RNAis

RNA interference (RNAi) is a gene-silencing mechanism in which double-stranded RNA triggers sequence-specific suppression of homologous gene expression. In many eukaryotes, RNAi operates through small RNA molecules of about 21 to 24 nucleotides, including small interfering RNAs (siRNAs) and microRNAs (miRNAs), which guide effector complexes to target transcripts.

Double-stranded RNA is processed by the enzyme Dicer into siRNA or miRNA duplexes. The guide strand is incorporated into an Argonaute-containing RNA-induced silencing complex (RISC). siRNA typically directs endonucleolytic cleavage of perfectly complementary mRNA, whereas miRNA usually represses translation or promotes mRNA destabilization despite imperfect complementarity. Both pathways rely on Argonaute and other nucleases to effect silencing.

Endogenous RNAi pathways regulate development, genome stability, and defense against transposons and viruses in many organisms. In plants and invertebrates, RNAi also contributes to antiviral defense and transposon silencing. Exogenous RNAi triggers, such as experimentally delivered dsRNA or siRNA, are used to study gene function in research.

RNAi has been harnessed for therapy and research. Synthetic siRNAs and siRNA-based conjugates can silence disease-related genes in cells and tissues. Several siRNA-based therapeutics have been approved, including patisiran for hereditary transthyretin-mediated amyloidosis, with ongoing development for other diseases. Challenges include efficient delivery to specific tissues, avoidance of off-target effects and activation of innate immune sensors, and achieving durable silencing.

RNAi was described in the late 1990s by Fire and Mello in Caenorhabditis elegans, establishing a foundation for understanding post-transcriptional gene regulation. Subsequent work identified Dicer and Argonaute proteins as core components, revealing a conserved mechanism present across many animal and plant lineages.