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

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Title: mRNA Delivery by Lipoamino Fatty Acid–Peptide Polyplexes in Different Lung Cell Models and Lungs.
Authors: Thalmayr, Sophie1,2,3 (AUTHOR), Müller, Joschka2,3,4 (AUTHOR), Polewka, Vivien3,5 (AUTHOR), Gialdini, Irene2,4,6 (AUTHOR), Nguyen, Anny3,4,5 (AUTHOR), Dohmen, Christian3,5,6 (AUTHOR), Lamb, Don C.1,2,6 (AUTHOR), Merkel, Olivia M.2,3,4 (AUTHOR), Wagner, Ernst1,2,3 (AUTHOR) ernst.wagner@cup.uni-muenchen.de
Source: Polymers (20734360). Jun2026, Vol. 18 Issue 11, p1368. 30p.
Subjects: Messenger RNA, Pulmonology, Pulmonary alveoli, Fatty acid derivatives, Peptide amphiphiles, Hyaluronic acid, Transgene expression, Polyethylene glycol
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. [ABSTRACT FROM AUTHOR]
Copyright of Polymers (20734360) is the property of MDPI and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: mRNA Delivery by Lipoamino Fatty Acid–Peptide Polyplexes in Different Lung Cell Models and Lungs.
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  Data: <searchLink fieldCode="AR" term="%22Thalmayr%2C+Sophie%22">Thalmayr, Sophie</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Müller%2C+Joschka%22">Müller, Joschka</searchLink><relatesTo>2,3,4</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Polewka%2C+Vivien%22">Polewka, Vivien</searchLink><relatesTo>3,5</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Gialdini%2C+Irene%22">Gialdini, Irene</searchLink><relatesTo>2,4,6</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nguyen%2C+Anny%22">Nguyen, Anny</searchLink><relatesTo>3,4,5</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Dohmen%2C+Christian%22">Dohmen, Christian</searchLink><relatesTo>3,5,6</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lamb%2C+Don+C%2E%22">Lamb, Don C.</searchLink><relatesTo>1,2,6</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Merkel%2C+Olivia+M%2E%22">Merkel, Olivia M.</searchLink><relatesTo>2,3,4</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wagner%2C+Ernst%22">Wagner, Ernst</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<i> ernst.wagner@cup.uni-muenchen.de</i>
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  Label: Abstract
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  Data: 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. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Polymers (20734360) is the property of MDPI and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.3390/polym18111368
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      – Code: eng
        Text: English
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        PageCount: 30
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      – SubjectFull: Messenger RNA
        Type: general
      – SubjectFull: Pulmonology
        Type: general
      – SubjectFull: Pulmonary alveoli
        Type: general
      – SubjectFull: Fatty acid derivatives
        Type: general
      – SubjectFull: Peptide amphiphiles
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      – SubjectFull: Hyaluronic acid
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      – SubjectFull: Transgene expression
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      – SubjectFull: Polyethylene glycol
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      – TitleFull: mRNA Delivery by Lipoamino Fatty Acid–Peptide Polyplexes in Different Lung Cell Models and Lungs.
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              Text: Jun2026
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