Mori fructus-derived extracellular vesicle-like nanoparticles regulate dyslipidemia and prevent atherosclerosis progression via miRNAs.

BACKGROUND

Atherosclerosis, driven majorly by dyslipidemia, is a major risk factor for acute and chronic cardiovascular diseases. Hence, the development of bioactive products that can regulate lipid metabolism and prevent the onset and progression of atherosclerosis is urgently needed.

PURPOSE: This study aims to investigate the effect of Mori fructus-derived extracellular vesicle-like nanoparticles (MFEVLPs) on lipid abnormality and atherosclerosis progression.

METHODS

MFEVLPs were isolated by ultracentrifugation and purified using a sucrose density gradient centrifuge. They were then characterized by TEM and NTA. The miRNA profile was detected using small RNA-seq. FFA-stimulated HepG2 cells and high-fat-diet-fed ApoE-/- mice (including models, MFEVLPs-treated groups, and atorvastatin-treated group) were used to investigate the effect of MFEVLPs on lipid abnormality and atherosclerosis progression. miRNA mimics and luciferase assay were used to analyze the interactions between MFEVLPs-derived miRNAs and target genes.

RESULTS

MFEVLPs reduced plaque area and augmented plaque stability in ApoE-/- mice. MFEVLP suppressed liver lipid synthesis and decreased liver and serum lipid content in vitro and in vivo. The MFEVLPs contained a large number of miRNAs, of which 20 miRNAs could target genes related to lipogenesis (SREBP1, FAS, and ACC) and cholesterol biosynthesis (HMGCR). MFEVLPs-derived miRNAs, such as miR398-y, miR160-z, miR165-y, miR166-y, and miR5168-y, were successfully delivered into the blood and accumulated in the liver of mice. Furthermore, MFEVLPs-derived miRNAs specifically bound to the 3'-UTR sequence of HMGCR and suppressed its expression.

CONCLUSIONS

Collectively, our results for the first time demonstrated that MFEVLPs could prevent dyslipidemia and atherosclerosis. We also found that MFEVLPs-derived miRNAs could target genes related to lipogenesis and cholesterol biosynthesis, offering new treatment modalities for the prevention of dyslipidemia-induced disorders.