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<p>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.</p> Graphical Abstract

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月16日

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  • Xianglong Zhou,
  • Jianhui Xiang,
  • Hanhong Fang,
  • Yang Liu,
  • Fulin Zhou,
  • Jiheng Xiao,
  • Weicheng Chen,
  • Haoran Zhou,
  • Guohui Liu,
  • Xiao Lv,
  • Yiqiang Hu,
  • Liming Xiong

摘要

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.

Graphical Abstract