Anionic Lipid Nanoparticles Preferentially Deliver mRNA to the Hepatic Reticuloendothelial System. Issue 16 (10th March 2022) - Pattipeiluhu, Roy
Abstract: Lipid nanoparticles (LNPs) are the leading nonviral technologies for the delivery of exogenous RNA to target cells in vivo. As systemic delivery platforms, these technologies are exemplified by Onpattro, an approved LNP‐based RNA interference therapy, administered intravenously and targeted to parenchymal liver cells. The discovery of systemically administered LNP technologies capable of preferential RNA delivery beyond hepatocytes has, however, proven more challenging. Here, preceded by comprehensive mechanistic understanding of in vivo nanoparticle biodistribution and bodily clearance, an LNP‐based messenger RNA (mRNA) delivery platform is rationally designed to preferentially target the hepatic reticuloendothelial system (RES). Evaluated in embryonic zebrafish, validated in mice, and directly compared to LNP–mRNA systems based on the lipid composition of Onpattro, RES‐targeted LNPs significantly enhance mRNA expression both globally within the liver and specifically within hepatic RES cell types. Hepatic RES targeting requires just a single lipid change within the formulation of Onpattro to switch LNP surface charge from neutral to anionic. This technology not only provides new opportunities to treat liver‐specific and systemic diseases in which RES cell types play a key role but, more importantly, exemplifies that rational design of advanced RNA therapies must be preceded by a robust understanding of the dominant nano–biointeractions involved. Abstract : Lipid nanoparticles (LNPs) capable of delivering therapeutic RNA to specific cells in the body are required if the immense potential of these plug‐and‐play technologies is to be realized. Using embryonic zebrafish as a predictive in vivo model and with a thorough understanding of the nano–biointeractions involved, LNPs capable of preferential messenger RNA delivery to hepatic reticuloendothelial system cells are rationally designed.