Atomistic Insights into Organization of RNA Loaded Lipid Nanoparticles

RNA-based therapies have shown promise in a wide range of applications, from cancer therapy, treatment of inherited diseases to vaccination. Encapsulation of RNA into ionizable lipid (IL) containing lipid nanoparticles (LNPs) has enabled its safe and targeted delivery. We present here the first simulations of self-assembly process of pH-sensitive RNA-carrying LNPs and their internal morphology. At low pH, our simulations confirm a solid, electron-rich core with lipids encapsulating RNA in hexagonal phase. At neutral pH, representing the environment after LNP administration into human tissues, LNPs expelled most of the encapsulated RNA and water and formed separate bulk IL-rich and ordered helper-lipid-rich phase. Helper lipids arranged themselves to be in contact with RNA or water. The presented models provide atomistic understanding of LNP structure and open a way to investigate them in-silico, varying the LNP composition or interacting with other biostructures aiming at increasing the efficiency of RNA-based medicine.