Speaker
Description
Lipid-based drug delivery systems, such as lipid nanoparticles (LNPs), are a promising branch of current medical research. The most notable recent example of such LNP-based molecular delivery are the novel COVID-19 vaccines, where a LNP containing engineered ionizable lipids (ILs) carries an mRNA molecule into the human body. Delivering of short-interfering or messenger RNA into cells is also a very versatile strategy how to silence precisely defined genes or prepare personalised anti-cancer vaccines.
To deliver its cargo into the cell’s cytoplasm, the LNP must first cross the outer cellular membrane. There are several proposed mechanisms of this process, however, the exact nature of the LNP-membrane dynamics has so far gained only limited attention as it is challenging to study experimentally. In contrast, molecular dynamics simulations can provide an insight into complex structures with atomic and femtosecond resolution. In this project we use molecular dynamics to visualize and describe the interactions of the ionizable and membrane lipids, to help understand the fine details of a LNP entering the cell on a molecular level.
We simulated LNPs (in charged and uncharged form of the IL) both on the atomic level (to describe the physical-chemical details of the interaction with biological membrane) and in the coarse-grained resolution to evaluate larger-scale dynamics of LNP-membrane fusion, mimicking a possible endocytosis mechanism.
On the atomic level, the ionizable lipids do not significantly disrupt the membrane structure, however, in the uncharged form they make the centre of the bilayer more hydrophilic. On the coarse-grained level, LNPs induced a change in membrane phase increasing its curvature significantly. Such rapid changes in endosomal membrane stability can explain the mechanism of RNA release. The understanding of LNP behaviour inside cells will be another step towards efficient in-silico design of LNP composition.
