The discovery of RNA interference (RNAi) in the late 1990s was almost immediately recognized as providing a general mechanism for specifically targeting thousands of disease-associated genes. But the difficulty of delivering the necessary RNA oligomers to cells in vivo has vexed the field ever since. Two recent papers in Cell 1, 2 now suggest that single-stranded RNAs (ssRNAs) could be a valuable alternative to the more commonly used double-stranded molecules.

Double-stranded, small interfering RNAs (ds-siRNAs) are the most efficient way of inducing RNAi, but they do not readily cross cellular membranes and require special delivery vehicles to gain access to the cytoplasm of cells. The need to formulate ds-siRNAs not only increases the complexity of designing siRNA-based therapies but has also been the source of many of the adverse effects observed in clinical trials of RNA drugs. In addition, both strands of the double-stranded molecule can, in principle, be incorporated into the RNA-induced silencing complexes that mediate RNAi. Although methods to guide the strand selection toward the desired RNA strand have been developed over the years, researchers remain worried about off-target effects and associated toxicities.