Biological & Soft Matter Seminar: Structural Interiors of Lipid Nanoparticles Regulate RNA Delivery to Cells
Prof. Cecília Leal, University of Illinois, Urbana-Champaign
The scientific community is witnessing the enormous societal impact of research in lipid-based mRNA cellular delivery with the deployment of the COVID-19 vaccine. These lipid nanoparticle (LNP) materials could be useful in many more therapies, but the technology is not always successful because the delivery of RNA to certain cells fails. Some cell types do not undergo endocytosis or, most often, LNPs and RNA remain trapped in endosomal compartments. The development of ionizable lipids was an important discovery for LNPs. Ionizable lipids in combination with other lipids in the LNPs have been recently referred to as “structural lipids”. This is because as endosomal membrane-proteins pump protons onto the endosomal lumen, these lipids become charged and flip the internal structure of the LNPs to a honey-comb arrangement. This structure has been elusively observed to lead to more efficient RNA release into the cytosol before the onset of the endosome-lysosome degradation pathway. Indeed, LNP internal structure controls RNA delivery efficiency. We will share our work over the past 5 years in establishing that LNP nanostructure regulates endosomal escape via a process of protein-free fusion between LNPs and endosomal membranes.