Influence of cationic lipid composition on uptake and intracellular processing of lipid nanoparticle formulations of siRNA

This study reports on the in vivo gene silencing potency of lipid nanoparticle-siRNA systems containing ionizable cationic lipids. It is concluded that the superior potency of DLinKC2-DMA compared with DLinKDMA or DLinDMA can be attributed to their higher uptake thus improved ability to stimulate siRNA release from endosome.Graphical Abstract: Uptake of lipid nanoparticle (LNP) formulations of siRNA into cells. (1) LNP-siRNA associates with cell membrane followed by (2) internalization. As the pH decreases in the endosomes the ionizable cationic lipids associate with endogenous anionic lipids to destabilize the endosomal membrane of LNP-siRNA. For LNP-siRNA systems containing DLinDMA, DLinKDMA and DLinKC2-DMA siRNA is then released to the cytosol (3) leading to gene silencing. (4) LNP-siRNA systems containing DLinDAP exhibit poor gene silencing potency due to degradation of DLinDAP by endogenous lipases thus inhibiting membrane destabilization and the ability of siRNA to escape the endosome.

Source: Nanomedicine : Nanotechnology, Biology, and Medicine - June 14, 2012 Category: Nanotechnology Authors: Paulo J.C. Lin, Yuen Yi C. Tam, Ismail Hafez, Ammen Sandhu, Sam Chen, Marco A. Ciufolini, Ivan R. Nabi, Pieter R. Cullis Tags: QV Pharmacology, Pharmaceutical Technology, Gene Transfection, Lipid NPs Source Type: research