Delivery of RNAi Therapeutics to the Airways—From Bench to Bedside

Qiu, Yingshan; Lam, Jenny K. W.; Leung, Susan W. S.; Liang, Wanling

Long dsRNAs (around 500-1000 nucleotides in length) have been employed to study gene functions. After the exogenous dsRNA is introduced into the cytoplasm of the cells, it is cleaved by RNase III enzyme Dicer into short dsRNA called siRNA. The siRNA which is 21-23 nucleotides in length is loaded into a protein complex called the RNA-induced silencing complex (RISC). The siRNA is then unwound, and the sense strand (also known as the passenger strand) of the siRNA is degraded, whereas the remaining antisense strand (also known as the guide strand) guides the activated RICS to the target messenger RNA (mRNA) through full complementary binding. The mRNA is then cleaved by Argonaute 2 (Ago2) in the RISC, leading to the silencing of the target gene [14, 15] . Since long dsRNA is known to trigger immunostimulatory response through the activation of Dicer-related antiviral pathways and induction of type 1 interferon (IFN) [16] , it is less suitable for therapeutic use. In contrast, synthetic siRNA is a more promising gene silencing mediator because of the lower risk of immune response. It is also the most widely investigated RNAi molecule for therapeutic applications, with over 26 clinical trial studies being initiated since 2004 [17] .