Polysaccharide hydrogel loaded with dual-drug liposomes for accelerating diabetic wound healing through mitochondrial protection and anti-inflammatory activity.

Mitochondrial dysfunction induced by hyperglycemia and excess reactive oxygen species leads to severe chronic inflammation, vascular impairment, and tissue necrosis, which severely impedes diabetic wound healing. Hydrogel dressings with oxidative stress-relieving and immunomodulatory properties are promising for diabetic wound management. However, effective therapeutic strategies that can simultaneously target salvage or compensation of mitochondrial function and the rapid and comprehensive management of reactive oxygen species are lacking. Herein, we develop a dynamic Schiff-base crosslinked polysaccharide hydrogel dressing containing dual-drug liposomes with anti-oxidant and anti-inflammatory characteristics that rapidly and sustainably modulates the oxidative stress microenvironment, protects mitochondria, and accelerates diabetic wound healing. The hydrogel consists of oxidized sodium alginate and carboxymethyl chitosan via Schiff-base and mixes with liposomal nanoparticles loaded with dual drugs of curcumin and tempol in the polymer network. The results reveal that the hydrogel possesses broad-spectrum antioxidant activity and ameliorates mitochondrial dysfunction. Meanwhile, the hydrogel-based dressing excels in modulating the inflammatory microenvironment and antimicrobial activity. Furthermore, epithelialization, collagen deposition and angiogenesis at the wound site are enhanced, resulting in rapid wound healing featuring new hair follicles. In conclusion, the liposome-hydrogel composite drug delivery system can effectively control drug release and improve mitochondrial dysfunction, which holds promising application and translation prospects in clinical diabetic wound therapy.