Apolipoprotein E binding drives structural and compositional rearrangement of mRNA-containing lipid nanoparticles

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dc.contributor.authorSebastiani, Fen_AU
dc.contributor.authorYanez Arteta, Men_AU
dc.contributor.authorLerche, Men_AU
dc.contributor.authorPorcar, Len_AU
dc.contributor.authorLang, Cen_AU
dc.contributor.authorBragg, RAen_AU
dc.contributor.authorElmore, CSen_AU
dc.contributor.authorKrishnamurthy, VRen_AU
dc.contributor.authorRussell, RAen_AU
dc.contributor.authorDarwish, TAen_AU
dc.contributor.authorPichler, Hen_AU
dc.contributor.authorWaldie, Sen_AU
dc.contributor.authorMoulin, Men_AU
dc.contributor.authorHaertlein, Men_AU
dc.contributor.authorForsyth, VTen_AU
dc.contributor.authorLindfors, Len_AU
dc.contributor.authorCárdenas, Men_AU
dc.date.accessioned2024-02-23T04:37:53Zen_AU
dc.date.available2024-02-23T04:37:53Zen_AU
dc.date.issued2021-03-23en_AU
dc.date.statistics2024-02-23en_AU
dc.description.abstractEmerging 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. © 2021 American Chemical Society. Open Access. This publication is licensed under CC-BY 4.0.en_AU
dc.description.sponsorshipF.S. acknowledges support from the Knowledge Foundation (Sweden) with a ProSpekt grant (20180101). M.C. thanks the Swedish Research Council for financial support (2014-3981, 2018-03990, and 2018-0483). The authors thank the ILL (Grenoble, France) for allocations of beam time on D22 with a corresponding DOI number: 10.5291/ILL-DATA.9-13-866. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 731019 (EUSMI) to access beamtime at the KWS-2 instrument operated by JCNS at Heinz Maier-Leibnitz Zentrum, Garching, Germany. We thank Aurel Radulescu for help with data reduction and instrument configuration at KWS-2 and Christopher Garvey for discussions during the beamtime. V.T.F. acknowledges the UK Engineering and Physical Sciences Research Council (EPSRC) for grants EP/C015452/1 and GR/R99393/01 under which the Deuteration Laboratory within ILL’s Life Sciences Group was created. We thank Gernot A. Strohmeier for purifying the deuterated cholesterol (average 89% D). We also thank Linda Thunberg for purifying the deuterated MC3. Yeast strain RH6829 for deuterated cholesterol was kindly provided by Howard Riezman (University of Geneva, Switzerland). The National Deuteration Facility in Australia is partly funded by The National Collaborative Research Infrastructure Strategy (NCRIS), an Australian Government initiative. This work benefited from the use of the SasView application, originally developed under NSF award DMR-0520547. SasView contains code developed with funding from the European Union’s Horizon 2020 research and innovation program under the SINE2020 project, grant agreement no. 654000.en_AU
dc.format.mediumPrint-Electronicen_AU
dc.identifier.citationSebastiani, F., Yanez Arteta, M., Lerche, M., Porcar, L., Lang, C., Bragg, R. A., Elmore, C. S., Krishnamurthy, V. R., Russell, R. A., Darwish, T., Pichler, H., Waldie, S., Moulin, M., Haertlein, M., Forsyth, V. T., Lindfors, L., & Cárdenas, M. (2021). Apolipoprotein E binding drives structural and compositional rearrangement of mRNA-containing lipid nanoparticles. ACS nano, 15(4), 6709-6722.en_AU
dc.identifier.issn1936-0851en_AU
dc.identifier.issn1936-086Xen_AU
dc.identifier.issue4en_AU
dc.identifier.journaltitleACS Nanoen_AU
dc.identifier.pagination6709-6722en_AU
dc.identifier.urihttp://dx.doi.org/10.1021/acsnano.0c10064en_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15428en_AU
dc.identifier.volume15en_AU
dc.languageEnglishen_AU
dc.language.isoenen_AU
dc.publisherAmerican Chemical Society (ACS)en_AU
dc.subjectAnatomyen_AU
dc.subjectCholesterolen_AU
dc.subjectLipidsen_AU
dc.subjectSolventsen_AU
dc.subjectNanoparticlesen_AU
dc.subjectProteinsen_AU
dc.subjectSmall angle scatteringen_AU
dc.titleApolipoprotein E binding drives structural and compositional rearrangement of mRNA-containing lipid nanoparticlesen_AU
dc.typeJournal Articleen_AU
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