Optimization of a degradable polymer–lipid nanoparticle for potent systemic delivery of mRNA to the lung endothelium and immune cells
Open accessAbstract
mRNA therapeutics hold great potential for treating a variety of diseases through protein-replacement, immunomodulation, and gene editing. However, much like siRNA therapy the majority of progress in mRNA delivery has been confined to the liver. Previously, we demonstrated that poly(β-amino esters), a class of degradable polymers, are capable of systemic mRNA delivery to the lungs in mice when formulated into nanoparticles with poly(ethylene glycol)-lipid conjugates. Using experimental design, a statistical approach to optimization that reduces experimental burden, we demonstrate herein that these degradable polymer-lipid nanoparticles can be optimized in terms of polymer synthesis and nanoparticle formulation to achieve a multiple order-of-magnitude increase in potency. Furthermore, using genetically engineered Cre reporter mice, we demonstrate that mRNA is functionally delivered to both the lung endothelium and pulmonary immune cells, expanding the potential utility of these nanoparticles.
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Through optimization of polymer construction and nanoparticle formulation, a hybrid polymer-lipid nanoparticle showed comparable lung-specificity but two orders-of-magnitude more effective mRNA delivery than the base nanoparticle.
“Through optimization of the polymer construction and nanoparticle formulation, they obtained a nanoparticle which showed comparable lung-specificity but two orders-of-magnitude more effective in mRNA delivery than the base nanoparticle.[194]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [194]
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References 44 · Cited by 218
Research works printed but not linked: 3
- [28]Lynn DM; Langer RJ Am. Chem. Soc 2000, 122 (44), 10761– 10768.
- [33]Fourth Odian, G..; John Wiley & Sons, Inc.: Hoboken, NJ, 2004.
- [38]Jones B; Nachtsheim CJ J. Qual. Technol 2011, 43 (1), 1– 15.
- Authors
- Kaczmarek, J. C., Kauffman, K. J., Fenton, O. S., Sadtler, K., Patel, A. K., Heartlein, M. W., DeRosa, F., & Anderson, D. G.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- University of Nottingham (GB)
- Translate Bio (United States) (US)
- Harvard–MIT Division of Health Sciences and Technology (US)
- Corresponding author
- Anderson, Daniel G.
- Venue
- Nano Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-09-13
- Volume
- 18
- Issue
- 10
- Pages
- 6449-6454
- ISSN
- 1530-6984 (ISSN-L)
- 1530-6992
- PMC
- PMC6415675
- OpenAlex
- W2890559446
- Cited by
- 218
- References
- 44
- Citations by year
- 2026: 17 · 2025: 34 · 2024: 37 · 2023: 35 · 2022: 36 · 2021: 17 · 2020: 27 · 2019: 14 · 2018: 1
- FWCI
- 5.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nano Letters (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- National Cancer Institute (P30-CA14051)
- Translate Bio
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Keywords
- mRNA delivery, poly(β-amino ester), degradable polymers, lung endothelium, systemic drug delivery, nanoparticle formulation optimization, Cre reporter mice, mRNA therapeutics
- MeSH terms
- Animals, Endothelium, Humans, Lipids, Lung, Polyethylene Glycols, Polymers, RNA, Messenger, Gene Transfer Techniques, RNA, Small Interfering, Mice, Nanoparticles
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