Progress on hydrogel delivery systems targeting metabolism disorders in the treatment of diabetic foot ulcers

Diabetic foot ulcer (DFU) is a severe and difficult-to-heal complication of diabetes in which systemic metabolic dysregulation is translated into local neurovascular injury and dysfunction of wound-healing cells. This narrative review examines the relationships among glucose, lipid, and amino acid/protein metabolism disorders, the dysfunction of macrophages, fibroblasts, and endothelial cells, and hydrogel-based therapeutic strategies. Persistent hyperglycemia disrupts the tricarboxylic acid cycle, activates the polyol and advanced glycation pathways, and induces pseudohypoxia, oxidative stress, and inflammatory metabolic reprogramming. Dyslipidemia promotes lipid peroxidation, mitochondrial injury, impaired fatty acid oxidation, and ferroptosis, whereas amino acid and protein metabolic abnormalities disturb insulin signaling, arginine metabolism, collagen-precursor availability, and extracellular matrix turnover. These metabolic alterations sustain pro-inflammatory macrophage programs, impair fibroblast migration and matrix production, and compromise endothelial angiogenesis. We further critically compare hydrogel systems that provide glucose-responsive insulin release, catalytic glucose consumption and oxygen generation, lipid-peroxide scavenging, immunometabolic regulation, and support for extracellular matrix remodeling and vascular regeneration. Metabolism-targeted hydrogels provide a promising bridge between mechanistic metabolic intervention and local wound management; however, most available evidence remains preclinical. Future translation requires direct validation of metabolic regulation, standardized manufacturing, long-term biosafety assessment, and evaluation in clinically relevant DFU models.