TY  - JOUR
AU  - Sebastiani, Federica
AU  - Yanez Arteta, Marianna
AU  - Lerche, Michael
AU  - Porcar, Lionel
AU  - Lang, Christian
AU  - Bragg, Ryan A.
AU  - Elmore, Charles S.
AU  - Krishnamurthy, Venkata R.
AU  - Russell, Robert A.
AU  - Darwish, Tamim
AU  - Pichler, Harald
AU  - Waldie, Sarah
AU  - Moulin, Martine
AU  - Haertlein, Michael
AU  - Forsyth, V. Trevor
AU  - Lindfors, Lennart
AU  - Cárdenas, Marité
TI  - Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles
JO  - ACS nano
VL  - 15
IS  - 4
SN  - 1936-086X
CY  - Washington, DC
PB  - Soc.
M1  - FZJ-2021-01995
SP  - 6709 - 6722
PY  - 2021
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 33754708
UR  - <Go to ISI:>//WOS:000645436800066
DO  - DOI:10.1021/acsnano.0c10064
UR  - https://juser.fz-juelich.de/record/892285
ER  -