Disclosed are polynucleotides, compositions, and methods related to RNA interference (RNAi). Particular disclosed are toxic RNAi active seed sequences and methods of using toxic RNAi active sequences for killing cancer cells. The disclosed toxic RNAi active seed sequences preferentially target and inhibit the expression of multiple essential genes for cell survival and/or growth through a process called “death-induced by survival gene elimination” or “DISE.” The disclosed toxic RNAi active seed sequences may be referred to as “dual activity super toxic RNAi active dsRNAs” that include a toxic first strand and a toxic second strand that is complementary to the toxic first strand. As such, the disclosed dsRNAs may be expressed as shRNAs which are processed for RNA interference (RNAi) and either of the toxic first strand and the toxic second strand can function as a guide strand to initiate RNAi.
