Interactions between ionizable amino lipids and a short RNA hairpin: Insights from molecular dynamics simulations for lipid nanoparticle optimization

Lipid nanoparticles (LNPs) have been used as carriers for messenger RNA (mRNA) based therapeutics. The composition of a typical LNP includes an ionizable amino lipids, phospholipids, cholesterols and PEG-lipids. Each component is critical for the performance of the LNP delivery system; however, to optimize the LNPs for mRNA delivery, a deeper understanding of the interactions between the delivery and cargo is necessary. Here, we study in silico how three model ternary bilayers, each consisting of DSPC, cholesterol and a unique ionizable amino lipid, interact with a short RNA hairpin. Each of the model lipid bilayers have different types of ionizable amino lipids in them and they are similar in composition in all other aspects. Thus, we systematically investigate the role of ionizable amino lipids, the key component that drives the assembly and modulates the performance of LNPs, using all-atom molecular dynamics simulations. We found that there are global and local conformation changes to both RNA stem loop and model lipid bilayers, depending on the type of amino lipid that constitutes the bilayers. This can give us insights on why LNPs built from certain ionizable amino lipids have higher potency than others. Furthermore, the interactions between the RNA stem loop and each model bilayer correlate with the propensity of each bilayer to form distinct lipid component rich domains. By investigating how changes in the structure of ionizable lipids modulate the condition of RNA at the lipid bilayer interface of LNPs, we extract insights about RNA-lipid interactions favorable for higher therapeutic effect.