Development of Sulfonium- and Phosphonium-based Cationic Lipid Materials for mRNA Delivery - SUMMARY
The mRNA-based therapeutics has wide applications in disease prevention and
treatment. However, its wide practical application is largely limited by the delivery
concerns. Cationic lipids are effective carrier materials for mRNA delivery and the
chemical structure of lipid molecules is critical in determining the delivery efficacy.
However, currently, there are no wide-accepted guiding principles exist for rational lipid
molecule structure design to achieve presumed biological effects. The integration of
combinatorial chemistry and in vitro/in vivo screening approach has been demonstrated
useful in developing effective lipid carriers. Great efforts have been put into the synthesis
of new lipids with novel chemical structures. However, despite all the promising results,
almost all currently developed cationic lipids for mRNA delivery contain primary,
secondary, tertiary, or quaternized amino groups as the chargeable units to interact with
the cargo mRNAs. In this study, we propose to develop two new types of cationic lipid
molecules with sulfonium- and phosphonium-containing heads and biodegradable tails
and explore their applications in in vitro mRNA delivery. Our hypothesis is that contrary
to traditional amine-based cationic lipids, the sulfonium- and phosphonium-based lipids
will have unprecedented self-assembly behaviors, mRNA delivery performances, cell
targeting, and biocompatibility profiles. By using combinatorial library synthesis strategy,
in vitro screening approach, and formulation optimization methods, this project is the first
to develop biodegradable sulfonium- and phosphonium-based lipids and to explore their
feasibility and safety for intracellular mRNA delivery. The new lipid materials developed
in this study can also be used in future studies to deliver other types of therapeutics,
such as small molecule drugs, proteins, and genes.
