Speaker
Description
RNA-based therapy covers a wide range of applications, from cancer therapy, treatment of inherited diseases up to vaccination. The encapsulation of RNAs into ionizable lipids (ILs) containing lipid nanoparticles (LNPs) enabled their safe targeted delivery, but for design of more efficient RNA-LNPs, molecular understanding of LNP-structure and IL-RNA interactions is needed.
Here we simulated LNPs with composition corresponding to currently developed covid-19 vaccines. We observed, that in conditions acidobasically representing LNP preparation (acidic pH), lipids assembled around RNA into a hexagonal phase and formed a rough, non-spherical hydrated LNP.
The change of pH to neutral conditions, representing the environment after LNP administration into human tissues drastically affected the morphology of LNPs. Immediately after IL deprotonation, LNP became spherical and in microseconds time scale, they got gradually dehydrated. Further, we observed lipid separation and creation of an IL-rich phase and a phase rich in ordered saturated phospholipids, that organized to be in contact with water or RNA. During the simulations in neutral conditions, majority of RNA was expelled from LNP, as it lost the favorable electrostatic interactions by neutralization of ILs and the RNA remaining inside LNP was surrounded by helper phospholipid.
We present here the first ever simulation of self-assembly of LNPs containing ILs and their internal morphology. The simulations were performed combining coarse-grained and atomistic resolutions, capturing the dynamics of systems with up to ~3 million of atoms. The simulations support the hypothesis of a solid electron-rich hexagonal phase in the LNP which hosts the RNA. We also give evidence for the fragility of LNPs in neutral conditions, that can explain still very limited efficiency in RNA delivery.
