Modified RNAi agents

A double-stranded RNAi agent capable of inhibiting the expression of a target gene, comprising a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, wherein the duplex is represented by formula (III):

• sense:
• 5′ np -Na -(X X X) i-Nb -Y Y Y -Nb -(Z Z Z)j -Na -
• nq 3′
• antisense:
• 3′ np′-Na′-(X′X′X′)k-Nb′-Y′Y′Y′-Nb′-(Z′Z′Z′)l-Na′-
• nq′ 5′
• (III)
• wherein:
• i, j, k, and l are each independently 0 or 1, provided that at least one of i, j, k, and l is 1;
• p and q are each independently 0-6;
• each Na and Na′ independently represents an oligonucleotide sequence comprising 2-20 nucleotides which are either modified or unmodified or combinations thereof, each sequence comprising at least two differently modified nucleotides, each Nb and Nb′ independently represents an oligonucleotide sequence comprising 1-10 modified nucleotides;
• each np, np′, nq and nq′ independently represents an overhang nucleotide sequence comprising 0-6 nucleotides;
• and
• XXX, YYY, ZZZ, X′X′X′, Y′Y′Y′, and Z′Z′Z′ each independently represent one motif of three identical modifications on three consecutive nucleotides;
• and
• wherein the modification on Nb is different than the modification on Y and the modification on Nb′ is different than the modification on Y′.