Synergistic wound repair effects of a composite hydrogel for delivering tumor-derived vesicles and S-nitrosoglutathione†

Treating chronic wounds requires transition from proinflammatory M1 to anti-inflammatory M2 dominant macrophages. Based on the role of tumor extracellular vesicles (tEVs) in regulating the phenotypic switching from M1 to M2 macrophages, we propose that tEVs may have a beneficial impact on alleviating the overactive inflammatory microenvironment associated with refractory wounds. On the other hand, as a nitric oxide donor, S-nitrosoglutathione (GSNO) can regulate inflammation, promote angiogenesis, enhance matrix deposition, and facilitate wound healing. In this study, a guar gum-based hydrogel with tEVs and GSNO was designed for the treatment of diabetic refractory wounds. This hybrid hydrogel was formed through the phenyl borate bonds, which can automatically disintegrate in response to the high reactive oxygen species (ROS) level at the site of refractory diabetic wounds, releasing tEVs and GSNO. We conducted a comprehensive evaluation of this hydrogel in vitro, which demonstrated excellent performance. Meanwhile, using a full-thickness excision model in diabetic mice, the wounds exposed to the therapeutic hydrogel healed completely within 21 days. The increased closure rate was associated with macrophage polarization and collagen deposition, accelerated fibroblast proliferation, and increased angiogenesis in the regenerating tissues. Therefore, this multifunctional hybrid hydrogel appears to be promising for clinical applications.