Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles
| Autor: | Venkata R. Krishnamurthy, Marianna Yanez Arteta, Michael Lerche, Martine Moulin, Michael Haertlein, Christian Lang, Lennart Lindfors, V. Trevor Forsyth, Harald Pichler, Tamim A. Darwish, Robert A. Russell, Federica Sebastiani, Ryan A. Bragg, Lionel Porcar, Marité Cárdenas, Charles S. Elmore, Sarah Waldie |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Apolipoprotein E
Biodistribution Small interfering RNA Endosome General Physics and Astronomy Protein Corona 02 engineering and technology lipid nanoparticles Q1 010402 general chemistry Physical Chemistry 01 natural sciences Article small-angle scattering chemistry.chemical_compound Apolipoproteins E protein corona mRNA delivery Distribution (pharmacology) Tissue Distribution QD General Materials Science RNA Messenger RNA Small Interfering Fysikalisk kemi Messenger RNA Chemistry Cholesterol General Engineering 021001 nanoscience & nanotechnology 0104 chemical sciences ddc:540 Biophysics Nanoparticles lipids (amino acids peptides and proteins) 0210 nano-technology ApoE |
| Zdroj: | ACS nano 15(4), 6709-6722 (2021). doi:10.1021/acsnano.0c10064 'ACS Nano ', vol: 15, pages: 6709-6722 (2021) ACS Nano |
| ISSN: | 1936-086X |
| DOI: | 10.1021/acsnano.0c10064 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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