All-in-one: a CGRP-encapsulated Rh-GelMA supramolecular dual-network hydrogel orchestrating immune-vascular coupling for diabetic wound healing

Diabetic wounds present a complex pathological microenvironment that severely impairs healing. To address this challenge, we developed a supramolecular double-network hydrogel (CGRP@Rh-GelMA) consisting of a self-assembled rhein network and an in situ UV-crosslinked gelatin methacryloyl (GelMA) framework. This design endowed the hydrogel with strong mechanical robustness, wet-tissue adhesion, and sustained dual-drug release of rhein and calcitonin gene-related peptide (CGRP). In vitro, CGRP@Rh-GelMA exhibited broad-spectrum antibacterial activity and potent reactive oxygen species (ROS)-scavenging capacity. The hydrogel was also associated with reduced neutrophil extracellular trap (NETosis)-related markers, including myeloperoxidase (MPO) and citrullinated histone H3 (H3Cit), as well as a shift in macrophage phenotype toward a reparative M2-like state, thereby contributing to a pro-healing immune microenvironment. In addition, CGRP@Rh-GelMA enhanced endothelial cell migration and vascular network formation in vitro, indicating pro-angiogenic potential. In a diabetic rat wound model, CGRP@Rh-GelMA accelerated wound repair, accompanied by improved immune microenvironment remodeling and neovascularization, resulting in enhanced granulation tissue formation, more organized collagen deposition, and re-epithelialization. Proteomic profiling further revealed inflammation-related pathway changes consistent with suppression of NF-κB signaling and NETosis. Collectively, these findings suggest that CGRP@Rh-GelMA is a mechanically robust and multifunctional biomaterial platform for diabetic wound healing by coordinately promoting immune and vascular repair responses. A CGRP@Rh-GelMA supramolecular double-network hydrogel was developed, in which self-assembled rhein serves as both a bioactive component and a structural network, while photocrosslinked GelMA enhances mechanical stability, wet-tissue adhesion, and sustained dual-drug release. The rhein-containing hydrogel showed antibacterial and ROS-scavenging activities and was associated with reduced NETosis-related markers, including MPO and H3Cit. CGRP-containing hydrogel treatment was associated with a shift in macrophage phenotype toward a reparative M2-like state, elevated VEGF expression, and enhanced angiogenesis-related cellular responses. The hydrogel accelerated diabetic wound healing, and proteomic analysis revealed pathway changes consistent with suppression of NF-κB signaling and NETosis.