Lipid nanoparticle-mediated mRNA delivery to CD34+ cells in rhesus monkeys

Hyejin Kim; Ryan Zenhausern; Kara Gentry; Liming Lian; Sebastian G Huayamares; Afsane Radmand; David Loughrey; Ananda R Podilapu; Marine Z C Hatit; Huanzhen Ni; Andrea Li; Aram Shajii; Hannah E Peck; Keyi Han; Xuanwen Hua; Shu Jia; Michele Martinez; Charles Lee; Philip J Santangelo; Alice Tarantal; James E Dahlman

doi:10.1038/s41587-024-02470-2

Lipid nanoparticle-mediated mRNA delivery to CD34⁺ cells in rhesus monkeys

Nat Biotechnol. 2024 Nov 22. doi: 10.1038/s41587-024-02470-2. Online ahead of print.

Authors

Hyejin Kim^#¹, Ryan Zenhausern^#¹, Kara Gentry¹, Liming Lian¹, Sebastian G Huayamares¹, Afsane Radmand^{2

3}, David Loughrey¹, Ananda R Podilapu¹, Marine Z C Hatit¹, Huanzhen Ni¹, Andrea Li¹, Aram Shajii¹, Hannah E Peck¹, Keyi Han¹, Xuanwen Hua¹, Shu Jia¹, Michele Martinez⁴, Charles Lee^{4

5}, Philip J Santangelo¹, Alice Tarantal^{4

5

6}, James E Dahlman⁷

Affiliations

¹ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA.
² Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
³ Department of Chemical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
⁴ California National Primate Research Center, University of California, Davis, Davis, CA, USA.
⁵ Department of Pediatrics, University of California, Davis, Davis, CA, USA.
⁶ Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, USA.
⁷ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA. james.dahlman@emory.edu.

^# Contributed equally.

PMID: 39578569
DOI: 10.1038/s41587-024-02470-2

Abstract

Transplantation of ex vivo engineered hematopoietic stem cells (HSCs) can lead to robust clinical responses but carries risks of adverse events from bone marrow mobilization, chemotherapy conditioning and other factors. HSCs have been modified in vivo using lipid nanoparticles (LNPs) decorated with targeting moieties, which increases manufacturing complexity. Here we screen 105 LNPs without targeting ligands for effective homing to the bone marrow in mouse. We report an LNP named LNP⁶⁷ that delivers mRNA to murine HSCs in vivo, primary human HSCs ex vivo and CD34⁺ cells in rhesus monkeys (Macaca mulatta) in vivo at doses of 0.25 and 0.4 mg kg^-1. Without mobilization and conditioning, LNP⁶⁷ can mediate delivery of mRNA to HSCs and their progenitor cells (HSPCs), as well as to the liver in rhesus monkeys, without serum cytokine activation. These data support the hypothesis that in vivo delivery to HSCs and HSPCs in nonhuman primates is feasible without targeting ligands.

Abstract

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