Optimization of siRNA delivery to target sites: issues and future directions.

INTRODUCTION: The discovery of RNA interference (RNAi) earned the 2006 Nobel Prize in Physiology or Medicine for its biological significance and potential for developing novel therapeutics. The small interfering RNA (siRNA) is the most promising tool for translating RNAi to clinical use. Efforts are ongoing to improve siRNA delivery through developing novel biomaterials and delivery strategies. Given time, it appears that siRNA drugs will eventually become a reality. AREAS COVERED: The currently used approaches for siRNA delivery are discussed with a focus on siRNA therapeutics currently in clinical testing. A comparison of advantageous aspects of currently available platforms and the possibility of further optimization for increased efficiency and safety are presented. Future directions in siRNA delivery are also highlighted. EXPERT OPINION: The recent success in the field of siRNA delivery is based mainly on developing new biomaterials with extraordinarily high activities. Notably, the introduction of ionizable lipids and novel targeting ligands represent two huge steps for realizing siRNA therapy. The currently available systems are largely directed to the liver and the new challenge is to extend their applicability for treating diseases of other organs. Active targeting to different organs is the most promising approach for developing new siRNA-based therapeutics.