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Additionally, conservative region at nucleotide level must be targeted for RNAi in applying to virus because hepatitis C virus (HCV) could escape from therapeutic pressure with genome mutations. <jats:italic>In vitro<\/jats:italic> preparation of Dicer-generated siRNAs targeting a conserved, highly ordered HCV 5\u2032 untranslated region are capable of inducing strong RNAi activity. By dissecting the 5\u2032-end of an RNAi-mediated cleavage site in the HCV genome, we identified potent siRNA sequences, which we designate as Dicer-hunting siRNAs (dh-siRNAs). Furthermore, formulation of the dh-siRNAs in an optimized multifunctional envelope-type nano device inhibited ongoing infectious HCV replication in human hepatocytes <jats:italic>in vivo<\/jats:italic>. 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