Iterative Design of Ionizable Lipids for Intramuscular mRNA Delivery

Jan 18, 2023Journal of the American Chemical Society

Improving Ionizable Lipids Step-by-Step for Muscle Injection of mRNA

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Abstract

The combination of ionizable lipids with an ethanolamine core and an apparent pK between 6.6 and 6.9 maximizes intramuscular mRNA delivery.

Small structural changes in ionizable lipids can significantly improve mRNA delivery.
A nonlinear relationship exists between the lipid-to-mRNA mass ratio and protein expression.
The findings suggest that there may be a critical mass ratio for effective LNPs that depends on lipid structure.
Key design parameters impacting intramuscular mRNA delivery include hydrogen bonding, ionization behavior, and lipid-to-mRNA mass ratio.
An iterative design strategy was employed to generate potent ionizable lipids, revealing important structure-activity relationships.

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Lipid nanoparticles (LNPs) are the most clinically advanced delivery vehicles for RNA and have enabled the development of RNA-based drugs such as the mRNA COVID-19 vaccines. Functional delivery of mRNA by an LNP greatly depends on the inclusion of an ionizable lipid, and small changes to these lipid structures can significantly improve delivery. However, the structure-function relationships between ionizable lipids and mRNA delivery are poorly understood, especially for LNPs administered intramuscularly. Here, we show that the iterative design of a novel series of ionizable lipids generates key structure-activity relationships and enables the optimization of chemically distinct lipids with efficacy that is on-par with the current state of the art. We find that the combination of ionizable lipids comprising an ethanolamine core and LNPs with an apparent pKbetween 6.6 and 6.9 maximizes intramuscular mRNA delivery. Furthermore, we report a nonlinear relationship between the lipid-to-mRNA mass ratio and protein expression, suggesting that a critical mass ratio exists for LNPs and may depend on ionizable lipid structure. Our findings add to the mechanistic understanding of ionizable lipids and demonstrate that hydrogen bonding, ionization behavior, and lipid-to-mRNA mass ratio are key design parameters affecting intramuscular mRNA delivery. We validate these insights by applying them to the rational design of new ionizable lipids. Overall, our iterative design strategy efficiently generates potent ionizable lipids. This hypothesis-driven method reveals structure-activity relationships that lay the foundation for the optimization of ionizable lipids in future LNP-RNA drugs. We foresee that this design strategy can be extended to other optimization parameters beyond intramuscular expression. a

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Iterative Design of Ionizable Lipids for Intramuscular mRNA Delivery

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