Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 201

siRNA (called guide or antisense strand) guides the complex to an
mRNA with a homologous sequence, resulting in the cleavage of the
mRNA by a nuclease Argonaute 2 (AGO2) that is part of the RISC
complex (Figure 7.1) (reviewed in [88]). Collectively these studies,
along with many others that followed, have unraveled the promise
of RNAi as a therapeutic to treat practically any human disease,
including those caused by viral infections, through the use of siRNAs
designed to shut off expression of only the disease-causing mRNA.
Numerous in vitro studies have demonstrated the applicability
of RNAi to suppress virtually every class of virus, whether double-
stranded, single-positive, or negative-strand RNA or DNA genome
(Figure 7.1). The transcribed mRNAs of DNA viruses (such as hepatitis
B virus (HBV) and human papilloma virus (HPV)), the uncoated viral
genomic RNA of both negative-sense RNA viruses (such as Influenza)
and positive-sense RNA viruses (such as hepatitis C (HCV)) as well
as processed mRNAs are cytoplasmically located and vulnerable to
RNAi-mediated cleavage. Although retroviruses also have positive-
sense RNA genomes, they have a unique lifecycle that includes an
integration step, and have been discussed separately in this chapter.
RNAi targeting of retroviruses can be achieved at two diff erent stages
of the viral lifecycle-upon viral uncoating when the linear viral genomic
RNA is exposed and following transcription of the integrated proviral
DNA when the viral mRNA is again released into the cytoplasm.
RNAi-targeting of these diverse virus species can be accomplished
through classical RNAi mechanisms using short hairpin RNAs (shRNAs),
long hairpin RNAs (lhRNAs), or siRNAs, all of them leading to RISC-
mediated cleavage. Additionally, while not thought of as classical RNAi
mediators, antisense oligonucleotides (ASOs) and phosphorodiamidate
morpholino oligomers (PMOs) are two additional small RNA molecules
that lead to inhibition by RNase H-mediated cleavage and translational
inhibition, respectively (see Figure 7.1). All of these inhibitory RNAs
can be delivered via several diff erent methods. siRNAs can be delivered
in the naked form to some cell types under specialized conditions but
mostly require complexation with nanocarriers such as liposomes
or nanoparticles (Figure 7.2). shRNAs and lhRNA can be delivered
through non-viral plasmid expression vectors encased in nanocarriers
or through viral vectors (i.e., adenovirus and lentivirus). Although
viral vectors are not classified as “nanomaterials,” pioneering work on
RNAi-therapeutics utilizes viral vectors and therefore they will also be
included in this chapter.