Molecular Structure and Dynamics of Lipid Nanoparticles via Small-Angle Scattering

Lipid nanoparticles have revolutionized human health outcomes, as evidenced by the mRNA vaccines used to combat COVID-19. Despite the success of these self-assembled nucleic acid therapeutics, the physicochemical fundamental properties of the non-viral delivery vectors must be better understood to be more easily tuned and optimized. In this work, we use small-angle X-ray (SAXS) and neutron scattering (SANS) to provide a nanoscale picture of the lipid nanoparticles. Specifically, we investigate how the environmental changes lipid nanoparticles experience during storage and delivery and the fundamental properties of macromolecular cargo impact particle structure and dynamics. The effects of lipid charge state and nucleic acid properties are studied through static SAXS and SANS measurements as well as time-resolved SANS, which provides insight into molecular exchange. Such information demonstrates what drives degradation in storage, what parameters can be changed to improve component dissociation allowing more efficient endosomal escape, and how nucleic acid properties can impact lipid formulation selection.