Nanoparticles Containing Oxidized Cholesterol Deliver mRNA to the Liver Microenvironment at Clinically Relevant Doses
Open accessAbstract
Using mRNA to produce therapeutic proteins is a promising approach to treat genetic diseases. However, systemically delivering mRNA to cell types besides hepatocytes remains challenging. Fast identification of nanoparticle delivery (FIND) is a DNA barcode‐based system designed to measure how over 100 lipid nanoparticles (LNPs) deliver mRNA that functions in the cytoplasm of target cells in a single mouse. By using FIND to quantify how 75 chemically distinct LNPs delivered mRNA to 28 cell types in vivo, it is found that an LNP formulated with oxidized cholesterol and no targeting ligand delivers Cre mRNA, which edits DNA in hepatic endothelial cells and Kupffer cells at 0.05 mg kg−1. Notably, the LNP targets liver microenvironmental cells fivefold more potently than hepatocytes. The structure of the oxidized cholesterols added to the LNP is systematically varied to show that the position of the oxidative modification may be important; cholesterols modified on the hydrocarbon tail associated with sterol ring D tend to outperform cholesterols modified on sterol ring B. These data suggest that LNPs formulated with modified cholesterols can deliver gene‐editing mRNA to the liver microenvironment at clinically relevant doses.
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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 [126]
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Cationic cholesterol-dependent LNP delivery to lung stem cells, the liver, and heart
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Self-citationProtein and mRNA Delivery Enabled by Cholesteryl‐Based Biodegradable Lipidoid Nanoparticles
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The Transcriptional Response to Lung-Targeting Lipid Nanoparticles in Vivo
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Nanoparticle stereochemistry-dependent endocytic processing improves in vivo mRNA delivery
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Using Large Datasets to Understand Nanotechnology
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Self-citationTreating Cystic Fibrosis with mRNA and CRISPR
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Self-citationStructure and Morphology of Lipid Nanoparticles for Nucleic Acid Drug Delivery: A Review
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Therapeutic RNA Delivery for COVID and Other Diseases
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Self-citationDelivery of mRNA for regulating functions of immune cells
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Composition of lipid nanoparticles for targeted delivery: application to mRNA therapeutics
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Naturally Derived Membrane Lipids Impact Nanoparticle-Based Messenger RNA Delivery
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mRNA therapies: Pioneering a new era in rare genetic disease treatment
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Principles of lipid nanoparticle design for mRNA delivery
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Lipid Nanoparticles for Nucleic Acid Delivery to Endothelial Cells
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Development and applications of mRNA treatment based on lipid nanoparticles
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Lipid Nanoparticles for Delivery of CRISPR Gene Editing Components
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Targeting strategies for mRNA delivery
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Substituting racemic ionizable lipids with stereopure ionizable lipids can increase mRNA delivery
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Self-citationChemistry, manufacturing and controls strategies for using novel excipients in lipid nanoparticles
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Modulating intracellular pathways to improve non-viral delivery of RNA therapeutics
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Cell Subtypes Within the Liver Microenvironment Differentially Interact with Lipid Nanoparticles
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Cellular Trafficking of Nanotechnology‐Mediated mRNA Delivery
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Steering the course of CAR T cell therapy with lipid nanoparticles
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- Authors
- Paunovska, K., Da Silva Sanchez, A. J., Sago, C. D., Gan, Z., Lokugamage, M. P., Islam, F. Z., Kalathoor, S., Krupczak, B. R., & 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 GA 30332 USA
- Corresponding author
- Dahlman, James E.
- ORCID
- Venue
- Advanced Materials
- Publisher
- Wiley
- Published
- 2019-02-12
- Volume
- 31
- Issue
- 14
- Pages
- e1807748-e1807748
- ISSN
- 0935-9648 (ISSN-L)
- 1521-4095
- PMC
- PMC6445717
- OpenAlex
- W2913721132
- Cited by
- 205
- References
- 26
- Citations by year
- 2026: 21 · 2025: 31 · 2024: 40 · 2023: 40 · 2022: 34 · 2021: 15 · 2020: 19 · 2019: 4
- FWCI
- 5.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Advanced Materials (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (T32GM008433, T32GM105490)
- National Institute of Biomedical Imaging and Bioengineering (T32EB021962)
- 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 › Advanced Drug Delivery Systems
- Keywords
- lipid nanoparticles, oxysterols, mRNA delivery, liver microenvironment, genome editing, hepatic endothelial cells, Kupffer cells, nanoparticle targeting, in vivo delivery
- MeSH terms
- Animals, Cholesterol, Drug Carriers, Liver, Oxidation-Reduction, RNA, Messenger, Mice, Nanoparticles, Cellular Microenvironment
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