A single methylene group in oligoalkylamine‐based cationic polymers and lipids promotes enhanced mRNA delivery
Abstract
The development of chemically modified mRNA holds great promise as a new class of biologic therapeutics. However, the intracellular delivery and endosomal escape of mRNA encapsulated in nanoparticles has not been systematically investigated. Here, we synthesized a diverse set of cationic polymers and lipids from a series of oligoalkylamines and subsequently characterized their mRNA delivery capability. Notably, a structure with an alternating alkyl chain length between amines showed the highest transfection efficiency, which was linked to a high buffering capacity in a narrow range of pH 6.2 to 6.5. Variation in only one methylene group resulted in enhanced mRNA delivery to both the murine liver as well as porcine lungs after systemic or aerosol administration, respectively. These findings reveal a novel fundamental structure-activity relationship for the delivery of mRNA that is independent of the class of mRNA carrier and define a promising new path of exploration in the field of mRNA therapeutics.
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Compared with other organs, a stronger luciferase signal in the lungs indicated pulmonary specificity of C12-(2-3-2) oligoalkylamine lipid micelle nanoparticles.
“Compared with other organs, the stronger luciferase signal in the lungs indicated the pulmonary specificity.”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [192]
After 6 hours, obvious accumulation of ACE2 mRNA and proteins was observed in the lungs after i.v. delivery by lung-targeted nanoparticles.
“After 6 hours, obvious accumulation of ACE2 mRNA and proteins were observed in the lungs.[192, 193]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [192]
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References 17 · Cited by 101
- Authors
- Jarzębińska, A., Pasewald, T., Lambrecht, J., Mykhaylyk, O., Kümmerling, L., Beck, P., Hasenpusch, G., Rudolph, C., Plank, C., & Dohmen, C.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- Ethris (Germany) (DE)
- Technical University of Munich (DE)
- Corresponding author
- Dohmen, Christian
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2016-07-04
- Volume
- 55
- Issue
- 33
- Pages
- 9591-9595
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- OpenAlex
- W2462639992
- Cited by
- 101
- References
- 17
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 8 · 2023: 8 · 2022: 12 · 2021: 13 · 2020: 10 · 2019: 10 · 2018: 10 · 2017: 13 · 2016: 6
- FWCI
- 6.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Ministry of Education (0315986)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- mRNA delivery, cationic polymers, cationic lipids, methylene groups, structure-activity relationship, endosomal escape, nanocarriers, chemically modified mRNA, mRNA therapeutics, transfection efficiency, buffering capacity, aerosol delivery, systemic drug delivery, lung delivery
- MeSH terms
- Amines, Animals, Cations, Lipids, Polymers, RNA, Messenger, Structure-Activity Relationship, Swine, NIH 3T3 Cells, Mice
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