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000603710 1001_ $$0P:(DE-HGF)0$$aPhilipp, Julian$$b0
000603710 245__ $$apH-dependent structural transitions in cationic ionizable lipid mesophases are critical for lipid nanoparticle function
000603710 260__ $$aWashington, DC$$bNational Acad. of Sciences$$c2023
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000603710 520__ $$aLipid nanoparticles (LNPs) are advanced core-shell particles for messenger RNA (mRNA) based therapies that are made of polyethylene glycol (PEG) lipid, distearoylphosphatidylcholine (DSPC), cationic ionizable lipid (CIL), cholesterol (chol), and mRNA. Yet the mechanism of pH-dependent response that is believed to cause endosomal release of LNPs is not well understood. Here, we show that eGFP (enhanced green fluorescent protein) protein expression in the mouse liver mediated by the ionizable lipids DLin-MC3-DMA (MC3), DLin-KC2-DMA (KC2), and DLinDMA (DD) ranks MC3 ≥ KC2 > DD despite similar delivery of mRNA per cell in all cell fractions isolated. We hypothesize that the three CIL-LNPs react differently to pH changes and hence study the structure of CIL/chol bulk phases in water. Using synchrotron X-ray scattering a sequence of ordered CIL/chol mesophases with lowering pH values are observed. These phases show isotropic inverse micellar, cubic Fd3m inverse micellar, inverse hexagonal and bicontinuous cubic Pn3m symmetry. If polyadenylic acid, as mRNA surrogate, is added to CIL/chol, excess lipid coexists with a condensed nucleic acid lipidphase. The next-neighbor distance in the excess phase shows a discontinuity at the Fd3m inverse micellar to inverse hexagonal transition occurring at pH 6 with distinctly larger spacing and hydration for DD vs. MC3 and KC2. In mRNA LNPs, DD showed larger internal spacing, as well as retarded onset and reduced level of DD-LNP-mediated eGFP expression in vitro compared to MC3 and KC2. Our data suggest that the pH-driven Fd3m- transition in bulk phases is a hallmark of CIL-specific differences in mRNA LNP efficacy.
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000603710 7001_ $$aDabkowska, Aleksandra$$b1
000603710 7001_ $$00000-0002-0747-5688$$aReiser, Anita$$b2
000603710 7001_ $$0P:(DE-HGF)0$$aFrank, Kilian$$b3
000603710 7001_ $$00000-0001-9240-7278$$aKrzysztoń, Rafał$$b4
000603710 7001_ $$aBrummer, Christiane$$b5
000603710 7001_ $$0P:(DE-HGF)0$$aNickel, Bert$$b6
000603710 7001_ $$0P:(DE-HGF)0$$aBlanchet, Clement E.$$b7
000603710 7001_ $$00009-0004-5910-4709$$aSudarsan, Akhil$$b8
000603710 7001_ $$0P:(DE-HGF)0$$aIbrahim, Mohd$$b9
000603710 7001_ $$aJohansson, Svante$$b10
000603710 7001_ $$aSkantze, Pia$$b11
000603710 7001_ $$aSkantze, Urban$$b12
000603710 7001_ $$00009-0000-4992-1132$$aÖstman, Sofia$$b13
000603710 7001_ $$aJohansson, Marie$$b14
000603710 7001_ $$aHenderson, Neil$$b15
000603710 7001_ $$00000-0002-6008-4096$$aElvevold, Kjetil$$b16
000603710 7001_ $$00000-0002-3308-8948$$aSmedsrød, Bård$$b17
000603710 7001_ $$00000-0003-4191-2674$$aSchwierz, Nadine$$b18
000603710 7001_ $$00000-0002-6711-0605$$aLindfors, Lennart$$b19
000603710 7001_ $$0P:(DE-HGF)0$$aRädler, Joachim O.$$b20$$eCorresponding author
000603710 773__ $$0PERI:(DE-600)1461794-8$$a10.1073/pnas.2310491120$$gVol. 120, no. 50, p. e2310491120$$n50$$pe2310491120$$tProceedings of the National Academy of Sciences of the United States of America$$v120$$x0027-8424$$y2023
000603710 8564_ $$uhttps://www.pnas.org/doi/epdf/10.1073/pnas.2310491120
000603710 8564_ $$uhttps://bib-pubdb1.desy.de/record/603710/files/pH-dependent%20structural%20transitions%20in%20cationic%20ionizable%20lipid%20mesophases%20are%20critical%20for%20lipid%20nanoparticle%20function.pdf$$yOpenAccess
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