Cationic cholesterol- dependent LNP delivery to lung stem cells, the liver, and heart

• 成果类型: Article
• 署名作者: Radmand, Afsane; Kim, Hyejin; Beyersdorf, Jared; Dobrowolski, Curtis N.; Zenhausern, Ryan; Paunovska, Kalina; Huayamares, Sebastian G.; Hua, Xuanwen; Han, Keyi; Loughrey, David; Hatit, Marine Z. C.; Del Cid, Ada; Ni, Huanzhen; Shajii, Aram; Li, Andrea; Muralidharan, Abinaya; Peck, Hannah E.; Tiegreen, Karen E.; Jia, Shu; Santangelo, Philip J.; Dahlman, James E.
• 署名单位: University System of Georgia; Georgia Institute of Technology; University System of Georgia; Georgia Institute of Technology; University System of Georgia; Georgia Institute of Technology; Emory University; University System of Georgia; Georgia Institute of Technology; University System of Georgia; Georgia Institute of Technology
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14455
• DOI: 10.1073/pnas.2307801120
• 发表日期: 2024-03-12
• 关键词: messenger-rna; lipid nanoparticles; in-vivo; DISCOVERY; platform; potent

摘要

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.