Non-viral gene editingin uterowith lipid nanoparticles complexed to mRNA

Abstract

AbstractNanoparticle-based drug delivery systems have the potential to revolutionize medicine but their low vascular permeability and rapid clearance by phagocytic cells have limited their medical impact. Nanoparticles delivered at thein uterostage have the potential to overcome these key limitations, due to the high rate of angiogenesis and cell division in fetal tissue, and the under-developed immune system. However, very little is known about nanoparticle drug delivery at the fetal stage of development. In this report, using Ai9 CRE reporter mice, we demonstrate that lipid nanoparticle (LNP) mRNA complexes can deliver mRNA for gene editing enzymesin uteroafter an intrahepatic injection, and can access and edit major organs, such as the heart, the liver, kidneys, lungs and the gastrointestinal tract with remarkable efficiency and low toxicity. In addition, we show here that Cas9 mRNA and sgRNA complexed to LNPs were able to edit the fetal organsin uteroafter an intrahepatic injection. These experiments demonstrate the possibility of non-viral delivery of gene editing enzymesin uteroand nanoparticle drug delivery has great potential for delivering macromolecules to organs outside of the liverin utero, which provides a promising strategy for treating a wide variety of devastating genetic diseases before birth.