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Although RNA interference is widely used for gene silencing, unintended gene modulation generated by off-target effects represents a major barrier to its applications in biology and medicine. Off-targeting can be induced by both the sense and antisense siRNA strands. An approach to minimizing off-target gene silencing by the sense strand would be the blockade of the 5'-end phosphorylation, thereby impeding its entry into the RNA-induced silencing complex (RISC). In this chapter, a biotin group at the 5'-end of the sense strand was use

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