, macrophage polarization, ROS-triggered antibacterial activity, local retention, therapeutic efficacy and biosafety of the RAEXO-loaded calcium alginate hydrogel (CaAGel@RAEXO) were systematically evaluated.ResultsRAEXO retained the morphology, size distribution and marker expression of native exosomes and were efficiently internalized by macrophages. RAEXO promoted Arg-1/IL-10–associated M2 polarization while suppressing iNOS, IL-1β and TNF-α expression, and exhibited potent bactericidal activity under ROS stimulation. Encapsulation of RAEXO into calcium alginate hydrogel yielded an injectable dressing with enhanced local retention and gradual peptide release in ROS-rich wound microenvironments. In a full-thickness infected diabetic wound model, CaAGel@RAEXO significantly reduced bacterial burden, accelerated wound closure, shortened healing time and restored well-organized epidermal and collagen structures, without obvious systemic toxicity.DiscussionThis ROS-responsive exosome–hydrogel hybrid provides a programmable therapeutic platform for the synergistic antimicrobial and immunomodulatory treatment of infected chronic diabetic wounds.