The invention provides ligand-modified double-stranded nucleic acids (dsNAs) useful as RNA interference agents. More particularly, there is provided a dsNA comprising: a sense strand comprising 21 to 83 nucleotides； an antisense strand comprising 15 to 39 nucleotides； a duplex formed by said sense and antisense strand, having a length of 15 to 35 base pairs； wherein the dsNA comprises a discontinuity between the 5'-terminus of the sense strand and the 3'-terminus of the antisense strand or between the 3'-terminus of the sense strand and the 5'-terminus of the antisense strand； wherein the sense strand comprises a tetraloop and the tetraloop comprises at least one ligand-conjugated nucleotide； and wherein said antisense strand is complementary to a target mRNA along at least 15 nucleotides of said antisense strand and the dsNA reduces target gene expression when introduced into a mammal or a mammalian cell.
