Stimuli-responsive hydrogel with spatiotemporal co-delivery of FGF21 and H₂S for synergistic diabetic wound repair

Chronic diabetic wounds pose significant clinical challenges due to persistent inflammation, impaired angiogenesis, and disrupted cellular homeostasis. To address these multifactorial barriers, we engineered an injectable, biodegradable, and biocompatible methylated silk fibroin (SilMA) hydrogel system co-loaded with cobalt sulfide (CoS) and fibroblast growth factor 21 (FGF21), designed for on-demand therapeutic release. In the acidic microenvironment characteristic of the inflammatory phase of diabetic wounds, the hydrogel rapidly releases hydrogen sulfide (H₂S) and Co²⁺ ions, mitigating inflammation and exerting antibacterial effects. Subsequently, during the proliferative and remodeling phases, sustained release of FGF21 promotes cellular proliferation, angiogenesis, and enzymatic homeostasis, thereby accelerating wound healing. Mechanistic studies reveal that the hydrogel facilitates M2 macrophage polarization and activates the JAK/STAT signaling pathway, leading to upregulation of vascular endothelial growth factor (VEGF). Additionally, it enhances antioxidant enzyme activities (superoxide dismutase, catalase, glutathione) while suppressing pro-oxidant enzymes (NADPH oxidase, lipoxygenase, cyclooxygenase). In vivo studies using a diabetic mouse model demonstrate that this dual-functional hydrogel significantly improves wound closure rates and tissue regeneration. These findings suggest that the SilMA-FGF21/CoS hydrogel represents a promising therapeutic strategy for the management of diabetic wounds.