Molecular Mechanisms of Innate Immune Sensing of Exogenous RNAs

RNA sensing by the immune system is a critical mechanism through which cells detect and respond to viral infections and other pathogenic threats. This process involves specialized receptors known as pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, which recognize distinct RNA structures or motifs associated with pathogens. Upon detection, these receptors activate signaling pathways that lead to the production of type I interferons and other cytokines, orchestrating an antiviral response. Exogenously delivered therapeutic RNAs, including small interfering RNAs and messenger RNAs, can unintentionally trigger innate immune responses by being recognized as foreign by PRRs. This can lead to inflammation or unintended immune responses that could reduce the efficacy of the therapy, by triggering therapeutic mRNA degradation and inhibition of translation. This review describes various RNA-sensing receptors and strategies to mitigate the immunogenicity of exogenously delivered RNAs.