Ionizable Cationic\nLipids and Helper Lipids Synergistically\nContribute to RNA Packing and Protection in Lipid-Based Nanomaterials

Lipid-based nanomaterials are used as a common delivery\nvehicle\nfor RNA therapeutics. They typically include a formulation containing\nionizable cationic lipids, cholesterol, phospholipids, and a small\nmolar fraction of PEGylated lipids. The ionizable cationic lipids\nare considered a crucial element of the formulation for the way they\nmediate interactions with the anionic RNA as a function of pH. Here,\nwe show, by means of molecular dynamics simulation of lipid formulations\ncontaining two different ionizable cationic lipids (DLinDMA and DLinDAP),\nthat the direct interactions of those lipids with RNA, taken alone,\nmay not be sufficient to determine the level of protection and packaging\nof mRNA. Our simulations help and highlight how the collective behavior\nof the lipids in the formulation, which determines the ability to\nenvelop the RNA, and the level of hydration of the lipid-RNA interface\nmay also play a significant role. This allows the drawing of a hypothesis\nabout the experimentally observed differences in the transfection\nefficiency of the two ionizable cationic lipids.