1 Coarse-Grained Simulation of mRNA-Loaded Lipid Nanoparticle Self-Assembly Douglas J. Grzetic, 1 * Nicholas B. Hamilton, 1,2 and John C. Shelley 1 * 1 Schrödinger, Inc., 101 SW Main St., Suite 1300, Portland OR 97204, USA 2 Department of Chemistry, University of Vermont, Burlington, VT 05405, USA Abstract 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 parameterized 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mRNA. 1 Introduction https://doi.org/10.26434/chemrxiv-2024-6x271 ORCID: https://orcid.org/0000-0001-9808-0739 Content not peer-reviewed by ChemRxiv. License: CC BY-NC-ND 4.0