Bioresponsive Nanoparticles for the Intracellular Delivery of RNAi Therapeutics - Nanotechnology for the Delivery of Therapeutic Nucleic Acids - page 130

therapeutic approach. The process of post-transcriptional gene
silencing occurs through mRNA engagement by an RNA-induced
silencing complex (RISC) triggered by siRNA duplexes [1-4].
Messenger RNA specificity is facilitated by complementary base
pairing of the guide strand retained after duplex disassembly and
passenger strand removal during the recruitment process into RISC.
The sequence specific nature of siRNA that allows for exclusive
inhibition of target genes along with the capability for exogenous
siRNA to enter the RNAi pathway presents “RNAi triggers” as highly
attractive drug candidates.
The therapeutic effectiveness of siRNA is compromised by
susceptibility to nuclease degradation, rapid renal clearance, and
reduced cellular entry due to its polyanionic and macromolecular
nature. Delivery is a key determinant in realizing the full clinical
potential of RNAi-based therapeutics [5]. Non-viral delivery systems
and chemical modifications have been developed to maximise payload
at target sites [6-9]. Our expanding knowledge of the RNAi pathway
has allowed identification of key molecules within the RNAi cascade
that has broadened our selection of potential drug candidates. The
action of these molecules is dependent on engagement with the RNAi
machinery at specific intracellular sites; therefore, cellular entry and
modulation of intracellular trafficking is of crucial importance.
Unique properties occurring at the nanoscale can be utilized
to improve delivery of RNAi therapeutics. Polycation-based
nanoparticles (termed polyelectrolyte complexes or polyplexes)
formed by electrostatic self-assembly of siRNA with polycations
offer flexible designs to fulfil both extracellular and intracellular
delivery requirements [10, 11]. The inclusion of polymers, linkages,
or functional groups that exhibit conformational change in response
to biological stimuli is a strategy to control spatial and temporal
delivery of siRNA. This work describes the application of these
“bioresponsive” polyplexes for modulation of intracellular trafficking
and gene silencing of different RNAi triggers.

6.2 Repertoire of Potential RNAi Therapeutics

An expanding panel of potential RNAi drugs has been generated
through the greater understanding of the RNAi pathway. The
discovery that exogenous long double stranded RNA could induce