Coarse-Grained Simulation of mRNA-Loaded Lipid Nanoparticle Self-Assembly

Ionizable lipid-containing lipid nanoparticles (LNPs)
have enabled
the delivery of RNA for a range of therapeutic applications. In order
to optimize safe, targeted, and effective LNP-based RNA delivery platforms,
an understanding of the role of composition and pH in their structural
properties and self-assembly is crucial, yet there have been few computational
studies of such phenomena. Here we present a coarse-grained model
of ionizable lipid and mRNA-containing LNPs. Our model allows access
to the large length- and time-scales necessary for LNP self-assembly
and is mapped and parametrized with reference to all-atom structures
and simulations of the corresponding components at compositions typical
of LNPs used for mRNA delivery. Our simulations reveal insights into
the dynamics of self-assembly of such mRNA-encapsulating LNPs, as
well as the subsequent pH change-driven LNP morphology and release
of mRNA.