Targeting SIRT3 dysfunction with a sprayable honokiol hydrogel for diabetic burn wound repair.

BACKGROUND: Diabetic burn wound healing is impaired by persistent mitochondrial oxidative stress, chronic inflammation, bacterial infection, and defective tissue regeneration. Although honokiol possesses antioxidant and anti-inflammatory properties, its therapeutic potential is limited by poor local retention. Moreover, the therapeutic significance of restoring mitochondrial sirtuin 3 (SIRT3) signaling in diabetic wound repair remains largely unexplored. This study developed a sprayable honokiol-loaded catechol-chitosan hydrogel as a mechanism-guided therapeutic strategy for diabetic burn wounds. METHODS: Two hydrogel formulations with distinct crosslinking densities were engineered using catechol-modified chitosan and oxidized dextran to achieve tunable adhesion and honokiol release profiles. Physicochemical properties, drug release, antioxidant and antimicrobial activities, and cytocompatibility were evaluated. Mechanistic studies were conducted in hyperglycemia-challenged endothelial cells and macrophages, followed by therapeutic assessment in streptozotocin-induced diabetic burn wound models. RESULTS: The hydrogels exhibited rapid in situ gelation, strong tissue adhesion, sustained honokiol release, favorable biocompatibility, antioxidant activity, and antimicrobial protection. Mechanistically, honokiol hydrogel treatment restored hyperglycemia-induced SIRT3 suppression, improved mitochondrial redox homeostasis, enhanced Nrf2 antioxidant signaling, and attenuated NFκB p65/MMP9-mediated inflammatory and matrix-degrading responses. These effects were associated with reduced oxidative stress and bacterial burden, enhanced reparative macrophage polarization, increased angiogenesis and granulation tissue formation, and accelerated wound closure. The sustained-release formulation demonstrated superior therapeutic efficacy. CONCLUSION: This study identifies SIRT3 dysfunction as a therapeutically actionable mechanism in diabetic burn wound healing and demonstrates that sustained local delivery of honokiol effectively restores mitochondrial and inflammatory homeostasis. By simultaneously targeting oxidative stress, inflammation, infection, and impaired regeneration, this sprayable hydrogel platform represents a promising translational pharmacological strategy for diabetic wound management.