Im Nature wurde letztes Jahr bereits auf die toxischen Eigenschaften der Nanolipide hingewiesen. Die Arbeiten zu den Nanolipiden liest sich kein Politiker durch. Auch hier gilt für mich:. Unwissenheit schützt vor Strafe nicht - erst recht nicht bei experimentellen Menschenversuchen.

Ionizable amino lipid interactions with POPC: implications for lipid nanoparticle function†
M. Ramezanpour ORCID logoa, M. L. Schmidt b, I. Bodnariuc ORCID logocd, J. A. Kulkarni ORCID logoef, S. S. W. Leung ORCID logob, P. R. Cullis ORCID logoe, J. L. Thewalt ORCID logobc and D. P. Tieleman ORCID logo*a aCentre for Molecular Simulation, Department of Biological >Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada. E-mail: >[email protected] bDepartment of Physics, Simon Fraser University, Burnaby, BC V5A 1S6, Canada cDepartment of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada dDepartment of Chemistry, University of Calgary, Calgary, AB T2N 1N4, Canada eDepartment of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6 T 1Z3, Canada fDepartment of Medical Genetics, University of British Columbia, Vancouver, BC V6 T 1Z3, Canada

Received 16th March 2019 , Accepted 15th July 2019
First published on 23rd July 2019

Abstract
Lipid nanoparticles (LNPs) composed of ionizable cationic lipids are currently the leading systems for siRNA delivery in liver disease, with the major limitation of low siRNA release efficacy into the cytoplasm. Ionizable cationic lipids are known to be of critical importance in LNP structure and stability, siRNA entrapment, and endosomal disruption. However, their distribution inside the LNPs and their exact role in cytoplasmic delivery remain unclear. A recent study [Kulkarni et al., On the formation and morphology of lipid nanoparticles containing ionizable cationic lipids and siRNA, ACS Nano, 2018, 12(5), 4787–4795] on LNP-siRNA systems containing the ionizable lipid DLin-KC2-DMA (also known as KC2 with an apparent pKa of ca. 6.7) suggested that neutral KC2 segregates from other components and forms an amorphous oil droplet in the core of LNPs. In this paper, we present evidence supporting the model proposed by Kulkarni et al. We studied KC2 segregation in the presence of POPC using molecular dynamics simulation, deuterium NMR, SAXS, and cryo-TEM experiments, and found that neutral KC2 has a high tendency to separate from POPC dispersions. KC2 confinement, upon raising the pH during the formulation process, could result in rearrangement of the internal structure of LNPs. As interactions between cationic KC2 and anionic endosomal lipids are thought to be a key factor in cargo release, *KC2 confinement inside the LNP may be responsible for the observed low release efficacy.. *