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journal article·2021-04-27Open access

Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles

Federica Sebastiani, Marianna Yanez Arteta, Michael Lerche, Lionel Porcar, Christian Lang, Ryan A. Bragg, Charles S. Elmore, Venkata R. Krishnamurthy, Robert A. Russell, Tamim Darwish, Harald Pichler, Sarah Waldie, Martine Moulin, Michael Haertlein, V. Trevor Forsyth, Lennart Lindfors, Marité Cárdenas

ACS Nano· Volume 15· Issue 4
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Source abstract

Abstract

Emerging therapeutic treatments based on the production of proteins by delivering mRNA have become increasingly important in recent times. While lipid nanoparticles (LNPs) are approved vehicles for small interfering RNA delivery, there are still challenges to use this formulation for mRNA delivery. LNPs are typically a mixture of a cationic lipid, distearoylphosphatidylcholine (DSPC), cholesterol, and a PEG-lipid. The structural characterization of mRNA-containing LNPs (mRNA-LNPs) is crucial for a full understanding of the way in which they function, but this information alone is not enough to predict their fate upon entering the bloodstream. The biodistribution and cellular uptake of LNPs are affected by their surface composition as well as by the extracellular proteins present at the site of LNP administration, e.g., apolipoproteinE (ApoE). ApoE, being responsible for fat transport in the body, plays a key role in the LNP's plasma circulation time. In this work, we use small-angle neutron scattering, together with selective lipid, cholesterol, and solvent deuteration, to elucidate the structure of the LNP and the distribution of the lipid components in the absence and the presence of ApoE. While DSPC and cholesterol are found to be enriched at the surface of the LNPs in buffer, binding of ApoE induces a redistribution of the lipids at the shell and the core, which also impacts the LNP internal structure, causing release of mRNA. The rearrangement of LNP components upon ApoE incubation is discussed in terms of potential relevance to LNP endosomal escape.
Source: europepmc · Quality: candidate unverified · Source record ↗

Research context

Nanomaterials

OpenAlex topics: RNA Interference and Gene Delivery · RNA Research and Splicing · Lipid Membrane Structure and Behavior

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Biofilms - Research Center for Biointerfaces and Department of Biomedical Science, Faculty of Health and Society, Malmö University, 20506 Malmö, Sweden

Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, 431 83 Gothenburg Sweden

Large Scale Structures, Institut Laue Langevin, Grenoble F-38042, France

Forschungszentrum Jülich GmbH, Jülich Centre for Neutron Science JCNS, Outstation at Heinz Maier-Leibnitz Zentrum, Lichtenbergstraße 1, 85748 Garching, Germany

Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, SK 10 4TG Cambridge, U.K.

Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, 431 83 Gothenburg, Sweden

Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, CB2 0AA Boston, Massachusetts 02451, United States

National Deuteration Facility (NDF), Australian Nuclear Science and Technology Organisation (ANSTO), Lucas Heights, 2232 Sydney, NSW, Australia

Austrian Centre of Industrial Biotechnology, Petersgasse 14, 8010, Graz, Austria

Institute of Molecular Biotechnology, Graz University of Technology, NAWI Graz, BioTechMed Graz, Petersgasse 14, 8010, Graz, Austria

Life Sciences Group, Institut Laue Langevin, Grenoble F-38042, France

Partnership for Structural Biology (PSB), Grenoble F-38042, France

Faculty of Natural Sciences, Keele University, Staffordshire, ST5 5BG, U.K.

Funding

Engineering and Physical Sciences Research Council · Vetenskapsr?det · Stiftelsen f?r Kunskaps- och Kompetensutveckling · Horizon 2020 Framework Programme · National Science Foundation USA · National Collaborative Research Infrastructure Strategy (NCRIS)

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