MULTIMERIC OLIGONUCLEOTIDES WITH DIVIDED STRANDS

1 . A multimeric oligonucleotide comprising subunits, wherein:

each of the subunits independently comprises a single-stranded or double-stranded oligonucleotide; each of the subunits is joined to another subunit by a covalent linker; and

at least one subunit comprises at least one partial single-stranded oligonucleotide.

2 . The multimeric oligonucleotide of claim 1 , wherein at least one subunit comprises two partial single-stranded oligonucleotides annealed to a complementary strand to form a double-stranded subunit.

3 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 1:

wherein:

is a single-stranded oligonucleotide;

is a partial single-stranded oligonucleotide; and

● is a covalent linker.

4 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 2:

wherein:

is a single-stranded oligonucleotide;

is a partial single-stranded oligonucleotide; and

● is a covalent linker.

5 . A multimeric oligonucleotide comprising Structure 3:

wherein: each

is independently a partial single-stranded oligonucleotide; and

● is a covalent linker.

6 . The multimeric oligonucleotide of claim 5 , wherein Structure 3 is a homodimer.

7 . The multimeric oligonucleotide of claim 5 , wherein Structure 3 is a heterodimer.

8 . The multimeric oligonucleotide of claim 1 , wherein at least one subunit comprises Structure 4:

wherein:

each is a partial single-stranded oligonucleotide;

• is a covalent linker joined to a partial single-stranded oligonucleotide and an adjoining oligonucleotide subunit; and

is a complementary strand.

9 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 5:

wherein:

each is a single-stranded oligonucleotide;

each is a partial single-stranded oligonucleotide;

each ● is a covalent linker joining a single-stranded oligonucleotide to a partial single-stranded oligonucleotide; and

is a complementary strand.

10 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 6:

wherein:

each is a single-stranded oligonucleotide;

each is a partial single-stranded oligonucleotide;

● each is a covalent linker joining adjacent oligonucleotides;

each is a complementary strand; and

each of a, h, c, d, e, f, g, h, i, j and k is independently an integer greater than or equal to zero, with the proviso that at least one of c, e, h, and j is greater than or equal to 1.

11 . The multimeric oligonucleotide of claim 10 , wherein each of a, h, c, d, e, f, g, h, i, j and k is independently an integer in the range of 0 to 10, with the proviso that at least one of c, e, h and j is greater than or equal to 1.

12 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 7:

wherein:

are each a single-stranded oligonucleotide;

are each a complementary strand;

are each a partial single-stranded oligonucleotide;

● are each a covalent linker;

m and n are each independently an integer greater than or equal to 1; and

o is an integer greater than or equal to 0.

13 . The multimeric oligonucleotide of claim 12 , wherein m and n are each independently an integer in the range of 1 to 10; and o is an integer in the range of 0 to 10.

14 . The multimeric oligonucleotide of claim 1 , wherein the multimeric, oligonucleotide comprises Structure 8

wherein:

are each a single-stranded oligonucleotide;

are each a complementary strand;

are each a partial single-stranded oligonucleotide;

● are each covalent linkers; and

p and q are each independently an integer greater than or equal to zero.

15 . The multimeric oligonucleotide of claim 14 , wherein p and q are each independently an integer in the range of 0 to 10; or wherein p and q are each independently an integer in the range of 0 to 3.

16 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 9:

wherein:

are each a single-stranded oligonucleotide;

are each a complementary strand;

are each a partial single-stranded oligonucleotide;

● are each a covalent linker;

r is an integer greater than or equal to 1; and

s is an integer greater than or equal to 0.

17 . The multimeric oligonucleotide of claim 16 , wherein r is an integer in the range of 1 to 10 and s is an integer in the range of 0 to 10; or wherein r is an integer in the range of 1 to 3 and s is 0 or 1.

18 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 10:

wherein:

each is a single-stranded oligonucleotide;

each is a partial single-stranded oligonucleotide;

each ● is a covalent linker joining adjacent oligonucleotides; and

each is a complementary strand.

19 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 11:

wherein:

each is a single-stranded oligonucleotide;

each is a partial single-stranded oligonucleotide;

each ● is a covalent linker joining adjacent oligonucleotides;

each is a complementary strand.

20 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 12:

wherein:

each is a single-stranded oligonucleotide;

each is a partial single-stranded oligonucleotide;

each ● is a covalent linker joining adjacent oligonucleotides; and

each is a complementary strand.

21 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 13:

wherein:

each is a single-stranded oligonucleotide;

each is a partial single-stranded oligonucleotide;

each ● is a covalent linker joining adjacent oligonucleotides; and

each is a complementary strand.

22 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 14:

wherein:

each is a single-stranded oligonucleotide;

each is a partial single-stranded oligonucleotide;

each ● is a covalent linker joining adjacent oligonucleotides; and

each is a complementary strand.

23 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 15:

wherein:

each is a single-stranded oligonucleotide;

each is a partial single-stranded oligonucleotide;

each ● is a covalent linker joining adjacent oligonucleotides; and

each is a complementary strand.

24 . The multimeric oligonucleotide of claim 1 , wherein the multimeric oligonucleotide comprises Structure 16:

wherein each

is a single-stranded oligonucleotide;

is a complementary strand;

is a partial single-stranded oligonucleotide;

● is a covalent linker; and

t and u are each independently an integer greater than or equal to 0 with the proviso that at least one of t and u are an integer greater than or equal to 1.

25 . The multimeric oligonucleotide of claim 24 , wherein t and u are each independently an integer in the range of 0 to 10 with the proviso that at least one of t and u are an integer greater than or equal to 1; or wherein t and u are each independently an integer in the range of 0 to 3 with the proviso that at least one oft and u are an integer greater than or equal to 1.

26 . The multimeric oligonucleotide of any of claims 1 - 25 , wherein each partial single-stranded oligonucleotide is 5-14 nucleotides in length.

27 . The multimeric oligonucleotide of any of claims 1 - 26 , wherein at least two subunits are active against different cellular targets.

28 . The multimeric oligonucleotide of claim 27 , wherein all of the subunits are active against different cellular targets.

29 . The multimeric oligonucleotide of any of claims 1 - 26 , wherein at least two subunits are active against the same cellular target.

30 . The multimeric oligonucleotide of claim 29 , wherein all of the subunits are active against different cellular targets.

31 . The multimeric oligonucleotide of any of claims 1 - 30 , wherein the multimeric oligonucleotide comprises four or more subunits.

32 . The multimeric oligonucleotide of claim 31 , wherein the multimeric oligonucleotide comprises four, five, six, seven, eight, nine, or ten subunits.

33 . The multimeric oligonucleotide of any of claims 1 - 32 , wherein each nucleic acid in the multimeric oligonucleotide is RNA, DNA, or an artificial or non-natural nucleic acid analog.

34 . The multimeric oligonucleotide of any of claims 1 - 33 , wherein at least one subunit is siRNA, saRNA, or miRNA.

35 . The multimeric oligonucleotide of claim 34 , wherein all of the subunits are siRNA.

36 . The multimeric oligonucleotide of claim 34 , wherein all of the subunits are saRNA.

37 . The multimeric oligonucleotide of claim 34 , wherein all of the subunits are miRNA.

38 . The multimeric oligonucleotide of any of claims 1 - 33 , wherein at least one subunit is a single-stranded subunit.

39 . The multimeric oligonucleotide of claim 38 , wherein the at least one single-stranded subunit is an antisense oligonucleotide.

40 . The multimeric oligonucleotide of any one of claims 1 - 39 , wherein at least one covalent linker ● is a cleavable covalent linker.

41 . The multimeric oligonucleotide of claim 40 , wherein the cleavable covalent linker comprises an acid cleavable bond, a reductant cleavable bond, a bio-cleavable bond, or an enzyme cleavable bond.

42 . The multimeric oligonucleotide of claim 40 or 41 , wherein the cleavable covalent linker is cleavable under intracellular conditions.

43 . The multimeric oligonucleotide of any of claims 1 - 42 , wherein each covalent linker is, independently, a disulfide bond or a compound of Structure 25:

wherein:

S is attached by a covalent bond or by a linker to an oligonucleotide subunit;

each R 1 is independently a C 2 -C 10 alkyl, C 2 -C 10 alkoxy, or C 1 -C 10 aryl group;

R 2 is a thiopropionate or disulfide group; and

each X is independently selected from:

44 . The multimeric oligonucleotide of claim 43 , wherein the compound of Structure 25 is

wherein each terminal S is attached by a covalent bond or by a linker to an oligonucleotide subunit.

45 . The multimeric oligonucleotide of claim 43 , wherein the compound of Structure 25 is a compound according to Structure 26:

wherein each terminal S is attached by a covalent bond or by a linker to an oligonucleotide subunit.

46 . The multimeric oligonucleotide of claim 43 , wherein the compound of Structure 25 is a compound according to Structure 27:

wherein each terminal S is attached by a covalent bond or by a linker to an oligonucleotide subunit.

47 . The multimeric oligonucleotide of claim 43 , wherein the compound of Structure 25 is a compound according to Structure 28:

wherein each terminal S is attached by a covalent bond or by a linker to an oligonucleotide subunit.

48 . The multimeric oligonucleotide any of claims 43 - 47 , wherein the covalent linker of Structure 25 is formed from a covalent linker precursor according to Structure 29:

wherein each R is independently a C 2 -C 10 alkyl, C 2 -C 10 alkoxy, or C 1 -C 10 aryl group; and

R 2 is a thiopropionate or disulfide group.

49 . The multimeric oligonucleotide of any of claims 1 - 48 , wherein at least one covalent linker is attached to the 3′ or 5′ terminus of an oligonucleotide subunit.

50 . The multimeric oligonucleotide of claim 49 , wherein all covalent linkers are attached to the 3′ or 5′ terminus of an oligonucleotide subunit.

51 . The multimeric oligonucleotide of any of claims 1 - 49 , wherein at least one covalent linker is attached to an internal nucleotide of an oligonucleotide subunit.

52 . The multimeric oligonucleotide of any of claims 1 - 51 , wherein at least one covalent linker e comprises a nucleotide linker.

53 . The multimeric oligonucleotide of claim 52 , wherein the nucleotide linker is between 2-6 nucleotides in length.

54 . The multimeric oligonucleotide of any of claims 1 - 53 , wherein each covalent linker is the same.

55 . The multimeric oligonucleotide of any of claims 1 - 53 wherein at least one covalent linker ● is different from the other covalent linkers.

56 . The multimeric oligonucleotide of any of claims 1 - 55 , at least two subunits are joined by a covalent linker ● between the 3′ end of a first subunit and the 3′ of a second subunit.

57 . The multimeric oligonucleotide of any of claims 1 - 56 , wherein at least two subunits are joined by a covalent linker ● between the 5′ end of a first subunit and the 3′ of a second subunit.

58 . The multimeric oligonucleotide as in any of claims 1 - 57 , wherein at least two subunits are joined by a covalent linker ● between the 5′ end of a first subunit and the 5′ of a second subunit.

59 . The multimeric oligonucleotide of any of claims 1 - 58 , further comprising a chemical or biological moiety that is not an oligonucleotide.

60 . The multimeric oligonucleotide as in any of claims 1 - 59 , wherein the multimeric oligonucleotide is at least 75, 80, 85, 90, 95, 96, 97, 98, 99, or 100% pure.

61 . A method of synthesizing a multimeric oligonucleotide comprising Structure 16:

wherein each is an single-stranded oligonucleotide, each is a partial single-stranded oligonucleotide, each is a complementary strand; each ● is a covalent linker joining adjacent oligonucleotides, and t and u are each independently an integer greater than or equal to 1;

the method comprising annealing Structure 17

and Structure 18

with complementary strands , thereby forming Structure 16.

62 . A method of synthesizing a multimeric oligonucleotide comprising Structure 8:

wherein each is a single-stranded oligonucleotide, each is a partial single-stranded oligonucleotide, each is a complementary strand; each ● is a covalent linker joining adjacent oligonucleotides, and p and q are each independently an integer greater than or equal to 1;

the method comprising annealing Structure 19,

Structure 20,

and one or more of Structure 21,

with complementary strands , thereby forming Structure 8.

63 . A method of synthesizing a multimeric oligonucleotide comprising Structure 9A:

wherein each is a single-stranded oligonucleotide, each is a partial single-stranded oligonucleotide, each is a complementary strand; each ● is a covalent linker joining adjacent oligonucleotides; and r and s are each independently an integer greater than or equal to the method comprising annealing Structure 22

and Structure 23

and one or more of Structure 24

with complementary strands , thereby forming Structure 9A.

64 . A method of synthesizing a multimeric oligonucleotide comprising Structure 9B:

wherein each is a single-stranded oligonucleotide; each is a partial single-stranded oligonucleotide; each is a complementary strand; each • is a covalent linker joining adjacent oligonucleotides; and r is an integer greater than or equal to 1;

the method comprising annealing Structure 22,

and one or more of Structure 24

and a partial single-stranded oligonucleotide with complementary strands , thereby forming Structure 9B.

65 . A composition comprising the multimeric oligonucleotide of any of claims 1 - 60 and a pharmaceutically acceptable excipient.

66 . A composition comprising the multimeric oligonucleotide of any of claims 1 - 60 for use in the manufacture of a medicament.

67 . A method for treating a subject comprising administering to the subject an effective amount of the multimeric oligonucleotide of any of claims 1 - 60 .