Centipede Protein-Laden Natural Nanocapsule Hybrid Hydrogel Mediates Sustained Bioactive Release for Synergistic Regeneration of Diabetic Foot Ulcers

Background: Diabetic foot ulcers (DFUs) are chronic wounds characterized by persistent inflammation, oxidative stress, impaired angiogenesis, and defective extracellular matrix remodeling. Current therapeutic approaches remain insufficient for refractory diabetic wounds due to limited drug retention and inadequate regulation of the wound microenvironment. This study aimed to develop a centipede-derived protein fraction-loaded nanocapsule hybrid hydrogel for sustained bioactive delivery and diabetic wound repair. Methods: A bioactive protein fraction was isolated from processed medicinal centipede material and screened using cellular compatibility assays. The selected tropomyosin-containing protein fraction was incorporated into nanocapsules and subsequently integrated into a gallic acid-modified polyacrylamide hydrogel matrix. The physicochemical properties, antioxidant activity, rheological behavior, and protein release characteristics of the nanocapsule-hydrogel system were systematically evaluated. A streptozotocin-induced diabetic rat wound model was established to assess therapeutic efficacy through wound closure analysis, histological staining, and immunohistochemical evaluation. Results: The prepared nanocapsules exhibited a spherical morphology, nanoscale size distribution, and sustained protein delivery capability. The PAM-GA hydrogel demonstrated antioxidant activity, injectability, shear-thinning behavior, self-healing ability, and enhanced retention of protein release. In vivo experiments showed that the PT@NC@PAM-GA hydrogel significantly accelerated wound closure and promoted tissue regeneration, accompanied by enhanced angiogenesis, collagen deposition, and reduced inflammatory responses. Conclusions: The centipede-derived protein fraction-loaded nanocapsule hybrid hydrogel effectively integrates bioactive protein delivery with a multifunctional hydrogel matrix, providing a potential strategy for sustained treatment of diabetic foot ulcers.