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Research Article

Lipid nanoparticles deliver mRNA to the blood–brain barrier

Yanina Kuzminich1,2, Avraham Shakked3, Randi Calkins3, Sebastian Rudden2,3, Camille Jones3, Jessie Doan3, Bora Jang3, Elisa Schrader Echeverri3, Ryan Zenhausern3, Liming Lian3, David Loughrey3, Hannah E. Peck3, Rachelle Wiese3, Dorothy Koveal3, Philip J. Santangelo3, James E. Dahlman3( )
George C. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, GA 30332, USA
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Graphical Abstract

Lipid nanoparticle without targeting ligands transfects brain endothelial cells upon systemic administration.

Abstract

Lipid nanoparticles (LNPs) have delivered RNA to hepatocytes in patients after intravenous administration. These clinical data support efforts to design LNPs that transfect cells in the central nervous system (CNS). However, delivery to the CNS has been difficult, in large part because quantifying on-target delivery alongside common off-target cell types in adult mice remains challenging. Here we report methods to isolate different cell types from the CNS, and subsequently present mRNA delivery readouts using a liver-detargeted LNP. These data suggest that LNPs without targeting ligands can transfect cerebral endothelial cells in mice after intravenous administration. Given the difficulty of crossing the blood–brain barrier, they also underscore the value of quantifying delivery in the CNS with cell-type resolution instead of whole-tissue resolution.

Keywords

central nervous systemnanomedicineblood–brain barrierlipid nanoparticlemRNA

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Nano Research
Volume 17 Issue 10,
October 2024
Pages 9126-9134
DOI: 10.1007/s12274-024-6827-7
Cite this article:
Kuzminich Y, Shakked A, Calkins R, et al. Lipid nanoparticles deliver mRNA to the blood–brain barrier. Nano Research, 2024, 17(10): 9126-9134. https://doi.org/10.1007/s12274-024-6827-7
Topics:
Nano biology
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Tenth Nano Research Award

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Received: 12 March 2024
Revised: 05 June 2024
Accepted: 13 June 2024
Published: 01 August 2024
© Tsinghua University Press 2024
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