Innate immune receptors sensing siRNA (RNA-sensing PRRs)

Innate immune receptors sensing siRNA are a specialized group of pattern recognition receptors (PRRs) that detect small interfering RNA (siRNA) and other double-stranded or single-stranded RNA molecules to initiate host defense mechanisms. This group primarily includes endosomal Toll-like receptors (TLR3, TLR7, and TLR8) and cytoplasmic sensors such as Retinoic acid-inducible gene I (RIG-I), Melanoma Differentiation-Associated protein 5 (MDA5), and Protein Kinase R (PKR) (azolifesciences.com, nih.gov). Their primary biological function is to distinguish self from non-self nucleic acids, triggering the production of Type I interferons and pro-inflammatory cytokines upon detecting viral or exogenous RNA (nih.gov, researchgate.net). In the field of siRNA therapeutics, these receptors are often viewed as off-targets because their activation can lead to systemic inflammation, cytokine release, and potential toxicity, which may interfere with the intended gene-silencing effect (researchgate.net, frontiersin.org). To overcome these challenges, therapeutic siRNAs are frequently engineered with chemical modifications, such as 2-O-methyl or 2-fluoro substitutions, to evade detection by these sensors (nih.gov, cas.org). Conversely, these receptors are also explored as therapeutic targets in cancer immunotherapy, where siRNA-based agonists can be used as adjuvants to stimulate a robust anti-tumor immune response (nih.gov, frontiersin.org).

Other names

siRNA sensorsRNA-sensing pattern recognition receptorsImmunostimulatory RNA receptorsNucleic acid-sensing TLRs and RLRsEndosomal and cytoplasmic RNA sensors

Recognition of specific RNA structural motifs or sequences (e.g., dsRNA, ssRNA, 5-triphosphate) by endosomal or cytoplasmic sensors, triggering signaling pathways such as MyD88 or TRIF to activate NF-κB and IRF transcription factors, leading to the production of Type I interferons and pro-inflammatory cytokines.