Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of<i>Angptl3</i>

Abstract

Significance Genome editing technologies enable the permanent repair of disease-causing genetic mutations. However, the application of this technology has been limited by the technical challenge of achieving safe, effective, and specific in vivo delivery of the CRISPR-Cas9 genome editing components. Here, we report the development of a newly identified lipid nanoparticle (LNP) for specific delivery of CRISPR-Cas9 mRNA to the liver. While LNPs have been FDA approved for delivery of siRNA to the liver, here we examine their application for genome editing. When compared head-to-head, our delivery platform significantly outperforms the FDA-approved LNP in the efficient delivery of Cas9 mRNA for knockdown of the Angptl3 gene and subsequent regulation of hypercholesterolemia, while matching the safety and specificity of the approved platform.