Endothelial-targeting miR-145 micelles restore barrier function and exhibit atheroprotective effects

Atherosclerosis remains the leading cause of death worldwide and is characterized by the accumulation of plaque beneath the endothelium. MicroRNA-145-5p (miR-145), which is downregulated in atherosclerosis, has been shown to mitigate plaque development by promoting the contractile vascular smooth muscle cell (VSMC) phenotype. Previously, our lab found that miR-145 micelles conjugated with MCP-1 peptides were able to inhibit atherosclerosis by targeting diseased VSMC <i>via</i> C-C chemokine receptor 2 (CCR2). Diseased endothelial cells similarly express CCR2; however, the impact of miR-145 micelles on endothelial cell function has not been explored. Thus, in this study, the <i>in vitro</i> therapeutic effects of miR-145 micelles in modulating the endothelium during atherosclerosis are evaluated. To that end, the MCP-1 peptide density on the micelle surface was first optimized for activated endothelial cell binding, followed by loading miR-145 into micelles with the optimal MCP-1 ratio. Following characterization, miR-145 micelle treatment of activated endothelial cells resulted in efficient miR-145 transfection, upregulation of atheroprotective genes, and suppression of atherogenic genes. Furthermore, the treatment enhanced the integrity of endothelial tight junctions and reduced monocyte migration. This work establishes miR-145 micelles as an effective nanotherapeutic for restoring endothelial cell health in cardiovascular disease for the first time.