Investigation of the stereochemical identity of lipid nanoparticles for RNA delivery

Lipid nanoparticles (LNPs) have proven to be a superior vehicle for the delivery of genetic material like RNA, also known as the basis for the COVID-19 vaccine. Much work has already been done on LNPs to understand their fundamentals and to identify optimal lipid compositions. Nevertheless, little is known about the influence of stereoisomers of single lipid components on transport efficiency and targeting properties of LNPs. We recently explored lipid stereoisomers, finding that isomeric differences can increase the transfection efficiency by several folds and also have an influence on cell selectivity. Recent reports show that the efficiency of endosomal escape can be attributed to the internal structure of LNPs. We postulated that the different isomers influence the lipid packing and thus the internal structure. In this proposal we plan to use SAXS to gain a deeper understanding of how lipid isomers change the nanostructure and thus the properties of the resulting LNP formulations.