The replacement of helper lipids with charged alternatives in lipid nanoparticles facilitates targeted mRNA delivery to the spleen and lungs

• DOI: 10.1016/j.jconrel.2022.03.046
• Publication Date: 2022-03-25T21:02:56Z
• Authors: Samuel T. LoPresti; Mariah L. Arral; Namit Chaudhary; Kathryn A. Whitehead
• Keywords: Solid lipid nanoparticle

The broad clinical application of mRNA therapeutics has been hampered by a lack delivery vehicles that induce protein expression in extrahepatic organs and tissues. Recently, it was shown to the spleen or lungs is possible upon addition charged lipid standard four-component nanoparticle formulation. This approach, while effective, further complicates an already complex drug formulation potential slow regulatory approval adversely impact manufacturing processes. We were thus motivated maintain system achieving shifts tropism. To end, we replaced helper lipidoid nanoparticles, DOPE, with one eight alternatives. These lipids included neutral lipids, DOPC, sphingomyelin, ceramide; anionic phosphatidylserine (PS), phosphatidylglycerol, phosphatidic acid; cationic DOTAP ethyl phosphatidylcholine. While maintained liver, shifted lungs, respectively. For example, replacing DOPE increased positive LNP surface charge at pH 7 5-fold altered ratio liver lung from 36:1 1:56. Similarly, PS reduced half 8:1 1:3. Effects consistent across ionizable chemistries. Regarding mechanism, nanoparticles formulated best transfected epithelial immune cells, Further, lung-tropic effect linked cell infiltration compared lipids. Together, these data show intravenous non-hepatocellular readily achievable maintaining modified chemistry.