A multifunctional hydrogel promotes diabetic wound healing by remodeling iron balance and energy metabolism

Patients with diabetes often exhibit delayed wound healing, which is characterized by the endothelial cells dysfunction and excessive accumulation of free tissue iron. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has been implicated in the pathogenesis of diabetic complications, though its role in angiogenesis under hyperglycemia remains unknown. In this study, we revealed a distinct ferroptosis-associated metabolic phenotype in endothelial cells derived from unhealed diabetic foot ulcers (DFUs) and under high glucose exposure in vitro, marked by elevated intracellular reactive oxygen species (ROS) levels and impaired mitochondrial function. Herein, a ferroptosis-modulating hydrogel (TC@BS) was designed to pioneer a 'dual-sink' strategy that concurrently neutralizes tissue iron pool via catechol-iron coordination and augments the angiogenic capacity of endothelial cells through preserving mitochondrial function. In specific, TC@BS exerted multifaceted ferroptosis-inhibitory effects by chelating extracellular iron, attenuating lipid oxidative stress, and maintaining mitochondrial homeostasis in endothelial cells. Utilizing a STZ-induced diabetic mouse model we further demonstrated that TC@BS application significantly accelerated wound healing compared to diabetic wounds, as evidenced by reduced wound area, enhanced neovascularization, and decreased iron accumulation. Mechanistically, PI3K/Akt signaling played a key role to suppress NOX4-dependent lipid peroxidation and ferroptosis following TC@BS administration in iron-rich microenvironments. Overall, our work underscores the significance of ferroptosis as a mechanistic driver of diabetic wounds and provides a conceptual framework for ferroptosis-centered regenerative intervention.