Engineered ginseng-immune hybrid vesicles restore mitochondrial homeostasis for endothelium-targeted therapy of lung ischemia–reperfusion injury

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.