Applications of RNA interference: current state and prospects for siRNA-based strategies in vivo

Abstract

Within the recent years, RNA interference (RNAi) has become an almost-standard method for in vitro knockdown of any target gene of interest. Now, one major focus is to further explore its potential in vivo, including the development of novel therapeutic strategies. From the mechanism, it becomes clear that small interfering RNAs (siRNAs) play a pivotal role in triggering RNAi. Thus, the efficient delivery of target gene-specific siRNAs is one major challenge in the establishment of therapeutic RNAi. Numerous studies, based on different modes of administration and various siRNA formulations and/or modifications, have already accumulated promising results. This applies to various animal models covering viral infections, cancer and multiple other diseases. Continuing efforts will lead to the development of efficient and "double-specific" drugs, comprising of siRNAs with high target gene specificity and of nanoparticles enhancing siRNA delivery and target organ specificity.

Fig. 1

RNA interference (RNAi) is an intracellular mechanism which can be triggered through different effector molecules (upper part). Upon their incorporation into the RNA-induced silencing complex (RISC), siRNAs are unwinded, and, as single-stranded so-called guidance RNAs, mediate the hybridization of the now activated complex (RISC*) to its target mRNA. This results in target mRNA cleavage and subsequent degradation, thus emphasizing the pivotal role of siRNAs in the process (left). The exploration of RNAi in vivo requires strategies for the intracellular delivery of siRNAs or “upstream” initiation molecules, i.e., molecules that lead to the intracellular formation of siRNAs (center)