工程化人参免疫混合体能恢复肺缺血再灌注损伤中内皮细胞的线粒体稳态，从而实现针对内皮细胞的治疗效果。

Abstract

Lung ischemia-reperfusion injury is a major complication after lung transplantation and is closely associated with oxidative stress, inflammatory amplification, mitochondrial dysfunction, and endothelial injury. Herein, we engineered SOD2@RGD-NGEVs by fusing SOD2-loaded, RGD-modified neutrophil-derived extracellular vesicles (EVs) with ginseng-derived EVs. This biomimetic platform combines the inflammatory tropism of neutrophil vesicles, the integrin-targeting capability of RGD, the mitochondrial antioxidant activity of SOD2, and the intrinsic anti-inflammatory, antioxidant, and tissue-reparative properties of ginseng-derived vesicles. SOD2@RGD-NGEVs displayed typical vesicular morphology, favorable stability, efficient uptake by hypoxia/reoxygenation (H/R)-injured human pulmonary microvascular endothelial cells, and enhanced pulmonary accumulation after nebulized administration. In vitro, SOD2@RGD-NGEVs reduced ROS and malondialdehyde levels, restored Nitric Oxide, SOD2, and glutathione levels, suppressed the expression of multiple pro-inflammatory factors, and promoted cell proliferation and migration more effectively than single-component treatments. Mechanistically, SOD2@RGD-NGEVs restored mitochondrial respiration, ATP production, membrane potential, fission-fusion balance, and mitochondrial biogenesis. In a rat model, nebulized SOD2@RGD-NGEVs alleviated lung tissue injury, oxidative stress, inflammation, and mitochondrial network disruption with favorable biosafety. Transcriptomic analysis further indicated regulation of immune-inflammatory responses, oxidative phosphorylation, mitochondrial translation and DNA damage repair. These findings suggest that SOD2@RGD-NGEVs provide a promising cell-free therapeutic strategy for lung transplantation-associated IRI and primary graft dysfunction. Graphical