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Successful reprogra...
Successful reprogramming of cellular protein production through mRNA delivered by functionalized lipid nanoparticles
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Arteta, Marianna Yanez (författare)
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Kjellman, Tomas (författare)
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Bartesaghi, Stefano (författare)
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Wallin, Simonetta (författare)
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Wu, Xiaoqiu (författare)
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Kvist, Alexander J. (författare)
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Dabkowska, Aleksandra (författare)
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Székely, Noémi (författare)
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Radulescu, Aurel (författare)
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- Bergenholtz, Johan, 1964 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Lindfors, Lennart (författare)
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(creator_code:org_t)
- 2018-03-27
- 2018
- Engelska.
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:15
- Relaterad länk:
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https://www.pnas.org...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- © 2018 National Academy of Sciences. All Rights Reserved. The development of safe and efficacious gene vectors has limited greatly the potential for therapeutic treatments based on messenger RNA (mRNA). Lipid nanoparticles (LNPs) formed by an ionizable cationic lipid (here DLin-MC3-DMA), helper lipids (distearoylphos-phatidylcholine, DSPC, and cholesterol), and a poly(ethylene glycol) (PEG) lipid have been identified as very promising delivery ve ctors of short interfering RNA (siRNA) in different clinical phases; however, delivery of high-molecular weight RNA has been proven much more demanding. Herein we elucidate the structure of hEPO modified mRNA-containing LNPs of different sizes and show how structural differences affect transfection of human adipocytes and hepatocytes, two clinically relevant cell types. Employing small-angle scattering, we demonstrate that LNPs have a disordered inverse hexagonal internal structure with a characteristic distance around 6 nm in presence of mRNA, whereas LNPs containing no mRNA do not display this structure. Furthermore, using contrast variation small-angle neutron scattering, we show that one of the lipid components, DSPC, is localized mainly at the surface of mRNA-containing LNPs. By varying LNP size and surface composition we demonstrate that both size and structure have significant influence on intracellular protein production. As an example, in both human adipocytes and hepatocytes, protein expression levels for 130 nm LNPs can differ as much as 50-fold depending on their surface characteristics, likely due to a difference in the ability of LNP fusion with the early endosome membrane. We consider these discoveries to be fundamental and opening up new possibilities for rational design of synthetic nanoscopic vehicles for mRNA delivery.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
- NATURVETENSKAP -- Kemi -- Fysikalisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Physical Chemistry (hsv//eng)
Nyckelord
- Adipocytes
- Gene therapy
- Hepatocytes
- HEPO mRNA
- Small-angle scattering
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Arteta, Marianna ...
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Kjellman, Tomas
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Bartesaghi, Stef ...
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Wallin, Simonett ...
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Wu, Xiaoqiu
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Kvist, Alexander ...
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visa fler...
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Dabkowska, Aleks ...
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Székely, Noémi
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Radulescu, Aurel
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Bergenholtz, Joh ...
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Lindfors, Lennar ...
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visa färre...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Farmaceutiska ve ...
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- NATURVETENSKAP
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NATURVETENSKAP
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och Kemi
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och Fysikalisk kemi
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Proceedings of t ...
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Göteborgs universitet