New publication in the Rädler Group

The pH-dependent response of CIL-LNPs (Cationic ionizable lipid-Lipid nanoparticles) is key to endosomal release and subsequently improved clinical outcome. We provide a systematic study of lyotropic order of three ionizable lipids and determine pH-dependent structural transitions in terms of crystal symmetry and spacings. The findings result in a refined perception of mode of action. Supported by molecular dynamics (MD) simulations, it stands to reason that the inverse micellar to inverse hexagonal transition of the excess CIL phase is the limiting step associated with release and less efficient in DD (DLin-DMA). This hypothesis is substantiated by delayed protein expression onset in DD-LNP-mediated transfection compared to MC3 and KC2. Our data suggest that not structure but structural transitions cause fusogenic activity.

J. Philipp, A. Dabkowskab, A. Reiser ... J. O. Rädler
pH- dependent structural transitions in cationic ionizable lipid mesophases are critical for lipid nanoparticle function
PNAS, Vol. 120, 502023, 2023