Engineering Small Interfering RNAs by Strategic Chemical Modification

Synthetic small interfering RNAs (siRNAs) have revolutionized functional genomics in mammalian cell cultures due to their reliability, efficiency, and ease of use. This success, however, has not fully translated into siRNA applications in vivo and in siRNA therapeutics where initial optimism has been dampened by a lack of efficient delivery strategies and reports of siRNA off-target effects and immunogenicity. Encouragingly, most aspects of siRNA behavior can be addressed by careful engineering of siRNAs incorporating beneficial chemical modifications into discrete nucleotide positions during siRNA synthesis. Here, we review the literature (Subheadings 1 –3) and provide a quick guide (Subheading 4) to how the performance of siRNA can be improved by chemical modification to suit specific applications in vitro and in vivo.