Journal Article

FZJ-2021-01995

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles

Sebastiani, F. (Corresponding author) ; Yanez Arteta, M. (Corresponding author) ; Lerche, M. ; Porcar, L. ; Lang, C.FZJ* ; 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. (Corresponding author)

2021
Soc. Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/27729  doi:10.1021/acsnano.0c10064

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.

Keyword(s): Health and Life (1st) ; Biology (2nd) ; Soft Condensed Matter (2nd) ; Medicine (2nd)

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Contributing Institute(s):

1. JCNS-FRM-II (JCNS-FRM-II)
2. Heinz Maier-Leibnitz Zentrum (MLZ)
3. Neutronenstreuung (JCNS-1)
4. JCNS-4 (JCNS-4)

Research Program(s):

1. 6G4 - Jülich Centre for Neutron Research (JCNS) (FZJ) (POF4-6G4) (POF4-6G4)
2. 632 - Materials – Quantum, Complex and Functional Materials (POF4-632) (POF4-632)

Experiment(s):

1. KWS-2: Small angle scattering diffractometer (NL3ao)

Appears in the scientific report 2021

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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