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

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 made from natural biosafety materials.