Abstract: Objective: To investigate the effects of Avicennia marina leaf-derived extracellular vesicles (AmLEVs) on skin wound healing in diabetic rats and explore the underlying mechanisms. Methods: Extracellular vesicles were isolated from Avicennia marina leaves by differential centrifugation combined with ultracentrifugation. The morphology of the extracellular vesicles was observed by transmission electron microscopy (TEM), and the particle size and zeta potential of AmLEVs were measured by dynamic light scattering (DLS) using a Malvern instrument. The antioxidant capacity of AmLEVs was evaluated using DPPH, ABTS, and hydroxyl radical assay kits. Human umbilical vein endothelial cells (HUVECs) and human skin fibroblasts (HSFs) were selected as experimental cells, and a high-glucose medium containing 25 mmol/L glucose was used to mimic the diabetic microenvironment. After co-culture with AmLEVs, the levels of intracellular reactive oxygen species (ROS) were detected using the DCFH-DA probe. Cell viability, cell migration, and angiogenic capacity were assessed by cell counting kit-8 (CCK-8) assay, scratch wound assay, and tube formation assay, respectively. The expression levels of VEGF mRNA and VEGF protein were determined by real-time quantitative PCR (RT-qPCR) and immunofluorescence staining. In addition, a full-thickness skin wound model was established in streptozotocin-induced diabetic Sprague-Dawley (SD) rats to evaluate the wound-healing effects of AmLEVs. Results: AmLEVs were successfully isolated, with a typical cup-shaped morphology of the nanovesicles and an average particle size of approximately 55 nm. In vitro experiments showed that AmLEVs exhibited strong scavenging activities against DPPH, ABTS, and hydroxyl radicals. Moreover, 100 μg/mL AmLEVs effectively reduced high glucose-induced ROS accumulation, thereby reversing the inhibitory effects of the hyperglycemic environment on the proliferation, migration, and tube formation of HUVECs, thus enhancing the viability of HSFs. Compared with the control group, the mRNA and protein expression levels of VEGF were decreased in the high-glucose injury group. However, these levels were increased when the high-glucose injury group was treated with 100 μg/mL AmLEVs. In vivo experiments demonstrated that the wound healing rate in the rats of diabetic group was significantly decreased compared with that in the rats of the control group. However, the wound healing rate was significantly increased when the diabetic rats were treated with AmLEVs. HE and Masson staining revealed that AmLEV treatment enhanced re-epithelialization and increased collagen deposition compared with the diabetic model group. Furthermore, immunofluorescence staining, RT-qPCR, and western blotting confirmed that VEGF mRNA and protein expressions in skin tissues were downregulated in diabetic rats but were significantly upregulated following AmLEV treatment. Conclusion: AmLEVs effectively promote diabetic wound healing. The underlying mechanisms may involve modulating cellular oxidative stress, enhancing angiogenesis, and improving cell migration, suggesting that AmLEVs can serve as a potential therapeutic agent for diabetic wound treatment.