Manipulation of Leukocytes Using Therapeutic RNAi Delivered by Targeted and Stabilized Nanoparticles - Nanotechnology for the Delivery of Therapeutic Nucleic Acids - page 182

regulation mediated by the endogenous miRNA machinery; such
interference could occur as a result of the saturation of enzymes or
transport proteins. In addition, the use of siRNAs for gene silencing
eliminates the clinical safety concerns associated with viral vectors.
All of these factors make siRNA molecules a promising platform for
RNAi-based therapy [4].
Despite the promising therapeutic potential, the biggest
challenge that hinders the translation of siRNAs into clinical
application is delivery [4, 6, 7]. For example, naked siRNAs cross
the cell membrane with low efficiency because of their large
molecular weight (~13 kDa), net negative charge, and hydrophilicity.
Furthermore, when injected intravenously, siRNAs are subjected to
rapid renal clearance and to degradation by serum RNases, resulting

in decreased half-lives . In addition, unless modified, siRNAs are

recognized by TLRs, which activate cellular cascades that stimulate
the immune system and cause a global suppression effect on gene
expression, generating off-target effects and the misinterpretation of
outcomes. Therefore, while the local delivery of naked siRNA can be
useful for treating certain mucosal or subcutaneous tissue diseases,
for systemic administration, suitable delivery systems are required to
ensure the siRNA reaches the cytoplasm of target cells and activates
the RISC. Fortunately, as the chemical properties of synthetic siRNAs
are relatively uniform, optimizing the formulation of a given siRNA
is likely to apply to other siRNAs, facilitating the development of
an siRNA delivery platform technology. Several carriers have been
demonstrated to induce gene silencing via systemic siRNA delivery
to the liver, kidney, and solid tumors. However, systemic delivery
to target leukocytes remains challenging and less advanced. This
chapter describes the current systemic RNAi delivery platforms
targeted to leukocytes, with a focus on the I-tsNP strategy [8-10],
which uses leukocyte integrins for the delivery of siRNAs exclusively
to cells of the immune system [11].

in vivo

8.2 Strategies for RNAi Delivery into Leukocytes

The efficient systemic delivery of siRNAs for gene silencing in
leukocytes has great potential for the treatment of a wide spectrum
of diseases involving leukocytes, including inflammation, viral
infection, and cancer. However, leukocytes and hematopoietic cancer