Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application

By A. Jackson, Peter S. Linsley. Nature reviews. Drug discovery, 2010

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RNA interference in the clinic: challenges and future directions (2010, background): “TLR3 is only activated by duplex siRNA, and whether the sequence is important is not yet know”
RNA therapeutics: Beyond RNA interference and antisense oligonucleotides (2012, background): “Specifically, siRNAs can enter the RISC and bind with certain base pairs mismatched to untargeted mRNAs, thus acting like endogenous miRNAs and leading to off-target gene silencin”
Innovative approaches for cancer treatment: current perspectives and new challenges (2019, background): “Occasionally, they can induce offtarget effects [178] or elicit innate immune responses, followed by specific inflammation [179, 180].”
RNAi-Based Insecticidal Crops: Potential Effects on Nontarget Species (2013, background): “Genes whose regulation is tied to RNAi tend to have longer 3′ UTRs with more potential seed regions that facilitate binding of siRNAs and microRNAs; those mRNAs that are not targeted by RNAi have shorter 3′ UTRs (Jackson et al. 2006).”