A Chemoinformatic-Guided\nSynthesis of a Spleen-Expressing\nmRNA Lipid Nanoparticle Platform

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