From the Guidelines
Small interfering Ribonucleic Acids (siRNAs) are double-stranded RNA molecules that regulate gene expression by inhibiting mRNA, typically consisting of a 19-25 base pair sequence.
Key Characteristics of siRNAs
- siRNAs are composed of a pharmacologically inactive sense strand and a pharmacologically active antisense strand 1
- The antisense strand is activated via selective removal of the sense strand by Argonaute 2 (Ago2), an RNA-induced silencing complex (RISC) endonuclease 1
- siRNAs work by catalyzing the destruction of and/or selectively inhibiting translation of complementary RNA transcript 1 ### Mechanism of Action
- siRNAs are taken up into cells via the endosomal pathway, and then load into the RNA-induced silencing complex (RISC) 2
- The antisense strand of siRNA directs recognition of its complementary target mRNA, and Ago2 in the RISC complex cleaves the target mRNA sequence, subsequently suppressing the target protein encoded by it 2 ### Properties of siRNAs
- siRNAs have a high molecular weight (∼10–15 kDa) and hydrophilic nature, limiting cellular uptake of unmodified double-stranded siRNA 3
- To enhance uptake, siRNA is often complexed within lipid nanoparticles (LNPs) or conjugated to a cell-specific targeting ligand, such as GalNAc 3
From the Research
Definition and Mechanism of siRNAs
- Small interfering RNAs (siRNAs) are small RNA molecules that promote potent and specific silencing of mutant, exogenous, or aberrant genes through a mechanism known as RNA interference (RNAi) 4, 5.
- siRNAs are synthesized exogenously to create short nucleotide sequences that trigger RNAi in cells and silence target gene expression in a sequence-specific way 4.
- The mechanism of siRNA as a gene silencer is well-established, and it has gained popularity as a nucleic acid-based medicine for the treatment of various diseases, including cancer 4, 6.
Characteristics and Potential of siRNAs
- siRNAs have novel potential for the treatment of cancer and other genetic disorders by targeting the mRNA of underlying genes and degrading it 4, 6.
- siRNAs have been tested in various scenarios, including control of anxiety, alcohol consumption, drug-receptor blockage, and inhibition of pain signaling 5.
- siRNAs have been identified as a promising strategy to control many genetic disorders, and their delivery by nanocarriers has been identified as a promising strategy in the study and treatment of cancer 4, 6.
Challenges and Delivery Strategies of siRNAs
- The delivery of siRNAs to targeted organs is highly restricted by several intracellular and extracellular barriers, and there is a great need to develop and establish siRNA delivery systems that protect siRNAs and deliver them efficiently to the desired sites 6, 7.
- Various design strategies have been developed to overcome siRNA delivery obstacles, including chemical modification, bioconjugation to specific ligands, and carrier-mediated strategies 6, 7.
- Nanotechnology-based systems, such as liposomes, niosomes, solid lipid nanoparticles (SLNs), dendrimers, and polymeric nanoparticles (PNs), have been discussed as potential delivery systems for siRNAs 6.