Engineering the "pro-healing niche": Hydrogel-driven immunometabolic reprogramming for diabetic foot ulcers

The refractory nature of diabetic foot ulcers (DFUs) stems from persistent immunometabolic dysregulation. Although a myriad of reviews have extensively categorized hydrogel dressings, most remain confined to passive material classifications and isolated phenotypic targets. To bridge this gap, this review delineates an integrated "hydrogel engineering-immunometabolic regulation-tissue regeneration" framework. We redefine hydrogels as "intelligent bioreactors" that actively construct a "pro-healing niche," dissecting the underlying mechano-metabolic crosstalk (e.g., VASP/HIF-1α and mTOR signaling). Furthermore, we elucidate the interventional mechanisms of diverse hydrogel strategies-including externally triggered, dynamically responsive, nanocomposite, and mechanically programmed platforms-across four critical pathways: glycolysis, lipid metabolism, amino acid metabolism, and oxidative stress. Crucially, by extracting raw healing data to calculate relative improvement rates and daily relative improvement rates, we quantitatively benchmark the discrepancies in healing kinetics among distinct strategies. Building upon this, we propose scenario-oriented clinical selection pathways: prioritizing near-infrared (NIR)-responsive or photocatalytic hydrogels for severely hypoxic DFUs, and recommending ultrasound-driven sequential "sterilization-then-antioxidation" hydrogels for neuropathic ulcers complicated by multidrug-resistant bacterial infections. Additionally, via precise metabolic reprogramming, these tailored hydrogels actively drive macrophage repolarization, restore T cell subset balance, and enhance dendritic cell efferocytosis. Finally, by integrating biomarker-driven standardized evaluations, GMP-compliant scale-up engineering, and AI-assisted modular production platforms, this review outlines a step-by-step clinical translational roadmap. This strategic roadmap aims to bridge the gap between laboratory prototypes and personalized precision medicine, ultimately providing a comprehensive blueprint for next-generation metabolic therapeutics in chronic wound management.