Macrophage metabolic reprogramming by vanadium released from glucose-responsive bio-gel accelerates diabetic wound repair

Dysregulated glucose metabolism in diabetic wound macrophages impairs polarization toward the reparative M2 phenotype, leading to compromised innate immunity, chronic inflammation, and delayed wound healing. However, effective strategies to restore macrophage metabolic function remain limited. Here, inspired by vanadium's potential to modulate glucose metabolism and the immunomodulatory properties of bioactive glasses, we developed vanadium-doped mesoporous bioactive glass nanospheres (V-MBG) to regulate macrophage-mediated inflammation in diabetic wounds. V-MBG reprogrammed the metabolic environment, promoted M2 polarization, suppressed inflammation, and significantly enhanced wound healing in diabetic models. Mechanistically, V-MBG remodeled the glycolysis-dependent energy pathway in LPS-stimulated M1 macrophages by enhancing glucose-driven oxidative phosphorylation (OXPHOS). This metabolic shift was mediated by activation of the INSR-PI3K signaling axis, which increased glucose uptake and rescued tricarboxylic acid (TCA) cycle suppression. Furthermore, V-MBG-induced citrate/acetyl-CoA metabolism contributed to M2 polarization. To achieve responsive and sustained delivery, V-MBG was incorporated into glucose-sensitive GCP hydrogels, which further accelerated wound repair by enhancing M2 macrophage polarization and mitigating inflammation. Our findings demonstrate that V-MBG is a metabolically active nanomaterial capable of reprogramming macrophage energy metabolism to improve diabetic wound regeneration. This work offers new insight into immune-metabolic regulation via material design and establishes a promising vanadium-based strategy for clinical diabetic wound therapy.