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

## TL;DR

This paper shows that particles from Exocarpium Citri Grandis can speed up wound healing by boosting cell growth and activating specific biological pathways.

## Contribution

The study introduces Exocarpium Citri Grandis-derived extracellular vesicle-like particles as a novel wound healing agent.

## Key findings

- ECG-EVLP significantly improved wound healing in vivo on Days 3, 7, 11, and 14 compared to PBS.
- ECG-EVLP enhanced cell proliferation in L929 and HaCat cells at various concentrations.
- The VEGF/AKT pathway activation and mitochondrial apoptosis inhibition are likely mechanisms for wound healing promotion.

## Abstract

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.

Our findings indicate that ECG‐EVLP can effectively promote wound healing and the activation of the VEGF/AKT signaling pathway in vitro and in vivo, coupled with the inhibition of the mitochondrial apoptosis pathway in cells following ECG‐EVLP stimulation might be its underlying mechanism. Additionally, sphingosine and naringin of ECG‐EVLP are identified as potential active components that might contribute to promoting wound healing.