000891766 001__ 891766
000891766 005__ 20210628150957.0
000891766 0247_ $$2doi$$a10.1016/j.omtn.2021.03.008
000891766 0247_ $$2Handle$$a2128/27607
000891766 0247_ $$2altmetric$$aaltmetric:102016778
000891766 0247_ $$2pmid$$a33868782
000891766 0247_ $$2WOS$$aWOS:000658506500001
000891766 037__ $$aFZJ-2021-01724
000891766 082__ $$a610
000891766 1001_ $$0P:(DE-HGF)0$$aDavies, Nigel$$b0$$eCorresponding author
000891766 245__ $$aFunctionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein
000891766 260__ $$aNew York, NY$$bNature Publ. Group$$c2021
000891766 3367_ $$2DRIVER$$aarticle
000891766 3367_ $$2DataCite$$aOutput Types/Journal article
000891766 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1618385047_2631
000891766 3367_ $$2BibTeX$$aARTICLE
000891766 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000891766 3367_ $$00$$2EndNote$$aJournal Article
000891766 520__ $$aLipid 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.
000891766 536__ $$0G:(DE-HGF)POF4-6G4$$a6G4 - Jülich Centre for Neutron Research (JCNS) (FZJ) (POF4-6G4)$$cPOF4-6G4$$fPOF IV$$x0
000891766 536__ $$0G:(DE-HGF)POF4-632$$a632 - Materials – Quantum, Complex and Functional Materials (POF4-632)$$cPOF4-632$$fPOF IV$$x1
000891766 588__ $$aDataset connected to CrossRef
000891766 65027 $$0V:(DE-MLZ)SciArea-160$$2V:(DE-HGF)$$aBiology$$x0
000891766 65027 $$0V:(DE-MLZ)SciArea-190$$2V:(DE-HGF)$$aMedicine$$x1
000891766 65027 $$0V:(DE-MLZ)SciArea-210$$2V:(DE-HGF)$$aSoft Condensed Matter$$x2
000891766 65017 $$0V:(DE-MLZ)GC-130-2016$$2V:(DE-HGF)$$aHealth and Life$$x0
000891766 693__ $$0EXP:(DE-MLZ)KWS2-20140101$$1EXP:(DE-MLZ)FRMII-20140101$$5EXP:(DE-MLZ)KWS2-20140101$$6EXP:(DE-MLZ)NL3ao-20140101$$aForschungs-Neutronenquelle Heinz Maier-Leibnitz $$eKWS-2: Small angle scattering diffractometer$$fNL3ao$$x0
000891766 7001_ $$0P:(DE-HGF)0$$aHovdal, Daniel$$b1
000891766 7001_ $$00000-0002-3577-4319$$aEdmunds, Nicholas$$b2
000891766 7001_ $$0P:(DE-HGF)0$$aNordberg, Peter$$b3
000891766 7001_ $$0P:(DE-HGF)0$$aDahlén, Anders$$b4
000891766 7001_ $$0P:(DE-HGF)0$$aDabkowska, Aleksandra$$b5
000891766 7001_ $$00000-0002-4521-3275$$aArteta, Marianna Yanez$$b6
000891766 7001_ $$0P:(DE-Juel1)130905$$aRadulescu, Aurel$$b7
000891766 7001_ $$00000-0003-3993-3302$$aKjellman, Tomas$$b8
000891766 7001_ $$0P:(DE-HGF)0$$aHöijer, Andreas$$b9
000891766 7001_ $$0P:(DE-HGF)0$$aSeeliger, Frank$$b10
000891766 7001_ $$0P:(DE-HGF)0$$aHolmedal, Elin$$b11
000891766 7001_ $$00000-0003-3582-7115$$aAndihn, Elisabeth$$b12
000891766 7001_ $$0P:(DE-HGF)0$$aBergenhem, Nils$$b13
000891766 7001_ $$00000-0002-1322-2580$$aSandinge, Ann-Sofie$$b14
000891766 7001_ $$0P:(DE-HGF)0$$aJohansson, Camilla$$b15
000891766 7001_ $$0P:(DE-HGF)0$$aHultin, Leif$$b16
000891766 7001_ $$0P:(DE-HGF)0$$aJohansson, Marie$$b17
000891766 7001_ $$0P:(DE-HGF)0$$aLindqvist, Johnny$$b18
000891766 7001_ $$0P:(DE-HGF)0$$aBjörsson, Liselotte$$b19
000891766 7001_ $$0P:(DE-HGF)0$$aJing, Yujia$$b20
000891766 7001_ $$0P:(DE-HGF)0$$aBartesaghi, Stefano$$b21
000891766 7001_ $$0P:(DE-HGF)0$$aLindfors, Lennart$$b22
000891766 7001_ $$00000-0002-7051-2189$$aAndersson, Shalini$$b23
000891766 773__ $$0PERI:(DE-600)2662631-7$$a10.1016/j.omtn.2021.03.008$$gVol. 24, p. 369 - 384$$p369 - 384$$tMolecular Therapy / Nucleic Acids$$v24$$x2162-2531$$y2021
000891766 8564_ $$uhttps://juser.fz-juelich.de/record/891766/files/1-s2.0-S2162253121000792-main.pdf$$yOpenAccess
000891766 8564_ $$uhttps://juser.fz-juelich.de/record/891766/files/manuscript_MolecularTherapyNucleicAcids.pdf$$yOpenAccess
000891766 909CO $$ooai:juser.fz-juelich.de:891766$$pdnbdelivery$$pVDB$$pVDB:MLZ$$pdriver$$popen_access$$popenaire
000891766 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)130905$$aForschungszentrum Jülich$$b7$$kFZJ
000891766 9130_ $$0G:(DE-HGF)POF3-623$$1G:(DE-HGF)POF3-620$$2G:(DE-HGF)POF3-600$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$9G:(DE-HGF)POF3-6G4$$aDE-HGF$$bForschungsbereich Materie$$lVon Materie zu Materialien und Leben$$vFacility topic: Neutrons for Research on Condensed Matter$$x0
000891766 9130_ $$0G:(DE-HGF)POF3-6G15$$1G:(DE-HGF)POF3-6G0$$2G:(DE-HGF)POF3-600$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bForschungsbereich Materie$$lGroßgeräte: Materie$$vFRM II / MLZ$$x1
000891766 9131_ $$0G:(DE-HGF)POF4-6G4$$1G:(DE-HGF)POF4-6G0$$2G:(DE-HGF)POF4-600$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bForschungsbereich Materie$$lGroßgeräte: Materie$$vJülich Centre for Neutron Research (JCNS) (FZJ)$$x0
000891766 9131_ $$0G:(DE-HGF)POF4-632$$1G:(DE-HGF)POF4-630$$2G:(DE-HGF)POF4-600$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bForschungsbereich Materie$$lFrom Matter to Materials and Life$$vMaterials – Quantum, Complex and Functional Materials$$x1
000891766 9141_ $$y2021
000891766 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2021-01-28
000891766 915__ $$0LIC:(DE-HGF)CCBYNCND4$$2HGFVOC$$aCreative Commons Attribution-NonCommercial-NoDerivs CC BY-NC-ND 4.0
000891766 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bMOL THER-NUCL ACIDS : 2019$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)0501$$2StatID$$aDBCoverage$$bDOAJ Seal$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)0500$$2StatID$$aDBCoverage$$bDOAJ$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)0700$$2StatID$$aFees$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)0510$$2StatID$$aOpenAccess
000891766 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bDOAJ : Blind peer review$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)0561$$2StatID$$aArticle Processing Charges$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)9905$$2StatID$$aIF >= 5$$bMOL THER-NUCL ACIDS : 2019$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)0320$$2StatID$$aDBCoverage$$bPubMed Central$$d2021-01-28
000891766 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2021-01-28
000891766 920__ $$lyes
000891766 9201_ $$0I:(DE-Juel1)JCNS-FRM-II-20110218$$kJCNS-FRM-II$$lJCNS-FRM-II$$x0
000891766 9201_ $$0I:(DE-588b)4597118-3$$kMLZ$$lHeinz Maier-Leibnitz Zentrum$$x1
000891766 9201_ $$0I:(DE-Juel1)JCNS-1-20110106$$kJCNS-1$$lNeutronenstreuung$$x2
000891766 9201_ $$0I:(DE-Juel1)JCNS-4-20201012$$kJCNS-4$$lJCNS-4$$x3
000891766 980__ $$ajournal
000891766 980__ $$aVDB
000891766 980__ $$aUNRESTRICTED
000891766 980__ $$aI:(DE-Juel1)JCNS-FRM-II-20110218
000891766 980__ $$aI:(DE-588b)4597118-3
000891766 980__ $$aI:(DE-Juel1)JCNS-1-20110106
000891766 980__ $$aI:(DE-Juel1)JCNS-4-20201012
000891766 9801_ $$aFullTexts