RNAi as New Class of Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 177

cytoplasm. In addition, the presence of disulfides on the nanoparticle
surface permits chemical modifications for targeted delivery [151,
152].
6.4.4 FusogenicProteins
As an alternative strategy to improve endosomal escape of siRNAs,
lipid- or polymer-based nanoparticles can be supplemented with
fusogenic or cell penetrating peptides (CPPs) — short peptides that
are capable of penetrating biological membranes and entering the
cell [43]. Because cargo molecules covalently attached to CPPs can
translocate into the cell in concert with CPPs, these peptides have
been utilized in manufacturing nanoparticles of improved efficiency
of cytoplasmic delivery of nucleic acids [62, 88, 89]. A rough sketch of
this kind of nanoparticle depicts a nucleic acid cargo enclosed inside
the liposome, which is further wrapped in a mixture of “masking”
polymers, cell-specific ligands, and CPPs. A polymeric coat helps
to maintain nanoparticle stability in serum, while cell-recognition
elements direct the nanoparticle to target cells or tissues, and CPPs
allow ultimate penetration of endosomal membranes and delivery of
the cargo directly to the cell cytoplasm. Even commercially available
transfection reagents such as Lipofectamine TM supplemented with
influenza-derived fusogenic peptides have shown enhanced silencing
properties due to more efficient endosomal release of siRNA [117].
Finally, membrane-destabilization mechanism of viroporins
has also been utilized for gene delivery purposes [93]. The main
action of these highly hydrophobic proteins is to create channels
in cell membranes, which facilitate ion flow across them and
eventually to osmolytic membrane rupture [53]. The membrane
disruption mechanism of viroporins, unlike fusogenic polymers,
is pH-insensitive and is therefore not limited to delivery through
endosomes.
6.4.5 DynamicPolyconjugates
In vivo delivery systems are becoming increasingly sophisticated
incorporating multiple components to optimize each stage of the
delivery process from the initial administration, transportation
through the circulatory system to the appropriate tissue, recognition
of the target cells and deposition of the siRNAs into the cytoplasm