Lipid shape and packing are key for optimal design of pH-sensitive mRNA lipid nanoparticles.

ABSTRACT: The ionizable-lipid component of RNA-containing nanoparticles controls the pH-dependent behavior necessary for an efficient delivery of the cargo-the so-called endosomal escape. However, it is still an empirical exercise to identify optimally performing lipids. Here, we study two well-known ionizable lipids, DLin-MC3-DMA and DLin-DMA using a combination of experiments, multiscale computer simulations, and electrostatic theory. All-atom molecular dynamics simulations, and experimentally measured polar headgroup pK_a values, are used to develop a coarse-grained representation of the lipids, which enables the investigation of the pH-dependent behavior of lipid nanoparticles (LNPs) through Monte Carlo simulations, in the absence and presence of RNA molecules. Our results show

SUBMITTER: Tesei G 

PROVIDER: S-EPMC10786277 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature