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@ARTICLE{Davies:891766,
      author       = {Davies, Nigel and Hovdal, Daniel and Edmunds, Nicholas and
                      Nordberg, Peter and Dahlén, Anders and Dabkowska,
                      Aleksandra and Arteta, Marianna Yanez and Radulescu, Aurel
                      and Kjellman, Tomas and Höijer, Andreas and Seeliger, Frank
                      and Holmedal, Elin and Andihn, Elisabeth and Bergenhem, Nils
                      and Sandinge, Ann-Sofie and Johansson, Camilla and Hultin,
                      Leif and Johansson, Marie and Lindqvist, Johnny and
                      Björsson, Liselotte and Jing, Yujia and Bartesaghi, Stefano
                      and Lindfors, Lennart and Andersson, Shalini},
      title        = {{F}unctionalized lipid nanoparticles for subcutaneous
                      administration of m{RNA} to achieve systemic exposures of a
                      therapeutic protein},
      journal      = {Molecular Therapy / Nucleic Acids},
      volume       = {24},
      issn         = {2162-2531},
      address      = {New York, NY},
      publisher    = {Nature Publ. Group},
      reportid     = {FZJ-2021-01724},
      pages        = {369 - 384},
      year         = {2021},
      abstract     = {Lipid nanoparticles (LNPs) are the most clinically advanced
                      delivery system for RNA-based drugs but have predominantly
                      been investigated for intravenous and intramuscular
                      administration. Subcutaneous administration opens the
                      possibility of patient self-administration and hence
                      long-term chronic treatment that could enable messenger RNA
                      (mRNA) to be used as a novel modality for protein
                      replacement or regenerative therapies. In this study, we
                      show that subcutaneous administration of mRNA formulated
                      within LNPs can result in measurable plasma exposure of a
                      secreted protein. However, subcutaneous administration of
                      mRNA formulated within LNPs was observed to be associated
                      with dose-limiting inflammatory responses. To overcome this
                      limitation, we investigated the concept of incorporating
                      aliphatic ester prodrugs of anti-inflammatory steroids
                      within LNPs, i.e., functionalized LNPs to suppress the
                      inflammatory response. We show that the effectiveness of
                      this approach depends on the alkyl chain length of the ester
                      prodrug, which determines its retention at the site of
                      administration. An unexpected additional benefit to this
                      approach is the prolongation observed in the duration of
                      protein expression. Our results demonstrate that
                      subcutaneous administration of mRNA formulated in
                      functionalized LNPs is a viable approach to achieving
                      systemic levels of therapeutic proteins, which has the added
                      benefits of being amenable to self-administration when
                      chronic treatment is required.},
      cin          = {JCNS-FRM-II / MLZ / JCNS-1 / JCNS-4},
      ddc          = {610},
      cid          = {I:(DE-Juel1)JCNS-FRM-II-20110218 / I:(DE-588b)4597118-3 /
                      I:(DE-Juel1)JCNS-1-20110106 / I:(DE-Juel1)JCNS-4-20201012},
      pnm          = {6G4 - Jülich Centre for Neutron Research (JCNS) (FZJ)
                      (POF4-6G4) / 632 - Materials – Quantum, Complex and
                      Functional Materials (POF4-632)},
      pid          = {G:(DE-HGF)POF4-6G4 / G:(DE-HGF)POF4-632},
      experiment   = {EXP:(DE-MLZ)KWS2-20140101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {33868782},
      UT           = {WOS:000658506500001},
      doi          = {10.1016/j.omtn.2021.03.008},
      url          = {https://juser.fz-juelich.de/record/891766},
}