Sebastiani, F, Yanez Arteta, M, Lerche, M, Porcar, L, Lang, C, Bragg, RA, Elmore, CS, Krishnamurthy, VR, Russell, RA, Darwish, T, Pichler, H, Waldie, S, Moulin, M, Haertlein, M, Forsyth, VT ORCID: https://orcid.org/0000-0003-0380-3477, Lindfors, L and Cárdenas, M (2021) Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles. ACS Nano, 15 (4). 6709 - 6722.

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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.

Item Type: Article
Additional Information: The final version of this article and all relevant information related to it can be found online at; https://pubs.acs.org/doi/10.1021/acsnano.0c10064
Uncontrolled Keywords: lipid nanoparticles; mRNA deliver; yApoE; protein corona; small-angle scattering
Subjects: Q Science > Q Science (General)
Q Science > QD Chemistry
Divisions: Faculty of Natural Sciences > School of Life Sciences
Related URLs:
Depositing User: Symplectic
Date Deposited: 11 Jun 2021 08:09
Last Modified: 14 Jul 2021 09:13
URI: https://eprints.keele.ac.uk/id/eprint/9705

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