Small interfering RNA (siRNA) (siRNA)

Small interfering RNA (siRNA) is a class of double-stranded RNA molecules, typically 20-25 base pairs in length, that operate within the RNA interference (RNAi) pathway (Fire et al., 1998, Nature). Rather than being a biological target itself, siRNA is a therapeutic modality designed to silence specific genes by promoting the degradation of their corresponding messenger RNA (mRNA) (Castanotto & Rossi, 2009, Nature). Upon entering the cytoplasm, siRNA is incorporated into the RNA-induced silencing complex (RISC), where the passenger strand is discarded and the guide strand directs the complex to a perfectly complementary mRNA sequence (Alnylam Pharmaceuticals, 2023). The Argonaute 2 (AGO2) enzyme within RISC then cleaves the mRNA, preventing its translation into a functional protein (Pratt & MacRae, 2009, Nature Structural & Molecular Biology). This mechanism allows for the highly specific down-regulation of disease-causing proteins, making it a powerful tool for treating genetic disorders like hereditary transthyretin-mediated amyloidosis (hATTR) and metabolic diseases like hypercholesterolemia (Hu et al., 2020, Signal Transduction and Targeted Therapy). The term "siRNA cargo" specifically refers to the siRNA molecule being packaged within delivery vehicles, such as lipid nanoparticles (LNPs) or conjugated to ligands like N-acetylgalactosamine (GalNAc), to ensure stable transport and cellular uptake (Whitehead et al., 2009, Nature Reviews Drug Discovery).

Other names

siRNA cargoShort interfering RNASilencing RNARNAi triggerDouble-stranded RNA

siRNA molecules are loaded into the RNA-induced silencing complex (RISC), where the guide strand directs the Argonaute 2 (AGO2) protein to cleave complementary messenger RNA (mRNA) sequences, leading to gene silencing (Pratt & MacRae, 2009, Nature Structural & Molecular Biology).