Peroxidase-Enriched Extracellular Vesicles from Ginkgo biloba Ameliorate Acute Lung Injury via ROS Scavenging, M2 Macrophage Polarization and Barrier Protection.

Acute lung injury (ALI) is a severe pulmonary disorder characterized by inflammation, oxidative stress, and poor pulmonary barrier, resulting in high incidence and mortality. Due to no specific therapeutic agents, therapeutic strategies are urgently required. Ginkgo biloba, a living fossil in the plant kingdom, has been employed for millennia in treating lung diseases. Here, we isolated and characterized extracellular vesicles from G. biloba (GbEVs). GbEVs demonstrated excellent stability and specific tropism for the lungs. Proteomic analysis and nontarget metabolomics revealed a distinct profile enriched in peroxidases and containing small amounts of ginkgolides and flavonoids, implying potential antioxidant and anti-inflammatory properties. In vitro, GbEVs significantly suppressed lipopolysaccharide (LPS)-induced cytokine storm and reactive oxygen species (ROS) production, thereby mitigating inflammatory responses, preserving epithelial-endothelial integrity, and restoring the balance of macrophage subsets. In the ALI model, GbEV administration significantly restored weight loss, improved pulmonary edema, alleviated tissue damage, and relieved pro-inflammatory states, especially maintaining the balance of M1/M2 macrophage polarization. Furthermore, we stablished a plant cell suspension culture system to scale up the production of GbEV-like nanovesicles with comparable properties, in similar morphology and bioactivity. Our research has identified GbEVs as a pharmacological basis for G. biloba and, for the first time, demonstrated its potent efficacy against inflammatory diseases, particularly pneumonia.