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

Author

Listed:
  • Huanzhen Ni

    (Georgia Institute of Technology)

  • Marine Z. C. Hatit

    (Georgia Institute of Technology)

  • Kun Zhao

    (Georgia Institute of Technology
    Shandong University)

  • 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
    Georgia Institute of Technology)

  • YongTae Kim

    (Georgia Institute of Technology
    Georgia Institute of Technology
    Georgia Institute of Technology
    Georgia Institute of Technology)

  • Philip J. Santangelo

    (Georgia Institute of Technology)

  • James E. Dahlman

    (Georgia Institute of Technology)

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.

Suggested Citation

  • 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 & James E. Dahlman, 2022. "Piperazine-derived lipid nanoparticles deliver mRNA to immune cells in vivo," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32281-5
    DOI: 10.1038/s41467-022-32281-5
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    Cited by:

    1. Jae-Hyeon Lee & Hansol Lim & Gaeun Ma & Seho Kweon & Seong Jin Park & Minho Seo & Jun-Hyuck Lee & Seong-Bin Yang & Han-Gil Jeong & Jooho Park, 2024. "Nano-anticoagulant based on carrier-free low molecular weight heparin and octadecylamine with an albumin shuttling effect," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Zhijian Li & Laura Amaya & Ruoxi Pi & Sean K. Wang & Alok Ranjan & Robert M. Waymouth & Catherine A. Blish & Howard Y. Chang & Paul A. Wender, 2023. "Charge-altering releasable transporters enhance mRNA delivery in vitro and exhibit in vivo tropism," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Lulu Xue & Alex G. Hamilton & Gan Zhao & Zebin Xiao & Rakan El-Mayta & Xuexiang Han & Ningqiang Gong & Xinhong Xiong & Junchao Xu & Christian G. Figueroa-Espada & Sarah J. Shepherd & Alvin J. Mukalel , 2024. "High-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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