Pathways of cellular internalisation of liposomes delivered siRNA and effects on siRNA engagement with target mRNA and silencing in cancer cells

Scientific Reports
Abdullah AlshehriSnow Stolnik

Abstract

Design of an efficient delivery system is a generally recognised bottleneck in translation of siRNA technology into clinic. Despite research efforts, cellular processes that determine efficiency of siRNA silencing achieved by different delivery formulations remain unclear. Here, we investigated the mechanism(s) of cellular internalisation of a model siRNA-loaded liposome system in a correlation to the engagement of delivered siRNA with its target and consequent silencing by adopting siRNA molecular beacon technology. Probing of cellular internalisation pathways by a panel of pharmacological inhibitors indicated that clathrin-mediated (dynamin-dependent) endocytosis, macropinocytosis (dynamine independent), and cell membrane cholesterol dependent process(es) (clathrin and caveolea-independent) all play a role in the siRNA-liposomes internalization. The inhibition of either of these entry routes was, in general, mirrored by a reduction in the level of siRNA engagement with its target mRNA, as well as in a reduction of the target gene silencing. A dramatic increase in siRNA engagement with its target RNA was observed on disruption of endosomal membrane (by chloroquine), accompanied with an increased silencing. The work thus illust...Continue Reading

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Citations

May 8, 2019·Journal of Liposome Research·Intouch SakpakdeejaroenChristine Dufès
Apr 23, 2020·Pharmaceutics·Darío Manzanares, Valentín Ceña
Jul 26, 2019·Journal of Interdisciplinary Nanomedicine·Intouch SakpakdeejaroenChristine Dufès
Oct 8, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Stephen B Shears, Huanchen Wang
Jul 1, 2020·Advanced Drug Delivery Reviews·Nina FilipczakVladimir P Torchilin
Nov 5, 2019·Journal of Controlled Release : Official Journal of the Controlled Release Society·A Nieto-OrellanaS Stolnik

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Methods Mentioned

BETA
flow cytometry
confocal microscopy
GTPase
gene knockdown
Assay

Software Mentioned

Weasel

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