Metabolic targeting by a small extracellular vesicle-based cellulose-GelMA hydrogel restores neurovascular regeneration in diabetic nerve injury.

Diabetic peripheral nerve injury (PNI-DM) causes severe sensory and motor dysfunction, yet the metabolic mechanisms impairing neurovascular repair remain unclear. Using histological and molecular analysis of human nerve and muscle tissues, we observed pronounced methylglyoxal-derived hydroimidazolone-1 (MG-H1)/methylglyoxal (MGO)-associated glycation stress, reduced expression of its detoxifying enzyme glyoxalase-1 (GLO-1), enhanced pyroptosis, disrupted neurovascular integrity, and distal muscle atrophy in PNI-DM patients compared with non-diabetic patients. These findings indicate a lesion-site association between PNI-DM and GLO-1/MGO metabolic imbalance. To develop a disease-oriented local intervention, we engineered adipose-derived stem cells to generate GLO-1-enriched small extracellular vesicles (G-sEVs) and incorporated them into a bacterial nanocellulose (BNC)-reinforced gelatin methacryloyl (GelMA) patch. The patch showed a stable nanofibrous architecture, excellent conformability, biocompatibility, and controlled release characteristics. In vitro and in vivo, G-sEV@BNC/GelMA mitigated MGO/MG-H1-associated carbonyl stress, reduced inflammation and pyroptosis, promoted neurovascular regeneration, and preserved neuromuscular integrity in diabetic rats. These findings support G-sEV@BNC/GelMA as a disease-context-specific perineural delivery strategy that couples MGO-related metabolic regulation with multicellular neurovascular repair in PNI-DM.