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Effective mRNA pulmonary delivery by dry powder formulation of PEGylated synthetic KL4 peptide
Open accessAbstract
Pulmonary delivery of messenger RNA (mRNA) has considerable potential as therapy or vaccine for a range of lung diseases. Inhaled dry powder formulation of mRNA is particularly attractive as it has superior stability and dry powder inhaler is relatively easy to use. A safe and effective mRNA delivery vector as well as a suitable particle engineering method are required to produce a dry powder formulation that is respirable and mediates robust transfection in the lung. Here, we introduce a novel RNA delivery vector, PEG12KL4, in which the synthetic cationic KL4 peptide is attached to a monodisperse linear PEG of 12-mers. The PEG12KL4 formed nano-sized complexes with mRNA at 10:1 ratio (w/w) and mediated effective transfection on human lung epithelial cells. PEG12KL4/mRNA complexes were successfully formulated into dry powder by spray drying (SD) and spray freeze drying (SFD) techniques. Both SD and SFD powder exhibited satisfactory aerosol properties for inhalation. More importantly, the biological activity of the PEG12KL4 /mRNA complexes were successfully preserved after drying. Using luciferase mRNA, the intratracheal administration of the liquid or powder aerosol of PEG12KL4 /mRNA complexes at a dose of 5 μg mRNA resulted in luciferase expression in the deep lung region of mice 24 h post-transfection. The transfection efficiency was superior to naked mRNA or lipoplexes (Lipofectamine 2000), in which luciferase expression was weaker and restricted to the tracheal region only. There was no sign of inflammatory response or toxicity of the PEG12KL4 /mRNA complexes after single intratracheal administration. Overall, PEG12KL4 is an excellent mRNA transfection agent for pulmonary delivery. This is also the first study that successfully demonstrates the preparation of inhalable dry powder mRNA formulations with in vivo transfection efficiency, showing the great promise of PEG12KL4 peptide as a mRNA delivery vector candidate for clinical applications.
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Metadata
- Authors
- Qiu, Y., Man, R. C. H., Liao, Q., Kung, K. L. K., Chow, M. Y. T., & Lam, J. K. W.
- Affiliations
- University of Hong Kong (HK)
- The University of Sydney (AU)
- Corresponding author
- Lam, Jenny K.W.
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 314
- Pages
- 102-115
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2980850909
- Cited by
- 178
- References
- 41
- Citations by year
- 2026: 11 · 2025: 28 · 2024: 25 · 2023: 37 · 2022: 36 · 2021: 24 · 2020: 15 · 2019: 1
- FWCI
- 14.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Controlled Release (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- University of Hong Kong (201711159172)
- King's College London
- National Natural Science Foundation of China (NSFC 81573373)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- mRNA delivery, pulmonary drug delivery, dry powder formulation, PEGylation, cationic peptides, spray drying, spray freeze drying, aerosol properties, intratracheal administration, luciferase expression, lipoplexes, dry powder inhaler, mRNA vaccines
- MeSH terms
- A549 Cells, Administration, Inhalation, Aerosols, Animals, Epithelial Cells, Female, Freeze Drying, Humans, Lipids, Lung, Mice, Inbred BALB C, Polyethylene Glycols, RNA, Messenger, Transfection, Intercellular Signaling Peptides and Proteins, Mice, Dry Powder Inhalers
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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