Enhancement of Stability and Activity of siRNA by Terminal Substitution with Serinol Nucleic Acid (SNA)

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Abstract
RNA interference (RNAi ), sequence‐specific gene silencing triggered by double‐stranded, small interfering RNA (siRNA), has become a facile and effective tool for biological research and holds potential for therapeutic applications. However, the application of siRNA is hindered by susceptibility to nucleases and off‐target effects. In this study, we introduced artificial nucleotides, serinol nucleic acid (SNA), with an acyclic scaffold, at the termini of siRNA strands. Our aim was appropriately to accommodate the antisense strand in an RNA‐induced silencing complex (RISC) by inhibiting sense‐strand incorporation and thus improve resistance to nuclease‐mediated degradation. Substitution of SNA into siRNA at both termini of the sense strand and at the 3′ terminus of the antisense strand improved antisense strand selectivity remarkably in the formation of RISC, RNAi activity, and nuclease resistance.

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