2. Academic Validation
  3. Piperazine-derived lipid nanoparticles deliver mRNA to immune cells in vivo

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

  • Nat Commun. 2022 Aug 15;13(1):4766. doi: 10.1038/s41467-022-32281-5.
Huanzhen Ni # 1,  Marine Z C Hatit # 1,  Kun Zhao # 1 2,  David Loughrey 1,  Melissa P Lokugamage 1,  Hannah E Peck 3,  Ada Del Cid 1,  Abinaya Muralidharan 4 5,  YongTae Kim 1 3 4 5,  Philip J Santangelo 1,  James E Dahlman 6
Affiliations

Affiliations

  • 1 Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
  • 2 School of Pharmaceutical Sciences, Shandong University, Jinan, China.
  • 3 Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
  • 4 George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
  • 5 Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA, USA.
  • 6 Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. james.dahlman@bme.gatech.edu.
  • # Contributed equally.
PMID: 35970837 DOI: 10.1038/s41467-022-32281-5
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.

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