Analyzing 2000 in Vivo Drug Delivery Data Points Reveals Cholesterol Structure Impacts Nanoparticle Delivery
Open accessAbstract
Lipid nanoparticles (LNPs) are formulated using unmodified cholesterol. However, cholesterol is naturally esterified and oxidized in vivo, and these cholesterol variants are differentially trafficked in vivo via lipoproteins including LDL and VLDL. We hypothesized that incorporating the same cholesterol variants into LNPs—which can be structurally similar to LDL and VLDL—would alter nanoparticle targeting in vivo . To test this hypothesis, we quantified how >100 LNPs made with six cholesterol variants delivered DNA barcodes to 18 cell types in wild-type, LDLR –/–, and VLDLR –/– mice that were both age-matched and female. By analyzing ∼2000 in vivo drug delivery data points, we found that LNPs formulated with esterified cholesterol delivered nucleic acids more efficiently than LNPs formulated with regular or oxidized cholesterol when compared across all tested cell types in the mouse. We also identified an LNP containing cholesteryl oleate that efficiently delivered siRNA and sgRNA to liver endothelial cells in vivo. Delivery was as—or more—efficient as the same LNP made with unmodified cholesterol. Moreover, delivery to liver endothelial cells was 3 times more efficient than delivery to hepatocytes, distinguishing this oleate LNP from hepatocyte-targeting LNPs. RNA delivery can be improved by rationally selecting cholesterol variants, allowing optimization of nanoparticle targeting.
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Barcoding has revealed that selective accumulation in liver endothelial cells, Kupffer cells and hepatocytes depends on cholesterol structures.
“For example, barcoding has been applied to study how the structure of cholesterol derivatives impact cell selectivity of lipid nanoparticles, revealing that selective accumulation in liver endothelial cells, Kupffer cells and hepatocytes125,126 depends on cholesterol structures.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [125]
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- Authors
- Paunovska, K., Gil, C. J., Lokugamage, M. P., Sago, C. D., Sato, M., Lando, G. N., Gamboa Castro, M., Bryksin, A. V., & Dahlman, J. E.
- Affiliations
- Georgia Institute of Technology (US)
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, Georgia 30332, United States
- Corresponding author
- Dahlman, James E.
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-07-17
- Volume
- 12
- Issue
- 8
- Pages
- 8341-8349
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- PMC
- PMC6115295
- OpenAlex
- W2883152153
- Cited by
- 160
- References
- 64
- Citations by year
- 2026: 18 · 2025: 27 · 2024: 36 · 2023: 17 · 2022: 30 · 2021: 9 · 2020: 8 · 2019: 9 · 2018: 6
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- ACS Nano (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Bayer
- Georgia Institute of Technology
- Division of Graduate Education (DGE-1650044, DGE-1451512)
- Cystic Fibrosis Foundation (DAHLMA15XX0)
- Parkinson's Disease Foundation (PDF-JFA-1860)
- 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 › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- lipid nanoparticles, esterified cholesterol, oxysterols, cholesteryl oleate, in vivo drug delivery, LDL receptor, VLDLR, liver endothelial cells, hepatocytes, siRNA delivery, DNA barcoding, nanoparticle targeting
- MeSH terms
- RNA, Guide, CRISPR-Cas Systems, Animals, Cholesterol, Drug Carriers, Female, Liver, Mice, Inbred C57BL, Drug Delivery Systems, RNA, Guide, Kinetoplastida, Mice, Knockout, RNA, Small Interfering, Endothelial Cells, Mice, Nanoparticles
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