Strategies to Prevent siRNA-Triggered Cellular Toxicity

Abstract

RNA interference (RNAi) allows selective gene silencing, is widely used for functional analysis of individual genes in mammalian cells, and represents an attractive therapeutic option for treating various diseases. However, growing evidence exists that chemically synthesized small interfering RNAs (siRNAs) as well as promoter-expressed short-hairpin RNAs (shRNAs) may cause cellular toxicity resulting in unspecific cellular phenotypes and, in case of therapeutic interventions, severe side effects. Various mechanisms have been identified including the induction of interferon-stimulated gene (ISG) expression as well as the disruption of natural microRNA biogenesis and function by competition of exogenous shRNAs for the endogenous RNAi machinery. This review highlights recent progress in the understanding of siRNA-triggered toxicity and outlines strategies to prevent undesirable side effects.