Impact of mRNA structures interacting with lipids on nanoparticle formulation properties

Lipid nanoparticles (LNPs) are an important delivery method for RNA therapeutics. However, due to a lack of structural information on the molecules within LNPs, we do not yet have a systematic understanding of how lipids and RNA interact and how this affects the formation of LNPs. mRNAs are typically more than several thousand nucleotides long and are expected to have different secondary structures depending on the sequence and solution conditions; how do differences in RNA structure lead to differences in tertiary structure through interactions with various lipids and thus to differences in LNP size and stability? We will address these questions in this PhD project using molecular simulations and experimental biophysical characterisation. The student will develop in silico models of RNA-lipid interactions using a multi-scale simulation approach. The model will be validated against experimental data such as small-angle neutron scattering and spectroscopic data. Experimental data can be integrated into molecular simulations to narrow down the potential molecular conformations. This approach will allow us to identify critical features of RNA and lipid molecules and solution conditions that contribute to improved formulation efficiency and stability of LNPs.