Overcoming the challenges of siRNA activation of innate immunity: design better therapeutic siRNAs.

RNA interference (RNAi) is a conserved regulatory mechanism of posttranscriptional gene silencing triggered by either endogenously (e.g. microRNAs) or exogenously double-stranded RNA as small interfering (si) RNAs. To date, the use of siRNA (21-nt) has become a standard laboratory tool to silence gene expression in mammalian cells in-vitro and in-vivo. The methodology also holds promise for treating a diversity of human diseases. However, one of the challenges of making siRNAs as therapeutic drugs includes the activation of innate immunity and silencing of unwanted genes. Therefore, the use of siRNAs in functional genomics and human therapies depends on the development of strategies to overcome siRNA unwanted effects. This chapter highlights some efficient strategies aimed at separating gene silencing from immunostimulation and improving siRNA gene silencing specificity.