iRNA AGENTS WITH BIOCLEAVABLE TETHERS

An iRNA agent comprising a first strand and optionally a second strand, wherein at least one subunit having a formula (I) is incorporated into at least one of the strands:

• wherein:
• X is N(CO)R7, NR7 or CH2;
• Y is NR8, O, S, CR9R10, or absent;
• Z is CR11R12 or absent;
• Each of R1, R2, R3, R4, R9, and R10 is, independently, H, ORa, ORb, (CH2)nORa, or (CH2)nORb, provided that at least one of R1, R2, R3, R4, R9, and R10 is ORa or ORb and that at least one of R1, R2, R3, R4, R9, and R10 is (CH2)nORa, or (CH2)nORb;
• Each of R5, R6, R11, and R12 is, independently, H, C1-C6 alkyl optionally substituted with 1-3 R13, or C(O)NHR7;
• or R5 and R11 together are C3-C8 cycloalkyl optionally substituted with R14;
• R7 is T-Rd, in which T is a tether comprising one or more linking groups, wherein at least one of the linking groups is cleavable;
• and Rd is H or a ligand;
• R8 is C1-C6 alkyl;
• R13 is hydroxy, C1-C4 alkoxy, or halo;
• R14 is NRcR7;
• Ra is H or
• Rb is H or
• Each of A and C is, independently, O or S;
• B is OH, O−, or
• Rc is H or C1-C6 alkyl;
• and
• n is 1-4;
• provided that X is N(CO)R7 or NR7;
• or one of R5, R6, R11, and R12 is C(O)NHR7;
• or R14 is present.