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000892285 1001_ $$00000-0002-7405-6125$$aSebastiani, Federica$$b0$$eCorresponding author
000892285 245__ $$aApolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles
000892285 260__ $$aWashington, DC$$bSoc.$$c2021
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000892285 520__ $$aEmerging therapeutic treatments based on the production of proteins by delivering mRNA have become increasingly important in recent times. While lipid nanoparticles (LNPs) are approved vehicles for small interfering RNA delivery, there are still challenges to use this formulation for mRNA delivery. LNPs are typically a mixture of a cationic lipid, distearoylphosphatidylcholine (DSPC), cholesterol, and a PEG-lipid. The structural characterization of mRNA-containing LNPs (mRNA-LNPs) is crucial for a full understanding of the way in which they function, but this information alone is not enough to predict their fate upon entering the bloodstream. The biodistribution and cellular uptake of LNPs are affected by their surface composition as well as by the extracellular proteins present at the site of LNP administration, e.g., apolipoproteinE (ApoE). ApoE, being responsible for fat transport in the body, plays a key role in the LNP’s plasma circulation time. In this work, we use small-angle neutron scattering, together with selective lipid, cholesterol, and solvent deuteration, to elucidate the structure of the LNP and the distribution of the lipid components in the absence and the presence of ApoE. While DSPC and cholesterol are found to be enriched at the surface of the LNPs in buffer, binding of ApoE induces a redistribution of the lipids at the shell and the core, which also impacts the LNP internal structure, causing release of mRNA. The rearrangement of LNP components upon ApoE incubation is discussed in terms of potential relevance to LNP endosomal escape.
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000892285 7001_ $$0P:(DE-HGF)0$$aYanez Arteta, Marianna$$b1$$eCorresponding author
000892285 7001_ $$0P:(DE-HGF)0$$aLerche, Michael$$b2
000892285 7001_ $$0P:(DE-HGF)0$$aPorcar, Lionel$$b3
000892285 7001_ $$0P:(DE-Juel1)168105$$aLang, Christian$$b4
000892285 7001_ $$0P:(DE-HGF)0$$aBragg, Ryan A.$$b5
000892285 7001_ $$0P:(DE-HGF)0$$aElmore, Charles S.$$b6
000892285 7001_ $$00000-0002-9015-7436$$aKrishnamurthy, Venkata R.$$b7
000892285 7001_ $$0P:(DE-HGF)0$$aRussell, Robert A.$$b8
000892285 7001_ $$0P:(DE-HGF)0$$aDarwish, Tamim$$b9
000892285 7001_ $$00000-0001-6043-2137$$aPichler, Harald$$b10
000892285 7001_ $$00000-0003-3458-887X$$aWaldie, Sarah$$b11
000892285 7001_ $$0P:(DE-HGF)0$$aMoulin, Martine$$b12
000892285 7001_ $$0P:(DE-HGF)0$$aHaertlein, Michael$$b13
000892285 7001_ $$0P:(DE-HGF)0$$aForsyth, V. Trevor$$b14
000892285 7001_ $$0P:(DE-HGF)0$$aLindfors, Lennart$$b15
000892285 7001_ $$00000-0003-0392-3540$$aCárdenas, Marité$$b16$$eCorresponding author
000892285 773__ $$0PERI:(DE-600)2383064-5$$a10.1021/acsnano.0c10064$$gVol. 15, no. 4, p. 6709 - 6722$$n4$$p6709 - 6722$$tACS nano$$v15$$x1936-086X$$y2021
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000892285 8564_ $$uhttps://juser.fz-juelich.de/record/892285/files/paper_LNP_ApoE_final_210318.pdf$$yOpenAccess
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