Structure and Dynamics of Self-Assembled Lipid Nanoparticles for Nucleic Acid Delivery

Nucleic acids can revolutionize human health outcomes, as evidenced by the mRNA vaccines used to combat COVID-19. Despite the success of these therapeutics, the fundamental physicochemical 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 assess how the storage and delivery conditions of the nanoparticles impact their structure and dynamics. The components which come together to encapsulate the nucleic acids have complex non-covalent interactions at the nanoscale which dictate their ability to withstand storage conditions and transport to cells while also disassociating upon intracellular delivery to release cargo. Here we show that the molecular interactions within the drug delivery vehicles, including exchange kinetics of the self-assembled molecules, are impacted by relevant environmental factors, including pH. Such information demonstrates what drives degradation and what parameters can be changed to improve delivery by increasing the efficiency of endosomal escape. Ultimately, these results can be used to optimize efficacy, enabling more flexible storage requirements, lower dosages, and improved therapeutic tolerances.