Mitophagy-activating nanozyme hydrogel for enhanced diabetic wound healing

Diabetic wound healing remains a formidable clinical challenge. Mitochondrial dysfunction-driven oxidative stress is a central pathological driver of impaired diabetic wound healing, yet targeted interventions for mitochondrial repair and mitophagy modulation are lacking. Herein, we report a mitochondria-targeted selenium-doped carbon dots (Se-CDs) nanozyme hydrogel system (Se-CDs@Gelatin-TA) with potent reactive oxygen species (ROS)-scavenging capacity and PINK1/Parkin-mediated mitophagy-regulating activity for diabetic wound regeneration. The Se-CDs exhibited biocompatibility, broad-spectrum antioxidant activities, specific mitochondrial targeting ability due to selenium doping, and intrinsic blue fluorescence enabled mitochondrial co-localization tracking without external labels. Encapsulation of Se-CDs into a gelatin-tannic acid hydrogel enabled sustained release of the nanozyme. In vitro studies demonstrated that Se-CDs effectively scavenged intracellular and mitochondrial ROS, suppressed high glucose-induced fibroblast apoptosis, and restored mitophagic flux through activation of the PINK1/Parkin pathway an effect abrogated by mitophagy inhibitor 3-MA and siRNA-mediated knockdown of PINK1/Parkin. In vivo, topical application of Se-CDs@Gelatin-TA hydrogel accelerated wound closure, reduced inflammatory infiltration, enhanced collagen deposition, and restored endogenous antioxidant enzyme activity in wound tissues. This work presents a novel nanozyme-based targeted strategy for diabetic wounds, leveraging Se-CDs to modulate mitophagy and redox homeostasis, and provides mechanistic insights into the role of PINK1/Parkin-mediated mitophagy in diabetic wound repair.