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@ARTICLE{YanezArteta:845113,
      author       = {Yanez Arteta, Marianna and Kjellman, Tomas and Bartesaghi,
                      Stefano and Wallin, Simonetta and Wu, Xiaoqiu and Kvist,
                      Alexander J. and Dabkowska, Aleksandra and Szekely, Noemi
                      and Radulescu, Aurel and Bergenholtz, Johan and Lindfors,
                      Lennart},
      title        = {{S}uccessful reprogramming of cellular protein production
                      through m{RNA} delivered by functionalized lipid
                      nanoparticles},
      journal      = {Proceedings of the National Academy of Sciences of the
                      United States of America},
      volume       = {115},
      number       = {15},
      issn         = {1091-6490},
      address      = {Washington, DC},
      publisher    = {National Acad. of Sciences},
      reportid     = {FZJ-2018-02432},
      pages        = {E3351 - E3360},
      year         = {2018},
      abstract     = {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 (distearoylphosphatidylcholine, DSPC, and
                      cholesterol), and a poly(ethylene glycol) (PEG) lipid have
                      been identified as very promising delivery vectors 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.},
      cin          = {JCNS (München) ; Jülich Centre for Neutron Science JCNS
                      (München) ; JCNS-FRM-II / Neutronenstreuung ; JCNS-1},
      ddc          = {000},
      cid          = {I:(DE-Juel1)JCNS-FRM-II-20110218 /
                      I:(DE-Juel1)JCNS-1-20110106},
      pnm          = {6G15 - FRM II / MLZ (POF3-6G15) / 6G4 - Jülich Centre for
                      Neutron Research (JCNS) (POF3-623)},
      pid          = {G:(DE-HGF)POF3-6G15 / G:(DE-HGF)POF3-6G4},
      experiment   = {EXP:(DE-MLZ)KWS2-20140101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29588418},
      UT           = {WOS:000429540300005},
      doi          = {10.1073/pnas.1720542115},
      url          = {https://juser.fz-juelich.de/record/845113},
}