Sustained-Release GelMA-Quercetin Hydrogel Accelerates Diabetic Foot Ulcer Healing via Foxo3-Mediated Macrophage Autophagy and M2 Polarization

Abstract

Background: Diabetic foot ulcers (DFUs) represent a prevalent complication of diabetes mellitus, featuring elevated incidence, high amputation risk, and heavy economic medical burdens. Current clinical treatments for DFUs primarily focus on comprehensive care with limited efficacy. Quercetin, a flavonoid compound with antioxidant properties, has shown potential therapeutic effects in inflammatory-related diseases. Objective: investigate the role of quercetin in activating Foxo3-induced macrophage autophagy and promoting M2 polarization in DFUs, and to evaluate the therapeutic efficacy of a quercetin co-crosslinked hydrogel for sustained drug delivery. Methods: Animal models of DFUs were established to validate quercetin’s ability to accelerate epithelialization and angiogenesis. RNA-seq screening revealed enhanced macrophage autophagy and upregulated Foxo3 expression under quercetin treatment. To optimize clinical applicability, a GelMA-Quercetin co-cross-linked hydrogel was developed for localized and sustained drug release. The in vivo therapeutic efficacy was evaluated by measuring wound closure, performing histological assessment, and analyzing macrophage polarization-related markers. Results: Quercetin markedly improved diabetic wound repair by facilitating M2 macrophage polarization, promoting ROS elimination, and inhibiting NLRP3 inflammasome activation. The GelMA-Quercetin hydrogel demonstrated sustained drug release, achieving 80% cumulative release within 48 h, and markedly improved wound closure compared to saline and GelMA-only controls. Hydrogel-treated wounds exhibited reduced inflammation, increased angiogenesis, and accelerated epithelial regeneration. Conclusion: This study demonstrates that quercetin activates the Foxo3-autophagy axis to drive M2 macrophage polarization, thereby resolving chronic inflammation in DFUs. The GelMA-Quercetin hydrogel provides a clinically translatable strategy for localized therapy, combining sustained drug delivery with enhanced wound healing. These findings highlight quercetin’s dual role as a molecular regulator and hydrogel-based therapeutic agent for DFUs.