Innate immune receptors recognizing siRNA

Innate immune receptors recognizing 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 (NIH, 2023; ResearchGate, 2023). This group primarily includes Toll-like receptors (TLR3, TLR7, and TLR8), RIG-I-like receptors (RIG-I and MDA5), and the double-stranded RNA-dependent protein kinase (PKR) (ResearchGate, 2016; Biocompare, 2012). These sensors are critical components of the innate immune system, functioning to identify viral genetic material and initiate a defensive response characterized by the production of Type I interferons and pro-inflammatory cytokines (NIH, 2021; Frontiers, 2016). In the development of siRNA-based therapeutics, these receptors often act as unintended targets, where their activation can lead to immunological off-target effects such as systemic inflammation or cytokine storms (Semanticscholar, 2016; NIH, 2014). To mitigate these risks, therapeutic siRNAs are frequently engineered with chemical modifications, such as 2'-O-methyl or 2'-fluoro substitutions, which allow them to bypass these immune sensors while maintaining gene-silencing potency (NIH, 2009; IMR Press, 2008). Conversely, some immunotherapies leverage these receptors as intentional targets to stimulate the immune system against tumors or chronic viral infections (Frontiers, 2016; Biocompare, 2012). The interaction between siRNA and these receptors is highly dependent on the sequence, structure, and delivery method of the RNA molecule (FDA, 2018; NIH, 2023).

Other names

siRNA-sensing receptorsRNA-sensing pattern recognition receptorsRNA-sensing PRRsNucleic acid-sensing receptors

Agonism of Toll-like receptors to stimulate immune response; Antagonism to reduce inflammation; Evasion through chemical modification of siRNA to prevent recognition.