TARGETED POLYMER BIOCONJUGATES

1 - 61 . (canceled)

62 . A polymer bioconjugate, comprising:

(a) a pH-dependent membrane-destabilizing polymer having an alpha end and an omega end, and comprising:

(i) a plurality of chargeable monomeric units comprising a species that is anionic at about neutral pH; and

(ii) a plurality of monomeric units comprising a hydrophobic group; and

(b) an RNAi agent covalently coupled to the alpha end or the omega end of the membrane-destabilizing polymer,

provided that the polymer bioconjugate does not self-assemble into a micelle when the polymer bioconjugate is at or below a concentration of 100 μg/mL in water at a neutral pH.

63 . The polymer bioconjugate of claim 62 , wherein the pH-dependent membrane-destabilizing polymer is a block copolymer.

64 . The polymer bioconjugate of claim 62 , wherein the polymer bioconjugate has a particle size diameter of not more than 30 nm.

65 . The polymer bioconjugate of claim 62 , wherein the RNAi agent is a polynucleotide.

66 . The polymer bioconjugate of claim 65 , wherein the polynucleotide is a dicer substrate.

67 . The polymer bioconjugate of claim 62 , wherein the RNAi agent is covalently coupled to the membrane-destabilizing polymer through a linking moiety.

68 . The polymer bioconjugate of claim 67 , wherein the linking moiety is cleavable and comprises a dicer substrate or a disulfide.

69 . The polymer bioconjugate of claim 62 , wherein the species that are anionic at about neutral pH are non-charged or substantially neutral at an acidic pH.

70 . The polymer bioconjugate of claim 62 further comprising one or more targeting ligands covalently coupled to the pH-dependent membrane-destabilizing polymer.

71 . The polymer bioconjugate of claim 70 , wherein the one or more targeting ligands are selected from the group consisting of a vitamin, a saccharide, a peptide, a hormone, an aptamer, a small molecule, or combinations thereof.

72 . The polymer bioconjugate of claim 71 , wherein the targeting ligand is covalently coupled to the end of the membrane-destabilizing polymer opposing the RNAi agent.

73 . The polymer bioconjugate of claim 62 , wherein the membrane-destabilizing polymer comprises x monomeric units comprising the species that are anionic at about neutral pH and y hydrophobic monomeric units comprising the hydrophobic groups, wherein the ratio of x to y is about 1:1 to about 5:1.

74 . The polymer bioconjugate of claim 73 , wherein at least one of the monomeric units comprises alkyl acrylic acid as the species that is anionic at about neutral pH.

75 . A compound comprising a plurality of polymer bioconjugates of claim 71 , each polymer bioconjugate comprising a membrane-destabilizing polymer coupled to the same targeting ligand, and coupled to the RNAi agent.

76 . The compound of claim 75 , wherein each membrane-destabilizing polymer is coupled to the RNAi agent at either the alpha or omega end of the polymer, and is coupled to the targeting ligand at the opposing end of the polymer.

77 . A compound, comprising:

a polymer bioconjugate comprising

(a) a pH-dependent membrane-destabilizing polymer having an alpha end and an omega end, and comprising

(i) a plurality of monomeric units comprising a species that is anionic at about neutral pH; and

(ii) a plurality of monomeric units comprising hydrophobic groups, and

(b) an RNAi agent covalently coupled to the alpha end or the omega end of the membrane-destabilizing polymer; and

(c) a proteinaceous targeting ligand covalently coupled to the pH-dependent membrane-destabilizing polymer.

78 . The compound of claim 77 , comprising a plurality of polymer bioconjugates covalently coupled to the proteinaceous targeting ligand.

79 . The compound of claim 78 , comprising at least 2 polymer bioconjugates covalently coupled to the proteinaceous targeting ligand.

80 . The compound of claim 79 , wherein the proteinaceous targeting ligand is covalently coupled to the pH dependent membrane destabilizing polymer at the end opposite the RNAi agent.

81 . The compound of claim 79 , wherein the proteinaceous targeting ligand is covalently coupled to the pH dependent membrane destabilizing polymer at a pendant group of a monomeric unit of the pH dependent membrane destabilizing polymer.

82 . A composition comprising the polymer bioconjugate of claim 62 .

83 . A method for intracellular delivery of an RNAi agent, comprising contacting a cell with the polymer bioconjugate of claim 62 .