Synergistic promotion of diabetic wound healing by glucose-responsive functional chitosan-based composite nanohydrogels.

The complex pathological microenvironment, characterized by hyperglycemia, chronic inflammation, and infection, significantly impedes diabetic wound healing. Multi-strategy collaboration is expected to improve the complex pathological microenvironment and accelerate diabetic wound healing. This work developed a dynamic borate bond-crosslinked chitosan/polyvinyl alcohol nanohydrogel loaded with glucose oxidase (GOx) and ZnS/Arg@MOF-818 nanoparticles for synergistic therapy via glucose depletion, photothermy, nitric oxide (NO), and hydrogen sulfide (H₂S)-mediated gas therapy. GOx enables glucose depletion, lowering local pH and triggering the on-demand release of ZnS/Arg@MOF-818 nanoparticles, which exhibited a photothermal conversion efficiency of 55 % and outstanding photothermal stability in vitro. The composite nanohydrogel Gel/ZnS/Arg@MOF-818 enabled sustained and stable release of NO/H2S with glucose existent. The synergistic effects of glucose depletion, photothermy, and controlled NO/H₂S release effectively disrupted biofilms, eradicated multidrug-resistant pathogens, reduced inflammation, and promoted angiogenesis. The composite nanohydrogel exhibited 100 % antibacterial efficacy against drug-resistant strains of Staphylococcus aureus, Escherichia coli, and Acinetobacter baumannii in vitro. In vivo, it significantly accelerated diabetic wound healing 98 % within 9 days, accompanied by CD31/VEGF-driven neovascularization, balanced cytokine expression, and organized collagen deposition, without significant systemic toxicity. Therefore, chitosan-based hydrogels crosslinked via borate ester bonds in this study exhibit considerable potential for future clinical applications in the management of chronic wounds.