Targeting single-cell multiomics-identified vascular impairment: Panax notoginseng extracellular vesicles-loaded adhesive QBK-2/EVs promotes angiogenesis in diabetic wound healing

Diabetic skin wounds, a severe complication affecting over 18.6 million people globally, are characterized by high amputation and mortality rates. However, the cellular heterogeneity of diabetic wounds and the specific molecular mechanisms underlying their impaired healing remain unclear. Furthermore, treatment strategies based on medicinal plants targeting these pathological mechanisms are lacking. This study explored diabetic wound pathogenesis using single-cell RNA sequencing (scRNA-seq), revealing a 52 % reduction in vascular endothelial cells (ECs) and a decreased abundance of proliferative ECs in diabetic wound tissues, which contributed to impaired vascular repair. Network pharmacology and RT-qPCR identified E-selectin (SELE) as the key target of <i>Panax notoginseng</i> in the treatment of diabetic wounds, which was corroborated by molecular docking. Plant-derived extracellular vesicles (EVs) represent a class of superior bioactive nanomaterials compared to traditional extracts, exhibiting high delivery efficiency, molecular transport capacity, and biocompatibility, enabling cross-species communication essential for therapeutic applications. To further overcome limitations associated with plant-derived extracts (e.g., short half-life), we <i>isolated Panax notoginseng</i> EVs and subsequently loaded them into a hydrogel via dynamic borate ester bonds formed between quaternized chitosan-phenylboronic acid (QCS-BA) and konjac glucomannan (KGM), ultimately generating the QBK-2/EVs composite system. This hydrogel not only effectively encapsulated and continuously released EVs, but also exhibited good injectability, self-healing property, tissue adhesion (42.83 kPa), and ROS/pH-responsive degradation. <i>In vitro</i>, QBK-2/EVs enhanced human umbilical vein endothelial cell proliferation, migration, and tube formation by downregulating SELE and upregulating angiogenesis markers (CD31, F-actin). <i>In vivo</i>, QBK-2/EVs accelerated wound healing in diabetic mice, promoted hemostasis, increased collagen deposition, and enhanced microvessel density (CD31), while simultaneously reducing the expression of SELE. Overall, this work establishes a mechanism-driven strategy for diabetic wound treatment through synergistic exosome-mediated angiogenesis and hydrogel-based delivery.