Neutrophil Membrane‐Engineered Extracellular Vesicles from Perivascular Adipose Tissue‐Derived Stromal Cells for Atherosclerotic Lesion Resolution and Enhanced Vascular Graft Remodeling

Abstract Atherosclerosis is characterized by endothelial dysfunction and progressive plaque formation. Despite advancements in lipid‐lowering and anti‐inflammatory therapies, the repair of vascular damage and targeted delivery to atherosclerotic lesions remain critical challenges. Here, the development of neutrophil membrane‐engineered extracellular vesicles (NVEVs) is developed as a therapeutic platform for restoring endothelial function within atherosclerotic microenvironments. NVEVs are engineered by fusing extracellular vesicles (EVs) derived from perivascular adipose tissue stromal cells with neutrophil membrane nanovesicles, yielding hybrid NVEVs with superior targeting of inflamed vasculature and pro‐angiogenic properties. In vitro characterization confirmed the presence of miRNAs associated with vasculogenesis and atheroprotection pathways, alongside desired particle size, surface charge, and protein composition. Systemic administration of NVEVs in collagen‐induced arthritis and atherosclerosis rat models significantly attenuated inflammation, stabilized vascular architecture, and reduced macrophage infiltration. Mechanistically, NVEVs activated lipid metabolism pathways, notably enhancing cholesterol efflux via miR‐206‐3p‐ABCA1‐dependent signaling, while suppressing pathways that drive plaque progression. Furthermore, NVEVs mitigated PANoptosis – an inflammatory cell death form – in endothelial cells exposed to atherosclerotic plasma. Coating vascular grafts with NVEVs promoted endothelialization and long‐term patency in rats. These findings underscore therapeutic potential of NVEVs to resolve vascular complications in atherosclerosis, offering a promising strategy to improve vascular repair and graft performance.