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<p>Diabetic wounds are characterized by persistent inflammation, impaired angiogenesis, and delayed tissue regeneration, yet effective strategies to regulate the pathological immune microenvironment remain limited. Here, integrated single-cell transcriptomics and multi-omics analyses revealed significant enrichment of endoplasmic reticulum stress (ERS)-related signaling in pro-inflammatory macrophages within diabetic wounds, suggesting a potential mechanism driving chronic inflammation. To target this process, we developed an injectable dynamic hydrogel (GPOK-2@EVs) incorporating Artemisia argyi-derived extracellular vesicles (EVs) for localized immunomodulatory therapy. The hydrogel was formed through dual dynamic crosslinking between phenylboronic acid-modified gelatin and oxidized konjac glucomannan, providing self-healing capability, injectability, tissue adhesion, and pH/ROS-responsive degradation for sustained EV release. In vitro experiments demonstrated that GPOK-2@EVs exhibited excellent biocompatibility and effectively reprogrammed macrophages toward an anti-inflammatory phenotype, accompanied by reduced inflammatory cytokine secretion, alleviated ERS activation, decreased ROS accumulation, and improved mitochondrial integrity. GPOK-2@EVs significantly enhanced endothelial angiogenic activities, including cytoskeletal remodeling, tube formation, and migration. In a diabetic mouse wound model, GPOK-2@EVs accelerated wound closure, promoted granulation tissue formation and collagen deposition, enhanced vascularization, and suppressed inflammatory and ERS responses. These findings demonstrate that EV-loaded dynamic hydrogels can modulate the inflammatory microenvironment and promote diabetic wound regeneration, providing a promising biomaterial strategy for chronic wound therapy.</p> Graphical Abstract <p></p>

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Single-cell transcriptomics-guided dynamic hydrogel delivery of artemisia argyi-derived EVs relieves ER stress and promotes diabetic wound regeneration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月6日

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  • Dazhuang Miao,
  • Xiaopeng Suo,
  • Xinqian Geng,
  • Ying Yang,
  • Gaoming Wang,
  • Yang Zhou,
  • Yunhe Jia,
  • Shuofei Yang,
  • Heping Li,
  • Gaohua Li

摘要

Diabetic wounds are characterized by persistent inflammation, impaired angiogenesis, and delayed tissue regeneration, yet effective strategies to regulate the pathological immune microenvironment remain limited. Here, integrated single-cell transcriptomics and multi-omics analyses revealed significant enrichment of endoplasmic reticulum stress (ERS)-related signaling in pro-inflammatory macrophages within diabetic wounds, suggesting a potential mechanism driving chronic inflammation. To target this process, we developed an injectable dynamic hydrogel (GPOK-2@EVs) incorporating Artemisia argyi-derived extracellular vesicles (EVs) for localized immunomodulatory therapy. The hydrogel was formed through dual dynamic crosslinking between phenylboronic acid-modified gelatin and oxidized konjac glucomannan, providing self-healing capability, injectability, tissue adhesion, and pH/ROS-responsive degradation for sustained EV release. In vitro experiments demonstrated that GPOK-2@EVs exhibited excellent biocompatibility and effectively reprogrammed macrophages toward an anti-inflammatory phenotype, accompanied by reduced inflammatory cytokine secretion, alleviated ERS activation, decreased ROS accumulation, and improved mitochondrial integrity. GPOK-2@EVs significantly enhanced endothelial angiogenic activities, including cytoskeletal remodeling, tube formation, and migration. In a diabetic mouse wound model, GPOK-2@EVs accelerated wound closure, promoted granulation tissue formation and collagen deposition, enhanced vascularization, and suppressed inflammatory and ERS responses. These findings demonstrate that EV-loaded dynamic hydrogels can modulate the inflammatory microenvironment and promote diabetic wound regeneration, providing a promising biomaterial strategy for chronic wound therapy.

Graphical Abstract