Exocarpium Citri Grandis-Derived Extracellular Vesicle-Like Particles for Accelerating Wound Healing via Regulating the Protein Expression on the VEGF/AKT Signaling Pathway.

Exocarpium Citri Grandis (ECG) is a plant endemic to Huazhou City, Guangdong Province, China. It is utilized both as a health food and in traditional medicine. Recently, Exocarpium Citri Grandis-derived extracellular vesicle-like particles (ECG-EVLP) have been isolated from ECG. Given the significant advantages of plant-derived extracellular vesicle-like particles (P-EVLP), these particles from various sources have been investigated for their potential in wound healing applications, reducing wound area in vitro or in vivo models. Although the anti-inflammatory and antioxidant activities of ECG-EVLP have been established in previous studies, their role in skin wound healing remains unexplored. Our findings indicate that ECG-EVLP can effectively promote wound healing. In vivo, wound healing was significantly improved in the ECG-EVLP group compared with the PBS group on Days 3, 7, 11, and 14. In vitro, ECG-EVLP significantly enhanced L929 cell proliferation at all concentrations (150, 300, and 450 μg/mL) after both 24 and 48 h. For HaCat cells, proliferation increased at the two high concentrations (300 and 450 μg/mL) after 24 h and extended to all concentrations, including all concentrations (150, 300, and 450 μg/mL), after 48 h. The activation of the VEGF/AKT signaling pathway, together with the inhibition of the mitochondrial apoptosis pathway, is likely the underlying mechanism. This interplay promotes cell proliferation, migration, and collagen production, thereby accelerating wound healing following ECG-EVLP stimulation. Additionally, sphingosine and naringin might be the effective components of ECG-EVLP in promoting wound healing.