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 ( 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.