Significance Nanoparticle-mediated delivery of siRNA to hepatocytes has treated disease in humans. However, systemically delivering RNA drugs to nonliver tissues remains an important challenge. To increase the number of nanoparticles that could be studied in vivo, we designed a high-throughput method to measure how &gt;100 nanoparticles delivered mRNA that was translated into functional protein in vivo. We quantified how &gt;250 lipid nanoparticles (LNPs) delivered mRNA in vivo, identifying two LNPs that deliver mRNA to endothelial cells. One of the LNPs codelivered Cas9 mRNA and single-guide RNA in vivo, leading to endothelial cell gene editing. This approach can identify nanoparticles that target new cells.

High-throughput in vivo screen of functional mRNA delivery identifies nanoparticles for endothelial cell gene editing