A Chemoinformatic-Guided Synthesis of a Spleen-Expressing mRNA Lipid Nanoparticle Platform.

Abstract

mRNA lipid nanoparticles (LNPs) are a powerful technology that are actively being investigated for their ability to prevent, treat, and study disease. However, a major limitation remains: achieving extrahepatic mRNA expression. The development of new carriers could enable the expression of mRNA in non-liver targets, thus expanding the utility of mRNA-based medicines. In this study, we use a combination of chemoinformatic-guided material synthesis and design of experiment optimization for the development of a spleen-expressing lipid nanoparticle (SE-LNP). We begin with the synthesis of a novel cholesterol derivative followed by SE-LNP formulation and design of experiment-guided optimization to identify three lead SE-LNPs. We then evaluate their in vitro delivery mechanism, in vivo biodistribution, and protein expression in mice, ultimately achieving spleen-preferential expression. The goal of this paper is thus to create LNPs that preferentially express mRNA in the spleen upon intravenous delivery, demonstrating the potential of LNPs to modulate gene expression in extrahepatic tissues for disease treatment.