Decoding the Structure-Function Relationships of RNA-Lipid Nanoparticles

Messenger RNA lipid nanoparticles (mRNA-LNPs) have transformed the field of nucleic acid therapeutics, enabling powerful new approaches in vaccines, gene therapy, and protein replacement technologies. Despite their clinical success, the fundamental relationships between nanoparticle structure, physicochemical properties, and biological function remain poorly understood. Our lab focuses on uncovering these structure-property-function relationships to guide the rational design of next-generation mRNA delivery systems. We investigate how nanoscale organization within mRNA-LNPs influences key performance metrics such as stability,  endosomal escape, and transfection efficiency.

Our research explores how formulation variables, including lipid composition, cargo type and loading, buffer chemistry, pH, storage conditions, shape the internal architecture and dynamics of mRNA-LNPs. We are particularly interested in understanding how lipid packing, mRNA-lipid interactions, and phase behavior govern nanoparticle performance under both fresh and frozen storage conditions. To study these systems, we integrate advanced biophysical and structural characterization tools such as small-angle X-ray scattering (SAXS), cryogenic electron microscopy (cryo-EM), and functional delivery assays. We also employ DENSS (DENsity from Solution Scattering) reconstruction methods to generate three-dimensional electron density maps directly from SAXS data, enabling visualization of nanoscale structural features in mRNA-LNPs. By connecting molecular organization to biological outcomes, our goal is to establish mechanistic design principles for more stable, efficient, and clinically translatable mRNA-LNP technologies.