Abstract

Lipid nanoparticles (LNPs) electric charge is known to control in vivo distribution and expression of mRNA-LNPs for intravascular (IV) administration. Whereas neutral LNPs predominantly end up targeting the liver,reducing the amount of cationic lipid in mRNA-LNPs creates a negative LNP, due to an excess of anionic mRNA, that targeted the spleen after IV injection, versus positively charged LNPs targeting the lung.A novel family of permanent cationic lipids has been developed to answer the next challenges in the development of RNA therapeutics. The combination of an imidazolium polar head and an accentuated molecularcone-shape through improved lipid tail branching, increases formulation stability and facilitates endosomal release, respectively. Due to these properties, cationic LNP (cLNP) have shown promising results in term ofstability, potency, in vivo distribution and targeting