Recent advances in RNA-based medicine have provided new opportunities for the global current challenge, i.e., the COVID-19 pandemic. Novel vaccines are based on a messenger RNA (mRNA) motif with a lipid nanoparticle (LNP) vector, consisting of high content of unique pH-sensitive ionizable lipids (ILs). Here we provide molecular insights into the role of the ILs and lipid mixtures used in current mRNA vaccines. We observed that the lipid mixtures adopted a nonlamellar organization, with ILs separating into a very disordered, pH-sensitive phase. We describe structural differences of the two ILs leading to their different congregation, with implications for the vaccine stability. Finally, as RNA interacts preferentially with IL-rich phases located at the regions with high curvature of lipid phase, local changes in RNA flexibility and base pairing are induced by lipids. A proper atomistic understanding of RNA-lipid interactions may enable rational tailoring of LNP composition for efficient RNA delivery.

IT4Innovations VSB─Technical University of Ostrava 17 listopadu 2172 15 708 00 Ostrava Poruba Czech Republic

Regional Centre of Advanced Technologies and Materials Czech Advanced Technology and Research Institute Palacký University Olomouc Šlechtitelů 27 779 00 Olomouc Czech Republic

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Computational Methods for Modeling Lipid-Mediated Active Pharmaceutical Ingredient Delivery