Iterative Design of Ionizable Lipids for Intramuscular mRNA Delivery

• DOI: 10.1021/jacs.2c10670
• Publication Date: 2023-01-18T20:41:21Z
• Authors: Grayson Tilstra; Julien Couture-Se...; Yan Ming Anson Lau; Alanna M. Manning; Daniel S. M. Wong; Wanda W. Janaeska; Titobioluwa A. Wu...; Janice Pang; Omar F. Khan
• Keywords: Rational design

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