Piperazine-derived lipid nanoparticles deliver mRNA to immune cells in vivo

Huanzhen Ni, Marine Z. C. Hatit, Kun Zhao, David Loughrey, Melissa P. Lokugamage, Hannah E. Peck, Ada Del Cid, Abinaya Muralidharan, YongTae Kim, Philip J. Santangelo and James E. Dahlman ()
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Huanzhen Ni: Georgia Institute of Technology
Marine Z. C. Hatit: Georgia Institute of Technology
Kun Zhao: Georgia Institute of Technology
David Loughrey: Georgia Institute of Technology
Melissa P. Lokugamage: Georgia Institute of Technology
Hannah E. Peck: Georgia Institute of Technology
Ada Del Cid: Georgia Institute of Technology
Abinaya Muralidharan: Georgia Institute of Technology
YongTae Kim: Georgia Institute of Technology
Philip J. Santangelo: Georgia Institute of Technology
James E. Dahlman: Georgia Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: Abstract In humans, lipid nanoparticles (LNPs) have safely delivered therapeutic RNA to hepatocytes after systemic administration and to antigen-presenting cells after intramuscular injection. However, systemic RNA delivery to non-hepatocytes remains challenging, especially without targeting ligands such as antibodies, peptides, or aptamers. Here we report that piperazine-containing ionizable lipids (Pi-Lipids) preferentially deliver mRNA to immune cells in vivo without targeting ligands. After synthesizing and characterizing Pi-Lipids, we use high-throughput DNA barcoding to quantify how 65 chemically distinct LNPs functionally delivered mRNA (i.e., mRNA translated into functional, gene-editing protein) in 14 cell types directly in vivo. By analyzing the relationships between lipid structure and cellular targeting, we identify lipid traits that increase delivery in vivo. In addition, we characterize Pi-A10, an LNP that preferentially delivers mRNA to the liver and splenic immune cells at the clinically relevant dose of 0.3 mg/kg. These data demonstrate that high-throughput in vivo studies can identify nanoparticles with natural non-hepatocyte tropism and support the hypothesis that lipids with bioactive small-molecule motifs can deliver mRNA in vivo.

Date: 2022
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DOI: 10.1038/s41467-022-32281-5

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