RNAi as New Class of Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 174

been shown to specifically deliver siRNAs to HIV-1 infected cells and
suppress HIV-1 replication [19, 165, 166]. This inhibition of HIV-1
occurred through the synergistic action of the aptamer, which itself
had anti-viral properties and the attached anti-HIV siRNA.

6.3 Intracellular Trafficking of siRNAs

Whether cationic lipids, nanoparticles or cell-type-specific delivery
reagents deliver them, the intracellular trafficking of siRNAs begins in
early endosomal vesicles [30]. The contents of the early endosomes
are transferred to sorting endosomes and subsequently to the late
endosomes that are acidified (pH 5-6) by membrane-bound proton-
pump ATPases. The contents of the late endosomes are transported
to the lysosomes, which are further acidified (pH ~4.5) and which
contain various nucleases that promote degradation of the siRNAs.
To avoid lysosomal degradation, siRNAs (free or complexed with the
delivery vehicle) must escape from the endosome into the cytosol,
where they can associate with the RNAi machinery. This endosomal
escape is one of the major barriers for efficient siRNA delivery.
In the following sections, we focus on strategies that have been
developed to promote endosomal release of siRNA, including the
use of fusogenic lipids, polymers with high buff ering capacity and
membrane-interacting peptides.

6.4 Strategies for Endosomal Escape

6.4.1 Cationic Lipids

There is a class of cationic lipids (e.g., phosphatidylethanolamines,
PE) that assembles in the inversed hexagonal phase — wherein the
lipid molecules adopt micelle-like structures to form non-bilayer
assemblies under physiological conditions [90, 102]. Complexes
composed of these cationic lipids and nucleic acids (lipoplexes) have
been shown to attach themselves to anionic membranes such as
endosomal membranes and rapidly fuse with them, resulting in the
release of their contents into the cell interior [90]. The incorporation
of cationic lipids, such as dioleoylphosphatidylethanolamine
(DOPE), into other lipoplexes improves the release of endosomal