Polysaccharide-Based Composite Hydrogel Loaded with ApiRegenin, a Platelet-Rich Plasma from Deer, Enhances Diabetic Wound Healing in db / db Mice

Chronic diabetic wounds are characterized by persistent inflammation, oxidative stress, and impaired neovascularization. To address this pathological problem, we developed a bioactive composite hydrogel by encapsulating the platelet-rich plasma derived from deer blood, named ApiRegenin; the hydrogel network was formed by a photoactivated cross-linking of gelatin methacryloyl (GelMA) and hydrophilic carboxymethyl chitosan (CMCS). The optimized formulation of 5% GelMA, 2% CMCS, and 20% ApiRegenin (Api–Gel) exhibited an interconnected porous microstructure, shear-thinning behavior, and rapid self-healing, and, more importantly, an optimized regenerative activity in skin wounds. In diabetic (db/db) mice, Api–Gel significantly accelerated wound closure, achieving complete re-epithelialization and appendage regeneration by day 14. Histological and immunofluorescence analyses revealed that Api–Gel promoted CD31/VEGF-mediated neovascularization, resolved local hypoxia (reducing HIF-1α), and drove macrophage polarization from the M1 to M2 phenotype. Transcriptomics identified that Api–Gel upregulated epidermal development and matrix deposition while suppressing inflammatory genes. Mechanistically, Api–Gel activated the endogenous Nrf2/HO-1 signaling pathway, initiating antioxidant defenses and scavenging intracellular reactive oxygen species under inflammatory stress. This multitargeted platform coordinates immunomodulation, angiogenesis, and antioxidant defense, offering promising translational potential for diabetic wound therapy.