Designing nanoparticles for highly efficient endothelial siRNA delivery

Abstract

RNA potently regulates gene expression. However, the utility of RNA has been limited by the ability to efficiently deliver it to specific cells in vivo. In vivo RNA delivery is challenging; vehicles must avoid phagocytosis in the bloodstream, reach the target tissue, and get into, and out of, an endosome, all without setting off an unwanted immune response. Despite these challenges, nanoparticles have delivered siRNA to hepatocytes after intravenous injections as low as 0.001 mg/kg. By contrast, efficient, durable, and robust silencing in other cell types has remained challenging. Herein we describe 7C I, a low molecular weight polymeric nanoparticle that delivers siRNA to endothelial cells in vivo at doses as low as 0.017 mg/kg. 7C1 nanoparticles reduced target mRNA expression for more than three weeks after a single injection, and delivered five siRNAs concurrently in vivo. Notably, 7C I transfects endothelial cells at low doses without significantly reducing gene expression in hepatocytes or immune cells. 7C I was optimized for stability and consistency, and used to study inflammation, cardiovascular disease, emphysema, primary tumor growth, and metastasis in labs across the United States. These data demonstrate that 7C I can be used to potently modify the expression of multiple endothelial genes in vivo.