Abstract

Diabetic wound healing is often significantly impaired due to impaired re-epithelialization and microvascular dysfunction, with the pathological mechanism mainly involving defects in keratinocyte migration ability and a “reactive oxygen species (ROS)-inflammation” vicious cycle induced by lipid overload, which further leads to endothelial cell apoptosis. To synergistically intervene in these interrelated pathological processes, this study developed a multifunctional self-contracting hydrogel system, which integrates fibroblast growth factor 21 (FGF21) to correct lipid metabolism abnormalities and restore energy metabolism homeostasis; molybdenum nanodots (MNDs) as efficient ROS scavengers to alleviate oxidative stress; and poly(N-isopropylacrylamide)-alginate (PNI) hydrogel as a dynamically contractile biomaterial that provides physiological mechanical traction to promote cell migration. In a diabetic mouse wound model, this composite hydrogel significantly accelerated wound closure. Mechanistic studies revealed that the system achieved therapeutic effects through a triple synergistic mechanism: (1) FGF21 improved metabolic imbalance and inhibited the occurrence of oxidative stress at the source; (2) MNDs effectively removed excessive ROS, blocked the “ROS-inflammation” positive feedback loop, reduced vascular damage, and protected the structure of new blood vessels; (3) the self-contracting PNI hydrogel, through continuous tissue traction effects, actively enhanced the directional migration of keratinocytes and epithelial layer reconstruction, thereby promoting re-epithelialization. This study verified a comprehensive treatment strategy integrating metabolic regulation, antioxidant defense, and biomechanical stimulation, capable of simultaneously targeting multiple key obstacles in diabetic wound repair. The research results fully demonstrated the potential application value of multi-target synergistic intervention in overcoming the stagnation of chronic wound hea