Multimodal Antiatherosclerotic Effects of Clinical-Grade Mesenchymal Stem Cell–Derived Extracellular Vesicles

BACKGROUND: Atherosclerosis remains a leading cause of cardiovascular diseases. Despite current lipid-lowering therapies, residual risk persists due to inflammation and elevated Lp(a) (lipoprotein[a]) levels. Mesenchymal stem cell–derived extracellular vesicles show promise as a novel therapeutic modality. This hypothesis-testing (new) study investigated the antiatherosclerotic effect and systemic lipid-modulating potential of the clinical-grade mesenchymal stem cell–derived extracellular vesicle product SNE-101, which is currently approved for acute ischemic stroke trials. METHODS: ApoE−/− (apolipoprotein E–deficient) mice (male, 6–8 weeks old; n=6 per group) were placed on a high-fat diet, and SNE-101 (6×10⁸ particles) was administered intravenously via the tail vein once weekly for 4 weeks. The primary exposure variable was SNE-101 treatment, and the primary outcome variable was aortic plaque burden, quantified as the percentage of Oil Red O–stained area. In vitro foam cell assays were performed to assess cholesterol efflux. RESULTS: In vitro, SNE-101 significantly reduced lipid accumulation and enhanced cholesterol efflux via upregulation of the PPARγ (peroxisome proliferator-activated receptor gamma)/LXRα (liver X receptor alpha)/ABCA1 (ATP-binding cassette transporter A1)/ABCgG1 (ATP-binding cassette transporter G1) axis ( P <0.050). In ApoE−/− mice, SNE-101 attenuated aortic plaque burden, inflammation, and hepatic steatosis. Extracellular vesicle treatment significantly improved systemic lipid profiles by reducing LDL-C (low-density lipoprotein-cholesterol), triglyceride, PCSK9 (proprotein convertase subtilisin/kexin type 9), and Lp(a) levels ( P <0.050) while restoring hepatic LDL-R (low-density lipoprotein-cholesterol) expression. CONCLUSIONS: Mesenchymal stem cell–derived extracellular vesicles (SNE-101) represent a promising therapeutic strategy for atherosclerosis. By enhancing cholesterol efflux, suppressing PCSK9 and Lp(a), and reducing systemic inflammation, SNE-101 addresses critical cardiovascular risks. This provides strong mechanistic guidance for its application in ongoing clinical trials for acute ischemic stroke.