System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Epublish

PubMed: 42280578 DOI: 10.3390/polym18111368

mRNA Delivery by Lipoamino Fatty Acid-Peptide Polyplexes in Different Lung Cell Models and Lungs.

Polymers (Basel) 18(11)

Authors: Sophie Thalmayr, Joschka Müller, Vivien Polewka, Irene Gialdini, Anny Nguyen, Christian Dohmen, Don C Lamb, Olivia M Merkel, Ernst Wagner

Affiliations

  • Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, 80799 Munich, Germany.
  • CNATM-Cluster for Nucleic Acid Therapeutics Munich, 81377 Munich, Germany.
  • Pharmaceutical Technology and Biopharmaceutics, Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • CNATM-Cluster for Nucleic Acid Therapeutics Munich, 81377 Munich, Germany. Ethris GmbH, 82152 Planegg, Germany.
  • Department of Chemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Ethris GmbH, 82152 Planegg, Germany.

Abstract

Local pulmonary delivery offers a non-invasive application route for mRNA therapeutics with the potential for high bioavailability at the target-site of applications such as mucosal vaccination or the treatment of lung diseases. However, efficient delivery remains challenging due to major lung-specific barriers, particularly mucus. Herein, pH-responsive, amphiphilic xenopeptides comprising lipoamino fatty acids and oligoamino acids (OAAs) connected in distinct branched U-shape or bundle topologies were evaluated as mRNA polyplexes for delivery to A549 and Calu-3 lung cells under standard submerged or air-liquid interface (ALI) transfection conditions, and upon intratracheal application in BALB/c mice. Optionally, polyplexes were coated with negatively charged hyaluronic acid (HA) or colloidally stabilized with poly(ethylene glycol) (PEG). For U-shapes, hydrophobic modification of the OAA domain boosted their efficiency. Interestingly, best-performing formulations varied across transfection conditions. While the bundle topology showed the highest potential in submerged cell culture, U-shaped carriers were more efficient under ALI conditions. Polyplex surface modification with HA or PEG did not strongly alter in vitro transfections, whereas hydrophobized U-shape core polyplexes combined with surface modification enhanced their efficiency in vivo. Thus, the cationizable core and surface properties of mRNA nanoparticles require specific balancing in various lung cell models and lung.

MeSH

Cells, Lung, Hyaluronic Acid, Nanoparticles, Rna, Messenger, Therapeutics, Transfection, Fatty Acids