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

    Year: 2021

    Journal: ACS Nano, Volume 15, APR 27, page 6709–6722

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

    Organizations: Knowledge Foundation (Sweden) [20180101]; Swedish Research Council [2014-3981, 2018-03990, 2018-0483]; European Union's Horizon 2020 research and innovation program [731019]; UK Engineering and Physical Sciences Research Council (EPSRC) [EP/C015452/1, GR/R99393/01]; National Collaborative Research Infrastructure Strategy (NCRIS), an Australian Government initiative; NSF [DMR-0520547]; European Union's Horizon 2020 research and innovation program under the SINE2020 project [654000]

    Keywords: lipid nanoparticles; mRNA delivery; ApoE; protein corona; small-angle scattering

    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.
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