eating human disease. Some reagents, such as small interfering RNAs (siRNAs), are applied directly to cells, tissues and organisms; others are engineered to be expressed in cells, such as hairpin structures that provide siRNAs when processed. The basic premise underlying the broad utility of RNAi is that, in theory, we can design siRNAs (or vectors encoding them) to target virtually any gene of interest. RNAi technologies use a cell\'s natural machinery to move exogenously applied siRNAs to the appropriate cellular compartment, where they encounter the correct mRNA target and induce its degradation.

Initial work on RNAi in flies and worms moved quickly to larger mammals and fuelled excitement for potential clinical applications. However, in a similar way to other developing fields in human therapy, such as gene- and antibody-therapy, early excitement has been tempered as a realistic understanding emerges of the milestones that must be reached before the eventual approval of human therapy. Over recent years various complex barriers to achieving efficient RNAi have become evident. These hurdles include: specificity for the target gene; delivery to the correct cell or tissues; the durability of RNAi activity and the ability to redose (if needed); and considerations of the stability of the target mRNA and encoded protein. We have also become aware of the problems posed by the various platforms used to elicit RNAi. However, with setbacks come opportunities. For example, early work in which siRNAs were applied to mouse airway epithelial cells to reduce viral burdens *in vivo* elicited inhibition of target gene expression^[@CR4]^, but it was later found that the induction of an innate immune response probably contributed to the efficacy in these and other experiments^[@CR5],[@CR6]^. Altering the chemical make-up of the synthetic RNA diminished the immune response, as did avoiding known pro-inflammatory sequences^[@CR7],[@CR8]^. This finding also opened investigators\' eyes to the possibility of purposefully using immun