PolymersJun 12, 2026

mRNA Delivery Using Lipid-Peptide Complexes in Various Lung Cell Types and Lung Tissue

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 13, 2026

Abstract

pH-responsive, amphiphilic xenopeptides may enhance mRNA delivery efficiency to lung cells.

Local pulmonary delivery presents a non-invasive approach for mRNA therapeutics targeting lung diseases.
Efficient delivery is challenged by barriers such as mucus present in the lungs.
U-shaped polyplexes demonstrated improved delivery efficiency under air-liquid interface conditions compared to bundle topologies.
Best-performing formulations differed based on the transfection environment, indicating a need for tailored approaches.
Surface modifications with hyaluronic acid or polyethylene glycol did not significantly impact in vitro transfection rates.
Hydrophobized U-shaped core polyplexes combined with surface modifications showed enhanced efficiency in vivo.

Simplified

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.

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Funding

Competing interests

O.M.M. is an advisory board member for Coriolis Pharma GmbH, Corden Pharma GmbH, AMW GmbH, and has equity interests in RNhale GmbH. C.D. is an employee of Ethris GmbH, Planegg, Germany who has provided mRNA constructs for this study. V.P. was an employee of Ethris during the experiments, but is no longer. The other authors declare no conflicts of interest.

PubMed

mRNA Delivery Using Lipid-Peptide Complexes in Various Lung Cell Types and Lung Tissue

Abstract

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Funding

Competing interests

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Abstract

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