RNAinterference

RNA interference (RNAi) is a biological process in which double-stranded RNA mediates sequence-specific silencing of gene expression at the transcriptional or post-transcriptional level. It is conserved across eukaryotes and involves small non-coding RNA species that guide gene regulation.

Mechanistically, in animals long double-stranded RNA is processed by the enzyme Dicer into small interfering RNAs (siRNAs) and microRNAs (miRNAs) of about 21–25 nucleotides. The siRNA or miRNA duplex is incorporated into the RNA-induced silencing complex (RISC). One strand (the guide) is retained while the other (the passenger) is discarded. The guide strand directs RISC to complementary mRNA sequences, where Ago2-type Argonaute proteins cleave the target in the case of siRNA with perfect complementarity; miRNA guidance typically results in translational repression or mRNA destabilization with imperfect pairing.

Endogenously, miRNAs and other components of the RNAi pathway regulate development, differentiation, metabolism, and other cellular processes by modulating gene expression. Exogenously delivered RNAi reagents, such as synthetic siRNAs or miRNA mimics, are used as research tools to silence specific genes and are being explored for therapeutic applications. Delivery remains a major challenge, with concerns including off-target effects and innate immune activation, as well as the need for efficient, selective delivery to target tissues.

RNA interference was demonstrated in Caenorhabditis elegans by Fire and Mello in 1998, a discovery that spurred advances in functional genomics and drug development. Several RNAi-based therapies have reached clinical use in various indications, highlighting the potential and ongoing challenges of translating RNAi into medicine.