Cationic cholesterol-dependent LNP delivery to lung stem cells, the liver, and heart
Afsane Radmand, Hyejin Kim, Jared Beyersdorf, Curtis N. Dobrowolski, Ryan Zenhausern, Kalina Paunovska, Sebastian G. Huayamares, Xuanwen Hua, Keyi Han, David Loughrey, Marine Z. C. Hatit, Ada Del Cid, Huanzhen Ni, Aram Shajii, Andrea Li, Abinaya Muralidharan, Hannah E. Peck, Karen E. Tiegreen, Shu Jia, Philip J. Santangelo, James E. Dahlman- Multidisciplinary
Adding a cationic helper lipid to a lipid nanoparticle (LNP) can increase lung delivery and decrease liver delivery. However, it remains unclear whether charge-dependent tropism is universal or, alternatively, whether it depends on the component that is charged. Here, we report evidence that cationic cholesterol-dependent tropism can differ from cationic helper lipid-dependent tropism. By testing how 196 LNPs delivered mRNA to 22 cell types, we found that charged cholesterols led to a different lung:liver delivery ratio than charged helper lipids. We also found that combining cationic cholesterol with a cationic helper lipid led to mRNA delivery in the heart as well as several lung cell types, including stem cell-like populations. These data highlight the utility of exploring charge-dependent LNP tropism.