2. Academic Validation
  3. Lipoamino bundle LNPs for efficient mRNA transfection of dendritic cells and macrophages show high spleen selectivity

Lipoamino bundle LNPs for efficient mRNA transfection of dendritic cells and macrophages show high spleen selectivity

  • Eur J Pharm Biopharm. 2023 Dec 6:S0939-6411(23)00314-4. doi: 10.1016/j.ejpb.2023.11.025.
Franziska Haase 1,  Jana Pöhmerer 2,  Mina Yazdi 3,  Melina Grau 4,  Yanira Zeyn 5,  Ulrich Wilk 6,  Tobias Burghardt 7,  Miriam Höhn 8,  Christoph Hieber 9,  Matthias Bros 10,  Ernst Wagner 11,  Simone Berger 12
Affiliations

Affiliations

  • 1 Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität Munich, Butenandtstrasse 5-13, 81377 Munich, Germany. Electronic address: [email protected].
  • 2 Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität Munich, Butenandtstrasse 5-13, 81377 Munich, Germany. Electronic address: [email protected].
  • 3 Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität Munich, Butenandtstrasse 5-13, 81377 Munich, Germany. Electronic address: [email protected].
  • 4 Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität Munich, Butenandtstrasse 5-13, 81377 Munich, Germany. Electronic address: [email protected].
  • 5 Department of Dermatology, University Medical Center of the Johannes Gutenberg University (JGU) Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. Electronic address: [email protected].
  • 6 Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität Munich, Butenandtstrasse 5-13, 81377 Munich, Germany. Electronic address: [email protected].
  • 7 Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität Munich, Butenandtstrasse 5-13, 81377 Munich, Germany. Electronic address: [email protected].
  • 8 Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität Munich, Butenandtstrasse 5-13, 81377 Munich, Germany. Electronic address: [email protected].
  • 9 Department of Dermatology, University Medical Center of the Johannes Gutenberg University (JGU) Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. Electronic address: [email protected].
  • 10 Department of Dermatology, University Medical Center of the Johannes Gutenberg University (JGU) Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. Electronic address: [email protected].
  • 11 Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität Munich, Butenandtstrasse 5-13, 81377 Munich, Germany; Center for Nanoscience, Ludwig-Maximilians-Universität Munich, Geschwister-Scholl-Platz 1, 80539 Munich, Germany; CNATM - Cluster for Nucleic Acid Therapeutics Munich, Germany. Electronic address: [email protected].
  • 12 Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität Munich, Butenandtstrasse 5-13, 81377 Munich, Germany; Center for Nanoscience, Ludwig-Maximilians-Universität Munich, Geschwister-Scholl-Platz 1, 80539 Munich, Germany; CNATM - Cluster for Nucleic Acid Therapeutics Munich, Germany. Electronic address: [email protected].
PMID: 38065313 DOI: 10.1016/j.ejpb.2023.11.025
Abstract

Messenger RNA (mRNA) is a powerful tool for nucleic acid-based therapies and vaccination, but efficient and specific delivery to target tissues remains a significant challenge. In this study, we demonstrate lipoamino xenopeptide carriers as components of highly efficient mRNA LNPs. These lipo-xenopeptides are defined as 2D sequences in different 3D topologies (bundles or different U-shapes). The polar artificial amino acid tetraethylene pentamino succinic acid (Stp) and various lipophilic tertiary lipoamino fatty acids (LAFs) act as ionizable amphiphilic units, connected in different ratios via bisamidated lysines as branching units. A series of more lipophilic LAF4-Stp1 carriers with bundle topology is especially well suited for efficient encapsulation of mRNA into LNPs, facilitated cellular uptake and strongly enhanced endosomal escape. These LNPs display improved, faster transfection kinetics compared to standard LNP formulations, with high potency in a variety of tumor cell lines (including N2a neuroblastoma, HepG2 and Huh7 hepatocellular, and HeLa cervical carcinoma cells), J774A.1 macrophages, and DC2.4 dendritic cells. High transfection levels were obtained even in the presence of serum at very low sub-microgram mRNA doses. Upon intravenous application of only 3 µg mRNA per mouse, in vivo mRNA expression is found with a high selectivity for dendritic cells and macrophages, resulting in a particularly high overall preferred expression in the spleen.

Keywords

Amino ethylene; Dendritic cells; LNPs; Lipoamino fatty acid; Macrophages; Spleen; Xenopeptides; mRNA.

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