Since its discovery in the late 1990s by Fire and Mello, RNA interference (RNAi) has proven a useful tool for scientists working in the fields of functional genomics, biotechnology, and therapeutic development. However, one of the obstacles of making small interfering RNAs (siRNAs), the main effector of RNAi, a therapeutic agent includes the activation of the immune system, off-target effects, and competition with endogenous microRNAs (miRNAs) for cellular miRNA-processing machinery. Therefore, the translation of RNAi technology into the clinic depends on the development of new strategies to surmount siRNA unwanted effects and identify siRNA sensing receptors as well as to understand the extend of the competition between exogenous and endogenous miRNAs. This minireview summarizes our current knowledge of siRNA sensing by the immune receptors and how to separate siRNA unwanted effects from gene silencing.
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