Dual response Hst1@CBTC hydrogel promoting diabetic wounds healing by improving mitochondrial autophagy and inhibiting ferroptosis via Nrf2/HO-1

(A) Design scheme of Hst1@CBTC based on dynamic borate covalent bonding, below the flowchart, the chemical functional groups of the key reactants involved are annotated; (B) Hst1@CBTC hydrogel regulates cellular homeostasis in oxidatively stressed tissues through activation of the Nrf2/HO-1 pathway, improvement of mitochondrial autophagy, and inhibition of ferroptosis in HaCats; Hst1@CBTC hydrogel promotes regeneration of difficult-to-heal wound tissues through inhibition of ferroptosis in HaCats and reduction of the negative effects of oxidative stress on cells in a mouse model of type II diabetic wounds. [Display omitted] •This study designed a pH/glucose dual-responsive hydrogel system based on boronate ester bonds, effectively enhancing the repair efficiency of oxidative stress diabetic non-healing wounds.•This study specifically designed a wound dressing that can adapt to the moist environment of diabetes, with good adhesion, adaptability, and self-healing properties.•This study reveals the potential pathway by which Hst1 improves mitochondrial autophagy and inhibits ferroptosis under oxidative stress: the Nrf2/HO-1 pathway. Impaired mitochondrial autophagy and ferroptosis in Human Immortalized Epidermal Cells (HaCats), caused by oxidative stress, are significant obstacles to diabetic wound healing. However, research on the mechanistic level of skin repair through the improvement of mitochondrial function and inhibition of iron-induced cell death by natural-based hydrogel materials is still lacking. In this study, we engineered pH and glucose-responsive Hst1@CBTC hydrogels leveraging dynamic borate bonding, exhibiting an impressive peptide release rate of up to 90 ± 4.2 %. In both in vitro and in vivo settings, the administered peptide demonstrated remarkable efficacy in counteracting cellular mitochondrial autophagy dysfunction and iron-induced cellular demise within oxidative stress environments. Consequently, the hydrogel facilitated expedited healing of recalcitrant diabetic wounds, showcasing a commendable wound closure rate of 94.7 ± 5.1 % within a span of 14 days. Of significant note, our findings elucidate the potential of Hst1@CBTC in ameliorating the cellular ferroptotic milieu by activating the Nrf/HO-1 pathway, thereby fostering mitochondrial autophagy restoration. This study proposes a theoretical solution to address mitochondrial dysfunction and ferroptosis in an oxidative stress environment. Additionally, it presents a safe hydrogel mad