Why the study?
Molecular insights into the role of pH-sensitive ionizable lipids and lipid mixtures used in current mRNA vaccines were needed to enable rational tailoring of lipid nanoparticle composition for efficient RNA delivery.
Molecular dynamics simulations reveal that ionizable lipids in mRNA vaccines form disordered, pH-sensitive phases that preferentially interact with RNA, providing insights for tailoring LNP composition.
May guide future LNP optimization for mRNA vaccines; leaves open in vivo validation and clinical relevance.
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.
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Paloncýová et al. (2021) studied this question.
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