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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\u2013liquid 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.<\/jats:p>","DOI":"10.3390\/polym18111368","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T08:09:16Z","timestamp":1780301356000},"page":"1368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["mRNA Delivery by Lipoamino Fatty Acid\u2013Peptide Polyplexes in Different Lung Cell Models and Lungs"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6457-3965","authenticated-orcid":false,"given":"Sophie","family":"Thalmayr","sequence":"first","affiliation":[{"name":"Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"},{"name":"Center for NanoScience (CeNS), Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 80799 Munich, Germany"},{"name":"CNATM\u2014Cluster for Nucleic Acid Therapeutics Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joschka","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"CNATM\u2014Cluster for Nucleic Acid Therapeutics Munich, 81377 Munich, Germany"},{"name":"Pharmaceutical Technology and Biopharmaceutics, Department of Pharmacy, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivien","family":"Polewka","sequence":"additional","affiliation":[{"name":"CNATM\u2014Cluster for Nucleic Acid Therapeutics Munich, 81377 Munich, Germany"},{"name":"Ethris GmbH, 82152 Planegg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8193-1840","authenticated-orcid":false,"given":"Irene","family":"Gialdini","sequence":"additional","affiliation":[{"name":"Center for NanoScience (CeNS), Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 80799 Munich, Germany"},{"name":"Department of Chemistry, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anny","family":"Nguyen","sequence":"additional","affiliation":[{"name":"CNATM\u2014Cluster for Nucleic Acid Therapeutics Munich, 81377 Munich, Germany"},{"name":"Pharmaceutical Technology and Biopharmaceutics, Department of Pharmacy, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Dohmen","sequence":"additional","affiliation":[{"name":"CNATM\u2014Cluster for Nucleic Acid Therapeutics Munich, 81377 Munich, Germany"},{"name":"Ethris GmbH, 82152 Planegg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0232-1903","authenticated-orcid":false,"given":"Don C.","family":"Lamb","sequence":"additional","affiliation":[{"name":"Center for NanoScience (CeNS), Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 80799 Munich, Germany"},{"name":"Department of Chemistry, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4151-3916","authenticated-orcid":false,"given":"Olivia M.","family":"Merkel","sequence":"additional","affiliation":[{"name":"Center for NanoScience (CeNS), Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 80799 Munich, Germany"},{"name":"CNATM\u2014Cluster for Nucleic Acid Therapeutics Munich, 81377 Munich, Germany"},{"name":"Pharmaceutical Technology and Biopharmaceutics, Department of Pharmacy, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8413-0934","authenticated-orcid":false,"given":"Ernst","family":"Wagner","sequence":"additional","affiliation":[{"name":"Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"},{"name":"Center for NanoScience (CeNS), Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 80799 Munich, Germany"},{"name":"CNATM\u2014Cluster for Nucleic Acid Therapeutics Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1056\/NEJMoa2035389","article-title":"Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine","volume":"384","author":"Baden","year":"2021","journal-title":"N. 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