pH triggered hierarchical responsive release of RVT to promote diabetic wound healing

Diabetic wounds remain difficult to treat due to persistent inflammation, oxidative stress, impaired angiogenesis, and bacterial infections. To address these challenges, a pH-responsive boronate crosslinked chitosan based hydrogel incorporating resveratrol loaded hydroxypropyl-β-cyclodextrin nanoparticles (PPCH Gel@RVT NPs) was developed, offering antioxidant, anti-inflammatory, and antibacterial properties. The pH-triggered design enables hierarchical release of resveratrol under acidic wound microenvironment, which is typical of chronic diabetic wounds, thereby enhancing local drug bioavailability and therapeutic precision. In vitro , PPCH Gel@RVT NPs effectively promoted macrophage repolarization from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype, thereby attenuating inflammatory signaling. In a full-thickness diabetic wound model, PPCH Gel@RVT NPs markedly accelerated wound closure, achieving a 98.9 % healing rate by day 14 and supporting robust tissue regeneration, including the formation of new epithelial layers, hair follicles, and blood vessels. Together, these findings indicate that PPCH Gel@RVT NPs integrate stimuli-responsive drug delivery with immunomodulation and microenvironment regulation to enhance diabetic wound healing, representing a promising strategy for the treatment of chronic diabetic wounds. • Enhances diabetic wound healing by modulating macrophage polarization from M1 to M2 phenotype, reducing inflammation, and promoting tissue regeneration. • Demonstrates strong antibacterial, antioxidant, and anti-inflammatory activities, while accelerating wound closure and angiogenesis in diabetic wound models. • Exhibits excellent in vivo safety with no significant adverse effects on major organs, ensuring suitability for clinical application.