RNA interference (RNAi) guided by small interfering RNAs (siRNA), because of its potential to target and silence the expression of specific genes is utilized as an effective tool in a variety of biological applications. RNAi guided by siRNAs is a powerful tool to attain gene silencing in mammalian cells. One of the features which make siRNA as an amazing biological tool is extremely specific knockdown of target genes by degradation of analogous mRNAs. However, various non-specific effects limit the use of RNAi including the activation of innate immunity and inhibition of inadvertent target genes. One of the most common non-specific effects is inducing the innate immune system including cytoplasmic and endosomal activation of innate immune system, potentially offending the single in mammals. This activation is mainly interceded by immune cells, regularly through a Toll-like receptor (TLR) pathway. The siRNA sequence association of these pathways changes with the sort and position of the TLR involved. In contrast, non-immune cell activation can also arise generally siRNAs which enter into cytoplasm interacting with cytoplasmic RNA sensors such as retinoic acid-inducible gene I. Here, we explain the off-target effects of siRNAs that activate innate immune system and methods to alleviate them, to help enable impressive application of this exciting technology, Also we bold the aspect of molecular strategies permitting the design of therapeutic siRNAs with minute off-target effects.
Keywords: RNAi; Toll-like receptor; innate immunity; off-target; protein kinase receptor.