Modified short interfering nucleic acid (siNA) molecules and uses thereof

Abstract

Disclosed herein are short interfering nucleic acid (siNA) molecules comprising modified nucleotides and uses thereof. The siNA molecules may be double stranded and comprise modified nucleotides selected from 2' -O-methyl nucleotides and 2' -fluoro nucleotides. Further disclosed herein are siNA molecules comprising (a) a phosphorylation blocker, conjugated moiety, or 5' -stabilized end cap; and (b) a short interfering nucleic acid (siNA).

Description

Modified Short Interfering Nucleic Acid (siNA) Molecules and Uses Thereof CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.62 / 986,150, filed March 6, 2020, and U.S. Provisional Application No.63 / 109,196, filed November 3, 2020, the disclosures of which are hereby incorporated by reference in their entireties. FIELD OF THE INVENTION

[0002] Described are short interfering nucleic acid (siNA) molecules comprising modified nucleotides, compositions, and uses thereof. BACKGROUND OF THE INVENTION

[0003] RNA interference (RNAi) is a biological response to double-stranded RNA that mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes. The short interfering nucleic acids (siNA), such as siRNA, have been developed for RNAi therapy to treat a variety of diseases. For instance, RNAi therapy has been proposed for the treatment of metabolic diseases, neurodegenerative diseases, cancer, and pathogenic infections (See e.g., Rondindone, Biotechniques, 2018, 40(4S), doi.org / 10.2144 / 000112163, Boudreau and Davidson, Curr Top Dev Biol, 2006, 75:73-92, Chalbatani et al., Int J Nanomedicine, 2019, 14:3111-3128, Arbuthnot, Drug News Perspect, 2010, 23(6):341-50, and Chernikov et. al., Front. Pharmacol., 2019, doi.org / 10.3389 / fphar.2019.00444, each of which are incorporated by reference in their entirety). However, major limitations of RNAi therapy are the ability to effectively deliver siRNA to target cells and the degradation of the siRNA.

[0004] The present disclosure improves the delivery and stability of siNA molecules by providing siNA molecules comprising modified nucleotides. The siNA molecules of the present disclosure provide optimized combinations and numbers of modified nucleotides, nucleotide lengths, design (e.g., blunt ends or overhangs, internucleoside linkages, conjugates), and modification patterns for improving the delivery and stability of siNA molecules.SUMMARY OF THE INVENTION

[0005] Disclosed herein is a short interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O- methyl nucleotide and the nucleotide at position 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide.

[0006] Disclosed herein is a short interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O- methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and the nucleotide at position 2, 5, 6, 8, 10, 14, 16, 17, and / or 18 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide.

[0007] In some embodiments, the first nucleotide sequence comprises 16, 17, 18, 19, 20, 21, 22, 23, or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2′-fluoro nucleotide. In some embodiments, 70%, 75%, 80%, 85%, 90%,95% or 100% of the nucleotides in the first nucleotide sequence are modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide. In some embodiments, between 2 to 15 modified nucleotides of the first nucleotide sequence are 2’- fluoro nucleotides. In some embodiments, between 2 to 10 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, between 2 to 6 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least 2, 3, 4, 5, or 6 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, less than or equal to 10, 9, 8, 7, 6, 5, 4, 3, or 2 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, between about 2 to 25 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 2 to 20 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 5 to 25 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 10 to 25 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 12 to 25 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, the second nucleotide sequence comprises 16, 17, 18, 19, 20, 21, 22, 23, or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2′-fluoro nucleotide. In some embodiments, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the nucleotides in the second nucleotide sequence are modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide. In some embodiments, between 2 to 15 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, between 2 to 10 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, between 2 to 6 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least 2, 3, 4, 5, or 6 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, less than or equal to 10, 9, 8, 7, 6, 5, 4, 3, or 2 modified nucleotides of the second nucleotide sequence are 2’-fluoronucleotides. In some embodiments, between about 2 to 25 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 2 to 20 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 5 to 25 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 10 to 25 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 12 to 25 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. Disclosed herein is a short interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O- methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (iii) comprises 1 or more phosphorothioate internucleoside linkage; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (iii) comprises 1 or more phosphorothioate internucleoside linkage. Disclosed herein is a short interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide, wherein the siNA further comprises a phosphorylation blocker, a galactosamine, or 5’- stabilized end cap. In some embodiments, at least 1, 2, 3, 4, 5, 6, or 7 nucleotides at position 3, 5, 7, 8, 9, 10, 11, 12, and / or 17 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 3 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 5 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 7 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 8 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 9 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 12 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 17 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, nucleotide at position 10 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 11 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 nucleotides at position 2, 5, 6, 8, 10, 14, 16, 17, and / or 18 from the 5’ end of the second nucleotide sequence is a 2’- fluoro nucleotide. In some embodiments, the nucleotide at position 2 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 5 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 6 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 8 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 10 from the 5’ end of the second nucleotidesequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 14 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotides at position 16 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 17 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 18 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotides in the second nucleotide sequence are arranged in an alternating 1:3 modification pattern, and wherein 1 nucleotide is a 2’-fluoro nucleotide and 3 nucleotides are 2’-O-methyl nucleotides. In some embodiments, the alternating 1:3 modification pattern occurs 2-5 times. In some embodiments, at least two of the alternating 1:3 modification pattern occur consecutively. In some embodiments, at least two of the alternating 1:3 modification pattern occurs nonconsecutively. In some embodiments, at least 1, 2, 3, 4, or 5 alternating 1:3 modification pattern begins at nucleotide position 2, 6, 10, 14, and / or 18 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 2 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 6 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 10 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 14 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 18 from the 5’ end of the antisense strand. In some embodiments, the nucleotides in the second nucleotide sequence are arranged in an alternating 1:2 modification pattern, and wherein 1 nucleotide is a 2’-fluoro nucleotide and 2 nucleotides are 2’-O-methyl nucleotides. In some embodiments, the alternating 1:2 modification pattern occurs 2-5 times. In some embodiments, at least two of the alternating 1:2 modification pattern occurs consecutively. In some embodiments, at least two of the alternating 1:2 modification pattern occurs nonconsecutively. In some embodiments, at least 1, 2, 3, 4, or 5 alternating 1:2 modification pattern begins at nucleotide position 2, 5, 8, 14, and / or 17 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 2 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2modification pattern begins at nucleotide position 5 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 8 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 14 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 17 from the 5’ end of the antisense strand. Disclosed herein is a short interfering nucleic acid (siNA) molecule represented by Formula ( 5’-An1Bn2An33’-Cq1Aq2Bq3Aq4Bq5Aq6Bq7Aq8Bq9Aq10Bq11Aq12-5’ wherein: the top strand is a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence comprises 15 to 30 nucleotides; the bottom strand is an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises 15 to 30 nucleotides; each A is independently a 2’-O-methyl nucleotide or a nucleotide comprising a 5’-stabilized end cap or a phosphorylation blocker; B is a 2’-fluoro nucleotide; C represents overhanging nucleotides and is a 2’-O-methyl nucleotide; n1= 1-4 nucleotides in length; each n2, n6, n8, q3, q5, q7, q9, q11, and q12is independently 0-1 nucleotides in length; each n3and n4is independently 1-3 nucleotides in length; n5is 1-10 nucleotides in length; n7is 0-4 nucleotides in length; each n9, q1, and q2is independently 0-2 nucleotides in length; q4is 0-3 nucleotides in length; q6is 0-5 nucleotides in length; q8is 2-7 nucleotides in length; and q10is 2-11 nucleotides in length.Disclosed herein is a short interfering nucleic acid (siNA) molecule represented by Formula (IX): 5’-A2-4B1A1-3B2-3A2-10B0-1A0-4B0-1A0-2-3’ 3’-C2A0-2B0-1A0-3B0-1A0-5B0-1A2-7B1A2-11B1A1-5’ wherein: the top strand is a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence comprises 15 to 30 nucleotides; the bottom strand is an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises 15 to 30 nucleotides; each A is independently a 2’-O-methyl nucleotide or a nucleotide comprising a 5’-stabilized end cap or a phosphorylation blocker; B is a 2’-fluoro nucleotide; C represents overhanging nucleotides and is a 2’-O-methyl nucleotide. Disclosed herein is a short interfering nucleic acid (siNA) molecule comprising (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 3, 7-9, 12, and 17 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1, 2, 4-6, 10, 11, and 13-16 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’- fluoro nucleotides are at positions 2 and 14 from the 5’ end of the second nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1, 3-13, and 15-17 from the 5’ end of the second nucleotide sequence. In some embodiments, the first nucleotide sequence consists of 19 nucleotides. In some embodiments, 2’-O-methyl nucleotides are at positions 18 and 19 from the 5’ end of the first nucleotide sequence. In some embodiments, the second nucleotide sequence consists of 21 nucleotides. In some embodiments, 2’-O- methyl nucleotides are at positions 18-21 from the 5’ end of the second nucleotide sequence. Disclosed herein is a short interfering nucleic acid (siNA) molecule comprising (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 3, 7, 8, and 17 from the 5’ end of the firstnucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1, 2, 4-6, and 9- 16 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 2 and 14 from the 5’ end of the first nucleotide sequence; and wherein 2’-O-methyl nucleotides are at positions 1, 3-13, and 15-17 from the 5’ end of the first nucleotide sequence. In some embodiments, the first nucleotide sequence consists of 19 nucleotides. In some embodiments, 2’-O-methyl nucleotides are at positions 18 and 19 from the 5’ end of the first nucleotide sequence. In some embodiments, the second nucleotide sequence consists of 21 nucleotides. In some embodiments, 2’-O-methyl nucleotides are at positions 18-21 from the 5’ end of the second nucleotide sequence. Disclosed herein is a short interfering nucleic acid (siNA) molecule comprising (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 3, 7-9, 12 and 17 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1, 2, 4-6, 10, 11, and 13-16 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein the nucleotides in the second nucleotide sequence are arranged in an alternating 1:3 modification pattern, and wherein 1 nucleotide is a 2’-fluoro nucleotide and 3 nucleotides are 2’-O-methyl nucleotides. In some embodiments, the first nucleotide sequence consists of 19 nucleotides. In some embodiments, 2’-O-methyl nucleotides are at positions 18 and 19 from the 5’ end of the first nucleotide sequence. In some embodiments, the second nucleotide sequence consists of 21 nucleotides. In some embodiments, 2’-O-methyl nucleotides are at positions 19-21 from the 5’ end of the second nucleotide sequence. In some embodiments, the alternating 1:3 modification pattern occurs 2-5 times. In some embodiments, at least two of the alternating 1:3 modification pattern occur consecutively. In some embodiments, at least two of the alternating 1:3 modification pattern occurs nonconsecutively. In some embodiments, at least 1, 2, 3, 4, or 5 alternating 1:3 modification pattern begins at nucleotide position 2, 6, 10, 14, and / or 18 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 2 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 6 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 10 from the 5’ end of the antisense strand. In someembodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 14 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 18 from the 5’ end of the antisense strand. Disclosed herein is a short interfering nucleic acid (siNA) molecule comprising (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 5 and 7-9 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6, and 10-17 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein the nucleotides in the second nucleotide sequence are arranged in an alternating 1:3 modification pattern, and wherein 1 nucleotide is a 2’-fluoro nucleotide and 3 nucleotides are 2’-O-methyl nucleotides. In some embodiments, the first nucleotide sequence consists of 19 nucleotides. In some embodiments, 2’-O-methyl nucleotides are at positions 18 and 19 from the 5’ end of the first nucleotide sequence. In some embodiments, the second nucleotide sequence consists of 21 nucleotides. In some embodiments, 2’-O-methyl nucleotides are at positions 19-21 from the 5’ end of the second nucleotide sequence. In some embodiments, the alternating 1:3 modification pattern occurs 2-5 times. In some embodiments, at least two of the alternating 1:3 modification pattern occur consecutively. In some embodiments, at least two of the alternating 1:3 modification pattern occurs nonconsecutively. In some embodiments, at least 1, 2, 3, 4, or 5 alternating 1:3 modification pattern begins at nucleotide position 2, 6, 10, 14, and / or 18 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 2 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 6 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 10 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 14 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 18 from the 5’ end of the antisense strand. Disclosed herein is a short interfering nucleic acid (siNA) molecule comprising (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 5 and 7-9 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6, and 10-17from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein the nucleotides in the second nucleotide sequence are arranged in an alternating 1:2 modification pattern, and wherein 1 nucleotide is a 2’-fluoro nucleotide and 2 nucleotides are 2’-O-methyl nucleotides. In some embodiments, the first nucleotide sequence consists of 19 nucleotides. In some embodiments, 2’-O-methyl nucleotides are at positions 18 and 19 from the 5’ end of the first nucleotide sequence. In some embodiments, the second nucleotide sequence consists of 21 nucleotides. In some embodiments, 2’-O-methyl nucleotides are at positions 18-21 from the 5’ end of the second nucleotide sequence. In some embodiments, the alternating 1:2 modification pattern occurs 2-5 times. In some embodiments, at least two of the alternating 1:2 modification pattern occur consecutively. In some embodiments, at least two of the alternating 1:2 modification pattern occurs nonconsecutively. In some embodiments, at least 1, 2, 3, 4, or 5 alternating 1:2 modification pattern begins at nucleotide position 2, 5, 8, 14, and / or 17 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 2 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 5 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 8 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 14 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 17 from the 5’ end of the antisense strand. Disclosed herein is a short interfering nucleic acid (siNA) molecule comprising (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 5 and 7-9 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6, and 10-17 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 2, 6, 14, and 16 from the 5’ end of the second nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1, 3-5, 7-13, 15, and 17 from the 5’ end the second nucleotide sequence. In some embodiments, the first nucleotide sequence consists of 19 nucleotides. In some embodiments, 2’-O-methyl nucleotides are at positions 18 and 19 from the 5’ end of the first nucleotide sequence. In some embodiments,the second nucleotide sequence consists of 21 nucleotides. In some embodiments, 2’-O- methyl nucleotides are at positions 18-21 from the 5’ end of the second nucleotide sequence. Disclosed herein is a short interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 5, 9-11, and 14 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6-8, and 12- 17 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 2 and 14 from the 5’ end of the second nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1, 3-13, and 15-17 from the 5’ end the second nucleotide sequence. In some embodiments, the first nucleotide sequence consists of 21 nucleotides. In some embodiments, 2’-O-methyl nucleotides are at positions 18-21 from the 5’ end of the first nucleotide sequence. In some embodiments, the second nucleotide sequence consists of 23 nucleotides. In some embodiments, 2’-O-methyl nucleotides are at positions 18-23 from the 5’ end of the second nucleotide sequence. In some embodiments, any of the sense strands disclosed herein further comprise a TT sequence adjacent to the first nucleotide sequence. In some embodiments, any of the sense strands disclosed herein further comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more phosphorothioate internucleoside linkages. In some embodiments, at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 1 and 2 from the 5’ end of the first nucleotide sequence. In some embodiments, at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 2 and 3 from the 5’ end of the first nucleotide sequence. In some embodiments, any of the antisense strands disclosed herein further comprise TT sequence adjacent to the second nucleotide sequence. In some embodiments, the antisense strand further comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more phosphorothioate internucleoside linkages. In some embodiments, at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 1 and 2 from the 5’ end of the second nucleotide sequence. In some embodiments, at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 2 and 3 from the 5’ end of the second nucleotide sequence. In some embodiments, at least onephosphorothioate internucleoside linkage is between the nucleotides at positions 1 and 2 from the 3’ end of the second nucleotide sequence. In some embodiments, at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 2 and 3 from the 3’ end of the second nucleotide sequence. In some embodiments, the first nucleotide from the 5’ end of any of the first nucleotide sequences disclosed herein comprises a 5’ stabilizing end cap. In some embodiments, the first nucleotide from the 5’ end of any of the second nucleotide sequences disclosed herein comprise a 5’ stabilizing end cap. In some embodiments, the first nucleotide from the 5’ end of any of the first nucleotide sequences dislosed herein comprises a phosphorylation blocker. In some embodiments, the first nucleotide from the 5’ end of any of the second nucleotide sequences dislosed herein comprises a phosphorylation blocker. In some embodiments, any of the first nucleotide sequences or second nucleotide sequences disclosed herein comprise at least one modified nucleotide selected fromR is H or alkyl (or AmNA(N-Me)) when R is alkyl)GuNA(N-R), R = Me, Et, iPr, tBu , wherein B is a nucleobase. Disclosed herein is a short-interfering nucleic acid (siNA) molecule comprising: (a) a phosphorylation blocker of Formulawherein R1is a nucleobase,R4is –O-R30or –NR31R32, R30is C1-C8substituted or unsubstituted alkyl; and R31and R32together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; and (b) a short interfering nucleic acid (siNA). In some embodiments, the siNA is any of the siNAs disclosed herein. In some embodiments, the siNA comprises any of the sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein. In some embodiments, the siNA comprises any of the the sense strands disclosed herein. In some embodiments, the siNA comprises any of the antisense strand disclosed herein. In some embodiments, the siNA comprises a first nucleotide sequence selected from any one of SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence selected from any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense sequence selected from any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense sequence selected from any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA comprises a ds-siNA sequence selected from any one of ds-siNA-001 to ds-siNA-0178. In some embodiments, the siNA further comprises any of the 5’ end caps disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilizing nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. Disclosed herein is a short-interfering nucleic acid (siNA) molecule comprising: (a) a 5’-stabilized end cap of Formula (Ia):, wherein R1is a nucleobase, aryl, heteroaryl, or H, O OOOOH O O O O NSO OS S N S S N S N N R2N is H , , H ,O O, H , H , O O O HO S O O OH O OCH S P OH P P P3OH,OOH , OH , OH ,(CR21R22)n-Z, or -(C2-C6alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n- Z or -(C2-C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, -OP(O)OH(CH2)mCO2R23, -OP(S)OH(CH2)mCO2R23, -P(O)(OH)2, - P(O)(OH)(OCH3), -P(O)(OH)(OCD3), -SO2(CH2)mP(O)(OH)2, -SO2NR23R25, -NR23R24, R21and R22are independently hydrogen or C1-C6alkyl; R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or -C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4; and (b) a short interfering nucleic acid (siNA). In some embodiments, the siNA comprises any of the the sense strands disclosed herein. In some embodiments, the siNA comprises any of the antisense strand disclosed herein. In some embodiments, the siNA comprises a first nucleotide sequence selected from any one of SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence selected from any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense sequence selected from any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense sequence selected from any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA comprises a ds-siNA sequence selected from any one of ds-siNA-001 to ds-siNA-0178. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilizing nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein.Disclosed herein is a short-interfering nucleic acid (siNA) molecule comprising: (a) a 5’-stabilized end cap of Formula (wherein R1is a nucleobase, aryl, heteroaryl, or H,, , , - , - , - ,n- , - (C2-C6alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n- Z or -(C2-C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, -OP(O)OH(CH2)mCO2R23, -OP(S)OH(CH2)mCO2R23, -P(O)(OH)2, - P(O)(OH)(OCH3), -P(O)(OH)(OCD3), -SO2(CH2)mP(O)(OH)2, -SO2NR23R25, -NR23R24, R21and R22are independently hydrogen or C1-C6 alkyl; R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or -C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4; and (b) a short interfering nucleic acid (siNA). In some embodiments, the siNA comprises any of the the sense strands disclosed herein. In some embodiments, the siNA comprises any of the antisense strand disclosed herein. In some embodiments, the siNA comprises a first nucleotide sequence selected from any one of SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence selected from anyone of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense sequence selected from any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense sequence selected from any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA comprises a ds-siNA sequence selected from any one of ds-siNA-001 to ds-siNA-0178. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilizing nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. Disclosed herein is a short-interfering nucleic acid (siNA) molecule comprising: (a) a 5’-stabilized end cap selected from the group consisting of Formula (1) to Formula (15), Formula (9X) to Formula (12X), and Formula (9Y) to Formula (12Y):Formula (1) Formula (2) Formula (3) Formula (4)Formula (8) Formula (9) Formula (9X) Formula (9Y)Formula (12) Formula (12X) Formula (12Y)Formula (13) Formula (14) Formula (15) , wherein R1is a nucleobase, aryl, heteroaryl, or H; and (b) a short interfering nucleic acid (siNA). In some embodiments, the siNA comprises any of the the sense strands disclosed herein. In some embodiments, the siNA comprises any of the antisense strand disclosed herein. In some embodiments, the siNA comprises a first nucleotide sequence selected from any one of SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence selected from any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense sequence selected from any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense sequence selected from any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA comprises a ds-siNA sequence selected from any one of ds-siNA- 001 to ds-siNA-0178. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilizing nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. Disclosed herein is a short-interfering nucleic acid (siNA) molecule comprising: (a) a 5’-stabilized end cap selected from the group consisting of Formulas (1A)-(15A), Formulas (9B)-(12B), Formulas (9AX)-(12AX), Formulas (9AY)-(12AY), Formulas (9BX)-(12BX), and Formulas (9BY)-(12BY):Formula (1A) Formula (2A) Formula (3A) Formula (4A)Formula (5A) Formula (6A) Formula (7A)Formula (13A) Formula (14A) Formula (15A) , and (b) a short interfering nucleic acid (siNA). In some embodiments, the siNA comprises any of the the sense strands disclosed herein. In some embodiments, the siNA comprises any of the antisense strand disclosed herein. In some embodiments, the siNA comprises a first nucleotide sequence selected from any one of SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence selected from any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense sequence selected from any one of SEQ ID NOs: 307-362 and 415-444.In some embodiments, the siNA comprises an antisense sequence selected from any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA comprises a ds-siNA sequence selected from any one of ds-siNA-001 to ds-siNA-0178. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilizing nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. Disclosed herein is a short-interfering nucleic acid (siNA) molecule comprising: (a) a 5’-stabilized end cap of Formula (Ic):, wherein R1is a nucleobase, aryl, heteroaryl, or H,(C2-C6alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n- Z or –(C2-C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, –OP(S)OH(CH2)mCO2R23, –P(O)(OH)2, - P(O)(OH)(OCH3), -P(O)(OH)(OCD3), –SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, or –NR23SO2R24; R21and R22either are independently hydrogen or C1-C6alkyl, or R21and R22together form an oxo group; R23is hydrogen or C1-C6 alkyl; R24is –SO2R25or –C(O)R25; orR23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4; and (b) a short interfering nucleic acid (siNA). In some embodiments, the siNA comprises any of the the sense strands disclosed herein. In some embodiments, the siNA comprises any of the antisense strand disclosed herein. In some embodiments, the siNA comprises a first nucleotide sequence selected from any one of SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence selected from any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense sequence selected from any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense sequence selected from any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA comprises a ds-siNA sequence selected from any one of ds-siNA-001 to ds-siNA-0178. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilizing nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. Disclosed herein is a short-interfering nucleic acid (siNA) molecule comprising: (a) a 5’-stabilized end cap selected from the group consisting of Formula (21) to Formula (35):Formula (21) Formula (22) Formula (23) Formula (24)Formula (25) Formula (26) Formula (27)Formula (33)Formula (34) Formula (35) , wherein R1is a nucleobase, aryl, heteroaryl, or H; and (b) a short interfering nucleic acid (siNA). In some embodiments, the siNA comprises any of the the sense strands disclosed herein. In some embodiments, the siNA comprises any of the antisense strand disclosed herein. In some embodiments, the siNA comprises a first nucleotide sequence selected from any one of SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence selected from any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense sequence selected from any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense sequence selected from any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA comprises a ds-siNA sequence selected from any one of ds-siNA- 001 to ds-siNA-0178. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilizing nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. Disclosed herein is a short-interfering nucleic acid (siNA) molecule comprising: (a) a 5’-stabilized end cap selected from the group consisting of Formulas (21A)-(35A),Formulas (29B)-(32B), Formulas (29AX)-(32AX), Formulas (29AY)-(32AY), Formulas (29BX)-(32BX), and Formulas (29BY)-(32BY):Formula (33A) Formula (34A) Formula (35A) ; and (b) a short interfering nucleic acid (siNA). In some embodiments, the siNA comprises any of the the sense strands disclosed herein. In some embodiments, the siNA comprises any of theantisense strand disclosed herein. In some embodiments, the siNA comprises a first nucleotide sequence selected from any one of SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence selected from any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense sequence selected from any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense sequence selected from any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA comprises a ds-siNA sequence selected from any one of ds-siNA-001 to ds-siNA-0178. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilizing nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. Disclosed herein is a short interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA further comprises any of the 5’ end caps disclosed herein. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some emboiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilizing nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. Disclosed herein is a interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415-444; and (b) an antisense strand comprising a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, any of the siNA disclosed herein further comprise a phosphorylation blocker.In some embodiments, the phosphorylation blocker has the structure of Formula whereinR4is –O-R30or –NR31R32, R30is C1-C8substituted or unsubstituted alkyl; and R31and R32together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring. In some embodiments, R4is –OCH3or –N(CH2CH2)2O. In some embodiments, the phosphorylation blocker is attached to the 5’ end of the sense strand. In some embodiments, the phosphorylation blocker is attached to the 5’ end of the sense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, and phosphorodithioate linker. In some embodiments, the phosphorylation blocker is attached to the 3’ end of the sense strand. In some embodiments, the phosphorylation blocker is attached to the 3’ end of the sense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, and phosphorodithioate linker. In some embodiments, the phosphorylation blocker is attached to the 5’ end of the antisense strand. In some embodiments, the phosphorylation blocker is attached to the 5’ end of the antisense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, and phosphorodithioate linker. In some embodiments, the phosphorylation blocker is attached to the 3’ end of the antisense strand. In some embodiments, the phosphorylation blocker is attached to the 3’ end of the antisense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, and phosphorodithioate linker. In some embodiments, any of the siNAs disclosed herein further comprise a conjugated moiety. In some embodiments, the conjugated moiety comprises a galactosamine. In some embodiments, the galactosamine is N-acetylgalactosamine (GalNAc) of Formula (VII):, wherein each n is independently 1 or 2. In some embodiments, the galactosamine is N- acetylgalactosamine (GalNAc) of Formula (VI):, wherein m is 1, 2, 3, 4, or 5; each n is independently 1 or 2; p is 0 or 1; each R is independently H; each Y is independently selected from –O-P(=O)(SH)–, –O-P(=O)(O)–, –O-P(=O)(OH)–, and -O-P(S)S-; Z is H or a second protecting group; either L is a linker or L and Y in combination are a linker; and A is H, OH, a third protecting group, an activated group, or an oligonucleotide. In some embodiments, wherein A is an oligonucleotide. In some embodiments, A is 1-2 oligonucleotides. In some embodiments, the oligonucleotide is dTdT. In some embodiments, the galactosamine is attached to the 3’ end of the sense strand. In some embodiments, the galactosamine is attached to the 3’ end of the sense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, or phosphorodithioate linker. In some embodiments, the galactosamine is attached to the 5’ end of the sense strand. In some embodiments, the galactosamine is attached to the 5’ end of the sense strand via one or more linkers independently selected from a phosphodiesterlinker, phosphorothioate linker, or phosphorodithioate linker. In some embodiments, the galactosamine is attached to the 3’ end of the antisense strand. In some embodiments, the galactosamine is attached to the 3’ end of the atnisense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, or phosphorodithioate linker. In some embodiments, the galactosamine is attached to the 5’ end of the antisense strand. In some embodiments, the galactosamine is attached to the 5’ end of the atnisense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, or phosphorodithioate linker. In some embodiments, any of the siNAs disclosed herein further comprise a 5’- stabilized end cap. In some embodiments, the 5’-stabilized end cap is a 5’ vinyl phosphonate or deuterated 5’ vinyl phosphonate. In some embodiments, the 5’-stabilized end cap has the structure of Formula (Ia):, wherein R1is a nucleobase, aryl, heteroaryl, or H,(CR21R22)n-Z, or –(C2-C6alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n- Z or –(C2-C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, –OP(S)OH(CH2)mCO2R23, –P(O)(OH)2, - P(O)(OH)(OCH3), -P(O)(OH)(OCD3), –SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, or –NR23SO2R24; R21and R22either are independently hydrogen or C1-C6alkyl, or R21and R22together form an oxo group;R23is hydrogen or C1-C6alkyl; R24is –SO2R25or –C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4. In some embodiments, the 5’-stabilized end cap has the structure of Formula (Ib):, wherein R1is a nucleobase, aryl, heteroaryl, or H,(C2-C6alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n- Z or –(C2-C6 alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, –OP(S)OH(CH2)mCO2R23, –P(O)(OH)2, - P(O)(OH)(OCH3), -P(O)(OH)(OCD3), –SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, or –NR23SO2R24; R21and R22either are independently hydrogen or C1-C6alkyl, or R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or –C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; andm is 1, 2, 3, or 4. In some embodiments, the 5’-stabilized end cap has the structure of Formula (Ic):, wherein R1is a nucleobase, aryl, heteroaryl, or H,(C2-C6alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n- Z or –(C2-C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, –OP(S)OH(CH2)mCO2R23, –P(O)(OH)2, - P(O)(OH)(OCH3), -P(O)(OH)(OCD3), –SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, or –NR23SO2R24; R21and R22either are independently hydrogen or C1-C6 alkyl, or R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or –C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl. In some embodiments, the 5’-stabilized end cap is selected from the group consisting of Formula (1) to Formula (15), Formula (9X) to Formula (12X), and Formula (9Y) to Formula (12Y):Formula (1) Formula (2) Formula (3) Formula (4)Formula (8) Formula (9) Formula (9X) Formula (9Y)3Formula (13) Formula (14) Formula (15) , wherein R1independently is a nucleobase, aryl, heteroaryl, or H. In some embodiments, the 5’- stabilized end cap is selected from the group consisting of Formulas (1A)-(15A), Formulas (9B)-(12B), Formulas (9AX)-(12AX), Formulas (9AY)-(12AY), Formulas (9BX)-(12BX), and Formulas (9BY)-(12BY):Formula (1A) Formula (2A) Formula (3A) Formula (4A)Formula (8A) Formula (9A) Formula (9AX) Formula (9AY)Formula (9B) Formula (9BX) Formula (9BY)HOOD D H3COOD COOD P O P O3P O HO HO HO D D D OOCH3 OOCH3 OOCH3Formula (10A) Formula (10AX) Formula (10AY) D DHOOH CO OD P O3 OP O D3COP O HO HO HO D D D O OCH3O OCH3 OOCH3Formula (10B) Formula (10BX) Formula (10BY)HOOH HCOOH H DCOP O3P O3 OP O HO HO HO D D D OOCH3O OCH3O OCH3Formula (11A) Formula (11AX) Formula (11AY) H H HHOOH3COOD COOP O P O3P O HO HO HO D D D OOCH3 OOCH3 OOCH3Formula (11B) Formula (11BX) Formula (11BY)HOOD HOD DOD P O3COP O3COP O HO HO HO H H H O OCH3 OOCH3 OOCH3Formula (12A) Formula (12AX) Formula (12AY) O DOD DHO H CO D COP O3P O3 OP O HO HO HO H H H OOCH3 OOCH3 OOCH3Formula (12B) Formula (12BX) Formula (12BY)Formula (13A) Formula (14A) Formula (15A) . In some embodiments, the 5’-stabilized end cap is selected from the group consisting of Formula (21) to Formula (35):Formula (21) Formula (22) Formula (23) Formula (24)Formula (28) Formula (29) Formula (30)Formula (31) Formula (32) Formula (33)Formula (34) Formula (35) , wherein R1is a nucleobase, aryl, heteroaryl, or H. In some embodiments, the 5’-stabilized end cap is selected from the group consisting of Formulas (21A)-(35A), Formulas (29B)-(32B), Formulas (29AX)-(32AX), Formulas (29AY)-(32AY), Formulas (29BX)-(32BX), and Formulas (29BY)-(32BY):Formula (29B) Formula (29BX) Formula (29BY). In some embodiments, the 5’-stabilized end cap is attached to the 5’ end of the antisense strand. In some embodiments, the 5’-stabilized end cap is attached to the 5’ end of the antisense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, or phosphorodithioate linker. In some embodiments, the 5’- stabilized end cap is attached to the 5’ end of the sense strand. In some embodiments, the 5’-stabilized end cap is attached to the 5’ end of the sense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, or phosphorodithioate linker. In some embodiments, any of the siNAs, sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein further comprise at least one thermally destabilizing nucleotides. In some embodiments, any of the antisense strands disclosed herein further comprise at least one thermally destabilizing nucleotide selected from:, ,some embodiments, any of the sense strands disclosed herein comprise at least one thermally destabilizing nucleotide selected. In some embodiments, any of the first nucleotide sequences disclosed herein further comprise at least one thermally destabilizing nucleotide selecteddisclosed herein further comprise at least one thermally destabilizing nucleotide selected. In some embodiments, any of the modified nucleotides disclosed herein is a thermally destabilizing nucleotide. In some embodiments, any of the siNAs disclosed herein specifically downregulate or reduce expression of a target gene. In some embodiments, the target geneis a viral gene. In some embodiments, the viral gene is from a DNA virus. In some embodiments, the DNA virus is a double-stranded DNA (dsDNA) virus. In some embodiments, the dsDNA virus is a hepadnavirus. In some embodiments, the hepadnavirus is a hepatitis B virus (HBV). In some embodiments, the HBV is selected from HBV genotypes A-J. In some embodiments, the target gene is selected from the S gene or X gene of the HBV. In some embodiments, the second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30 nucleotides within positions 200-720 or 1100-1700 of SEQ ID NO: 410. In some embodiments, the second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30 nucleotides within positions 200-280, 300-445, 460- 510, 650-720, 1170-1220, 1250-1300, or 1550-1630 of SEQ ID NO: 410. In some embodiments, the second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30 nucleotides within positions 200-230, 250-280, 300-330, 370-400, 405-445, 460-500, 670-700, 1180-1210, 1260-1295, 1520- 1550, or 1570-1610 of SEQ ID NO: 410. In some embodiments, the second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30 nucleotides starting at position 203, 206, 254, 305, 375, 409, 412, 415, 416, 419, 462, 466, 467, 674, 676, 1182, 1262, 1263, 1268, 1526, 1577, 1578, 1580, 1581, 1583, or 1584 of SEQ ID NO: 410. In some embodiments, the first nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to 15 to 30 nucleotides within positions 200-720 or 1100-1700 of SEQ ID NO: 410. In some embodiments, the first nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to 15 to 30 nucleotides within positions 200-280, 300-445, 460-510, 650-720, 1170-1220, 1250-1300, or 1550-1630 of SEQ ID NO: 410. In some embodiments, the first nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to 15 to 30 nucleotides within positions 200-230, 250-280, 300-330, 370-400, 405- 445, 460-500, 670-700, 1180-1210, 1260-1295, 1520-1550, or 1570-1610 of SEQ ID NO: 410. In some embodiments, the first nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to 15 to 30 nucleotides starting at position 203, 206, 254, 305, 375, 409, 412, 415, 416, 419, 462, 466, 467, 674, 676, 1182, 1262, 1263, 1268, 1526, 1577, 1578, 1580, 1581, 1583, or 1584 of SEQ ID NO: 410.In some embodiments, the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, at least one end of the siNA is a blunt end. In some embodiments, at least one end of the siNA comprises an overhang, wherein the overhang comprises at least one nucleotide. In some embodiments, both ends of the siNA comprise an overhang, wherein the overhang comprises at least one nucleotide. In some embodiments, the siNA is selected from ds-siNA-001 to ds-siNA-0178. In some embodiments, at least one 2’-fluoro nucleotide or 2’-O-methyl nucleotide is a 2’-fluoro or 2-O-methyl nucleotide mimic of Formula (V):, wherein R1is independently a nucleobase, aryl, heteroaryl, or H, Q1and Q2are independently S or O, R5is independently –OCD3, –F, or –OCH3, and R6and R7are independently H, D, or CD3. In some embodiments, the 2’-fluoro or 2’-O-methyl nucleotide mimic is a nucleotide mimic of Formula (16) – Formula (20):Formula (16) Formula (17) Formula (18) Formula (19) Formula (20) , wherein R1is a nucleobase and R2is independently F or –OCH3.Further disclosed herein are compositions comprising any of the siNAs disclosed herein. In some embodiments, the siNA targets an S gene of HBV. In some embodiments, the siNA specifically downregulates or reduces expression of the S gene of HBV. In some embodiments, the siNA targets an X gene of HBV. In some embodiments, the siNA specifically downregulates or reduces expression of the X gene of HBV. In some embodiments, the siNA comprises a first nucleotide sequence. In some embodiments, the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense strand. In some embodiments, the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense strand. In some embodiments, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA further comprises any of the 5’ end caps disclosed herein. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilized nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. Further disclosed herein are compositions comprising 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of any of the siNAs disclosed herein. In some embodiments, at least 1, 2, 3, 4, 5, or more siNAs target an S gene of HBV. In some embodiments, at least 1, 2, 3, 4, 5, or more siNAs specifically downregulate or reduce expression of the S gene of HBV. In some embodiments, at least 1, 2, 3, 4, 5, or more siNAs target an X gene of HBV. In some embodiments, at least 1, 2, 3, 4, 5, or more siNAs specifically downregulate or reduce expression of the X gene of HBV. In some embodiments, the siNA comprises a first nucleotide sequence. In some embodiments, the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense strand. In some embodiments, the sense strand comprises a nucleotide sequence of any one of SEQID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense strand. In some embodiments, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA further comprises any of the 5’ end caps disclosed herein. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilized nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. In some embodiments, any of the compositions disclosed herein further comprise an additional HBV treatment agent. In some embodiments, the additional HBV treatment agent is selected from a nucleotide analog, nucleoside analog, a capsid assembly modulator (CAM), a recombinant interferon, an entry inhibitor, a small molecule immunomodulator and oligonucleotide therapy. In some embodiments, the oligonucleotide therapy is an additional siNA. In some embodiments, the additional siNA is selected from any of ds-siNA-001 to ds-siNA-0178. In some embodiments, the oligonucleotide therapy is an antisense oligonucleotide (ASO), NAPs, or STOPs. In some embodiments, the ASO is ASO 1 or ASO 2. In some embodiments, the ASO specifically targets the S gene of HBV. In some embodiments, the ASO specifically targets the X gene of HBV. In some embodiments, the additional HBV treatment agent is selected from HBV STOPSTMALG- 010133, HBV CAM ALG-000184, ASO 1, recombinant interferon alpha 2b, IFN-a, PEG- IFN-a-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil, NVR3-778, BAY41-4109, JNJ-632, JNJ-3989 (ARO- HBV), RG6004, GSK3228836, REP-2139, REP-2165, AB-729, VIR-2218, RG6346 (DCR- HBVS), JNJ-6379, GLS4, ABI-HO731, JNJ-440, NZ-4, RG7907, EDP-514, AB-423, AB- 506, ABI-H03733 and ABI-H2158. In some embodiments, any of the compositions disclosed herein further comprise a liver disease treatment agent. In some embodiments, the liver disease treatment agent is selected from a peroxisome proliferator-activator receptor (PPAR) agonist, farnesoid X receptor (FXR) agonist, lipid-altering agent, and incretin-based therapy. In some embodiments, the PPAR agonist is selected from a PPARα agonist, dual PPARα / δ agonist, PPARγ agonist, and dual PPARα / γ agonist. In some embodiments, the dual PPARα agonist is a fibrate. In some embodiments, the PPARα / δ agonist is elafibranor. In someembodiments, the PPARγ agonist is a thiazolidinedione (TZD). In some embodiments, TZD is pioglitazone. In some embodiments, the dual PPARα / γ agonist is saroglitazar. In some embodiments, the FXR agonist is obeticholic acis (OCA). In some embodiments, the lipid- altering agent is aramchol. In some embodiments, the incretin-based therapy is a glucagon- like peptide 1 (GLP-1) receptor agonist or dipeptidyl peptidase 4 (DPP-4) inhibitor. In some embodiments, the GLP-1 receptor agonist is exenatide or liraglutide. In some embodiments, the DPP-4 inhibitor is sitagliptin or vildapliptin. Further disclosed herein are methods of treating a disease in a subject in need thereof, comprising administering to the subject any of the siNAs disclosed herein. In some embodiments, the siNA comprises a first nucleotide sequence. In some embodiments, the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense strand. In some embodiments, the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense strand. In some embodiments, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA further comprises any of the 5’ end caps disclosed herein. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilized nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. Further disclosed herein are methods of treating a disease in a subject in need thereof, comprising administering to the subject any of the compositions disclosed herein. In some embodiments, the compositon comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of any of the siNAs disclosed herein. In some embodiments, the siNA comprises a first nucleotide sequence. In some embodiments, the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense strand.In some embodiments, the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense strand. In some embodiments, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA further comprises any of the 5’ end caps disclosed herein. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilized nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. In some embodiments, the composition further comprises any of the additional HBV treatment agents disclosed herein. In some embodiments, the disease is a viral disease. In some embodiments, the viral disease is caused by a DNA virus. In some embodiments, the DNA virus is a double stranded DNA (dsDNA) virus. In some embodiments, the dsDNA virus is a hepadnavirus. In some embodiments, the hepadnavirus is a hepatitis B virus (HBV). In some embodiments, the HBV is selected from HBV genotypes A-J. In some embodiments, the method further comprises administering an additional HBV treatment agent. In some embodiments, the siNA or the composition and the additional HBV treatment agent are administered concurrently. In some embodiments, the siNA or the composition and the additional HBV treatment agent are administered sequentially. In some embodiments, the siNA or the composition is administered prior to administering the additional HBV treatment agent. In some embodiments, the siNA or the composition is administered after administering the additional HBV treatment agent. In some embodiments, the additional HBV treatment agent is selected from a nucleotide analog, nucleoside analog, a capsid assembly modulator (CAM), a recombinant interferon, an entry inhibitor, a small molecule immunomodulator and oligonucleotide therapy. In some embodiments, the oligonucleotide therapy is an additional siNA. In some embodiments, the additional siNA is selected from any of ds-siNA-001 to ds-siNA-0178. In some embodiments, the oligonucleotide therapy is an antisense oligonucleotide (ASO), NAPs, or STOPs. In some embodiments, the ASO is ASO 1 or ASO 2. In some embodiments, the additional HBV treatment agent is selected from HBV STOPSTMALG- 010133, HBV CAM ALG-000184, ASO 1, recombinant interferon alpha 2b, IFN-a, PEG- IFN-a-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil, NVR3-778, BAY41-4109, JNJ-632, JNJ-3989 (ARO-HBV), RG6004, GSK3228836, REP-2139, REP-2165, AB-729, VIR-2218, RG6346 (DCR- HBVS), JNJ-6379, GLS4, ABI-HO731, JNJ-440, NZ-4, RG7907, EDP-514, AB-423, AB- 506, ABI-H03733 and ABI-H2158. In some embodiments, the disease is a liver disease. In some embodiments, the liver disease is a nonalcoholic fatty liver disease (NAFLD) or hepatocellular carcinoma (HCC). In some embodiments, the NAFLD is nonalcoholic steatohepatitis (NASH). In some embodiments, the method further comprises administering to the subject a liver disease treatment agent. In some embodiments, the liver disease treatment agent is selected from a peroxisome proliferator-activator receptor (PPAR) agonist, farnesoid X receptor (FXR) agonist, lipid-altering agent, and incretin-based therapy. In some embodiments, the PPAR agonist is selected from a PPARα agonist, dual PPARα / δ agonist, PPARγ agonist, and dual PPARα / γ agonist. In some embodiments, the dual PPARα agonist is a fibrate. In some embodiments, the PPARα / δ agonist is elafibranor. In some embodiments, the PPARγ agonist is a thiazolidinedione (TZD). In some embodiments, TZD is pioglitazone. In some embodiments, the dual PPARα / γ agonist is saroglitazar. In some embodiments, the FXR agonist is obeticholic acis (OCA). In some embodiments, the lipid-altering agent is aramchol. In some embodiments, the incretin-based therapy is a glucagon-like peptide 1 (GLP-1) receptor agonist or dipeptidyl peptidase 4 (DPP-4) inhibitor. In some embodiments, the GLP-1 receptor agonist is exenatide or liraglutide. In some embodiments, the DPP-4 inhibitor is sitagliptin or vildapliptin. In some embodiments, the siNA or composition and the liver disease treatment agent are administered concurrently. In some embodiments, the siNA or composition and the liver disease treatment agent are administered sequentially. In some embodiments, the siNA or composition is administered prior to administering the liver disease treatment agent. In some embodiments, the siNA or composition is administered after administering the liver disease treatment agent. In some embodiments, the siNA or the composition is administered at a dose of at least 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg 14 mg / kg, or 15 mg / kg. In some embodiments, the siNA or the composition is administered at a dose of between 0.5 mg / kg to 50 mg / kg, 0.5 mg / kg to 40 mg / kg 0.5 mg / kg to 30 mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 40 mg / kg, 1 mg / kg to 30 mg / kg, 1 mg / kg to 20 mg / kg, 3 mg / kg to 50 mg / kg, 3 mg / kg to 40 mg / kg, 3 mg / kg to 30 mg / kg, 3 mg / kg to 20 mg / kg, 3 mg / kg to 15 mg / kg, 3 mg / kg to 10 mg / kg, 4 mg / kg to 50 mg / kg, 4 mg / kg to 40 mg / kg, 4 mg / kg to 30 mg / kg, 4 mg / kg to 20mg / kg, 4 mg / kg to 15 mg / kg, 4 mg / kg to 10 mg / kg, 5 mg / kg to 50 mg / kg, 5 mg / kg to 40 mg / kg, 5 mg / kg to 30 mg / kg, 5 mg / kg to 20 mg / kg, 5 mg / kg to 15 mg / kg, or 5 mg / kg to 10 mg / kg. In some embodiments, the siNA or the composition is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. In some embodiments, the siNA or the composition is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a week, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a month. In some embodiments, the siNA or the composition are administered at least once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days. In some embodiments, the siNA or the composition is administered for a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 51, 52, 53, 54, or 55 weeks. In some embodiments, the siNA or the composition is administered at a single dose of 5 mg / kg. In some embodiments, the siNA or the composition is administered at a single dose of 10 mg / kg. In some embodiments, the siNA or the composition is administered at three doses of 10 mg / kg once a week. In some embodiments, the siNA or the composition is administered at three doses of 10 mg / kg once every three days. In some embodiments, the siNA or the composition is administered at five doses of 10 mg / kg once every three days. In some embodiments, the siNA or the composition is administered at six doses of ranging from 1 mg / kg to 15 mg / kg, 1 mg / kg to 10 mg / kg, 2 mg / kg to 15 mg / kg, 2 mg / kg to 10 mg / kg, 3 mg / kg to 15 mg / kg, or 3 mg / kg to 10 mg / kg. In some embodiments, the first dose and second dose are administered at least 3 days apart. In some embodiments, the second dose and third dose are administered at least 4 days apart. In some embodiments, the third dose and fourth dose, fourth dose and fifth dose, or fifth dose and sixth dose are administered at least 7 days apart. In some embodiments, any of the siNAs or the compositions disclosed herein are formulated as a particle or viral vector. In some embodiments, the siNA or the composition are administered in a particle or viral vector. In some embodiments, the viral vector is a vector of adenovirus, adeno-associated virus (AAV), alphavirus, flavivirus, herpes simplex virus, lentivirus, measles virus, picornavirus, poxvirus, retrovirus, or rhabdovirus. In some embodiments, the viral vector is a recombinant viral vector. In some embodiments, the viral vector is selected from AAVrh.74, AAVrh.10, AAVrh.20, AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-7, AAV-8, AAV-9, AAV-10, AAV-11, AAV-12 and AAV-13. In some embodiments, the siNA or the composition is administered systemically. In some embodiments, the siNA or the composition is administered locally. In some embodiments, the siNA or the composition is administered intravenously, subcutaneously, or intramuscularly. In some embodiments, any of the siRNAs or compositions disclosed herein are used in the manufacture of a medicament for treating a disease. In some embodiments, the disease is a viral disease. In some embodiments, the viral disease is caused by a DNA virus. In some embodiments, the DNA virus is a double stranded DNA (dsDNA virus). In some embodiments, the dsDNA virus is a hepadnavirus. In some embodiments, the hepadnavirus is a hepatitis B virus (HBV). In some embodiments, the HBV is selected from HBV genotypes A-J. In some embodiments, an additional HBV treatment agent is further used in the manufacture of the medicament. In some embodiments, the additional HBV treatment agent is selected from a nucleotide analog, nucleoside analog, a capsid assembly modulator (CAM), a recombinant interferon, an entry inhibitor, a small molecule immunomodulator and oligonucleotide therapy. In some embodiments, the oligonucleotide therapy is an additional siNA. In some embodiments, the additional siNA is selected from any of ds- siNA-001 to ds-siNA-0178. In some embodiments, the oligonucleotide therapy is an antisense oligonucleotide (ASO), NAPs, or STOPs. In some embodiments, the ASO is ASO 1 or ASO 2. In some embodiments, the additional HBV treatment agent is selected from HBV STOPSTMALG-010133, HBV CAM ALG-000184, ASO 1, recombinant interferon alpha 2b, IFN-a, PEG-IFN-a-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil, NVR3-778, BAY41-4109, JNJ-632, JNJ-3989 (ARO-HBV), RG6004, GSK3228836, REP-2139, REP-2165, AB-729, VIR- 2218, RG6346 (DCR-HBVS), JNJ-6379, GLS4, ABI-HO731, JNJ-440, NZ-4, RG7907, EDP-514, AB-423, AB-506, ABI-H03733 and ABI-H2158. In some embodiments, any of the siRNAs or compositions disclosed herein are used in the manufacture of a medicament for treating a disease. In some embodiments, the disease is a liver disease. In some embodiments, the liver disease is a nonalcoholic fatty liver disease (NAFLD) or hepatocellular carcinoma (HCC). In some embodiments, the NAFLD is nonalcoholic steatohepatitis (NASH). In some embodiments, the siNA comprises a first nucleotide sequence. In some embodiments, the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260. In someembodiments, the siNA comprises a second nucleotide sequence. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense strand. In some embodiments, the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense strand. In some embodiments, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA further comprises any of the 5’ end caps disclosed herein. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilized nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. In some embodiments, a liver disease treatment agent is further used in the manufacture of the medicament. In some embodiments, the liver disease treatment agent is selected from a peroxisome proliferator-activator receptor (PPAR) agonist, farnesoid X receptor (FXR) agonist, lipid-altering agent, and incretin-based therapy. In some embodiments, the PPAR agonist is selected from a PPARα agonist, dual PPARα / δ agonist, PPARγ agonist, and dual PPARα / γ agonist. In some embodiments, the dual PPARα agonist is a fibrate. In some embodiments, the PPARα / δ agonist is elafibranor. In some embodiments, the PPARγ agonist is a thiazolidinedione (TZD). In some embodiments, TZD is pioglitazone. In some embodiments, the dual PPARα / γ agonist is saroglitazar. In some embodiments, the FXR agonist is obeticholic acis (OCA). In some embodiments, the lipid-altering agent is aramchol. In some embodiments, the incretin-based therapy is a glucagon-like peptide 1 (GLP-1) receptor agonist or dipeptidyl peptidase 4 (DPP-4) inhibitor. In some embodiments, the GLP-1 receptor agonist is exenatide or liraglutide. In some embodiments, the DPP-4 inhibitor is sitagliptin or vildapliptin. In some embodiments, any of the siNAs disclosed herein is used as a medicament. In some embodiments, the siNA comprises a first nucleotide sequence. In some embodiments, the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261- 306. In some embodiments, the siNA comprises a sense strand. In some embodiments, thesense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415- 444. In some embodiments, the siNA comprises an antisense strand. In some embodiments, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA further comprises any of the 5’ end caps disclosed herein. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilized nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. In some embodiments, any of the compositions disclosed herein are used as a medicament. In some embodiments, the composition comprises any of the siNAs disclosed herein. In some embodiments, the siNA comprises a first nucleotide sequence. In some embodiments, the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261- 306. In some embodiments, the siNA comprises a sense strand. In some embodiments, the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415- 444. In some embodiments, the siNA comprises an antisense strand. In some embodiments, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA further comprises any of the 5’ end caps disclosed herein. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilized nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. In some embodiments, any of the siNAs disclosed herein are used in the treatment of a disease. In some embodiments, the siNA comprises a first nucleotide sequence. In some embodiments, the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the siNA comprises a sense strand. In someembodiments, the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the siNA comprises an antisense strand. In some embodiments, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA further comprises any of the 5’ end caps disclosed herein. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilized nucleotides disclosed herein. In some embodiments, the siNA further comprises any of the modified nucleotides disclosed herein. In some embodiments, the disease is a viral disease. In some embodiments, the viral disease is caused by a DNA virus. In some embodiments, the DNA virus is a double stranded DNA (dsDNA virus). In some embodiments, the dsDNA virus is a hepadnavirus. In some embodiments, the hepadnavirus is a hepatitis B virus (HBV). In some embodiments, the HBV is selected from HBV genotypes A-J. In some embodiments, the disease is a liver disease. In some embodiments, the liver disease is a nonalcoholic fatty liver disease (NAFLD) or hepatocellular carcinoma (HCC). In some embodiments, the NAFLD is nonalcoholic steatohepatitis (NASH). In some embodiments, any of the compositions disclosed herein are used in the treatment of a disease. In some embodiments, the composition comprises any of the siNAs disclosed herein. In some embodiments, the siNA comprises a first nucleotide sequence. In some embodiments, the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the siNA comprises a second nucleotide sequence. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261- 306. In some embodiments, the siNA comprises a sense strand. In some embodiments, the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415- 444. In some embodiments, the siNA comprises an antisense strand. In some embodiments, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the siNA further comprises any of the 5’ end caps disclosed herein. In some embodiments, the siNA further comprises any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA further comprises any of the conjugated moieties disclosed herein. In some embodiments, the siNA further comprises any of the destabilized nucleotides disclosed herein. In someembodiments, the siNA further comprises any of the modified nucleotides disclosed herein. In some embodiments, the disease is a viral disease. In some embodiments, the viral disease is caused by a DNA virus. In some embodiments, the DNA virus is a double stranded DNA (dsDNA virus). In some embodiments, the dsDNA virus is a hepadnavirus. In some embodiments, the hepadnavirus is a hepatitis B virus (HBV). In some embodiments, the HBV is selected from HBV genotypes A-J. In some embodiments, the disease is a liver disease. In some embodiments, the liver disease is a nonalcoholic fatty liver disease (NAFLD) or hepatocellular carcinoma (HCC). In some embodiments, the NAFLD is nonalcoholic steatohepatitis (NASH). BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 illustrates an exemplary siNA molecule. FIG.2 illustrates an exemplary siNA molecule. FIGs.3A-3G illustrate exemplary double-stranded siNA molecules. FIG.4 shows a graph of the change in serum HBsAg from AAV-HBV mice treated with ds-siNA-0160, ds-siNA-0165, ds-siNA-0163, or ds-siNA-0166. FIG.5A shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01) or ds-siNA-0160 (G03). FIG.5B shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01) or ds-siNA-0160 (G15). FIG.5C shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01) or ds-siNA-0160 (G03). FIG.5D shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0160 (G03), or ds-siNA-0109 (G09). FIGs.5E-5F show a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01) or ds-siNA-0169 (G18). FIG.5G shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01) or ds-siNA-0169 (G04). FIG.5H shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01) or ds-siNA-0169 (G04). FIG.5I shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0169 (G04), or ds-siNA-0147 (G08).FIG.5J shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0166 (G06), or ds-siNA-0153 (G14). FIG.5K shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0163 (G05), or ds-siNA-0119 (G13). FIG.6A shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0160 (G15), or ds-siNA-080 (G14). FIG.6B shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0169 (G16), or ds-siNA-081 (G13). FIG.7A shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0165 (G18), or ds-siNA-0127 (G17). FIG.7B shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0168 (G20), or ds-siNA-0150 (G19). FIG.8A shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0160 (G06), ASO 1 (G18), or a combination of ds- siNA-0160 and ASO 1 (G20). FIG.8B shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0160 (G06), ASO 1 (G18), or a combination of ds- siNA-0160 and ASO 1 (G20). FIG.8C shows a graph of a synergy analysis of a combination therapy with unconjugated forms of ds-siNA-0164 and ASO 2 (e.g., ds-siNA-0160 and ASO 1 without GalNac). FIG.9 shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0166 (G03), ds-siNA-0155 (G08), or ds-siNA-0157. FIG.10 shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0165 (G10), ds-siNA-0160 (G06), or a combination therapy with ds-siNA-0160 and ds-siNA-0165 (G14). FIG.11 shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0165 (G05), or ds-siNA-0144 (G11). FIG.12 shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G01), ds-siNA-0163 (G04), ds-siNA-0122 (G09), or ds-siNA-0123 (G13).FIG.13 shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G 15) or ds-siNA-0147 (G 19). FIG.14 shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G 15, square), ds-siNA-0109 (G 21, circle), or ds-siNA-0172 (G 27, diamond). FIG.15 shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G 01, circle), ds-siNA-0109 (G 07, square), ds-siNA-0119 (G 11, triangle), or ds-siNA-0153 (G 13, diamond). FIG.16 shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G 01, circle), ASO 1 (G 20, square), ds-siNA-0147 (G 24, diamond), or a combination of ASO 1 and ds-siNA-0147 (G 25, triangle). FIG.17 shows a graph of the change in serum HBsAg from AAV-HBV mice treated with vehicle (G 01, circle), ASO 1 (G 20, square), ds-siNA-0109 (G 26, diamond), or a combination of ASO 1 and ds-siNA-0109 (G 27, triangle). DETAILED DESCRIPTION OF THE INVENTION Disclosed herein are short interfering nucleic acid (siNA) molecules comprising modified nucleotides. The siNA molecules described herein may be double-stranded siNA (ds-siNA) molecules. The siNA molecules described herein may comprise modified nucleotides selected from 2’-O-methyl nucleotides and 2’-fluoro nucleotides. The siNA molecules described herein may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more phosphorothioate internucleoside linkages. The siNA molecules described herein may comprise a phosphorylation blocker. The siNA molecules described herein may comprise a 5’-stabilized end cap. The siNA molecules described herein may comprise a galactosamine. The siNA molecules described herein may comprise one or more blunt ends. The siNA molecules described herein may comprise one or more overhangs. Further disclosed herein are short interfering nucleic acid (siNA) molecules comprising (a) a phosphorylation blocker; and (b) a short interfering nucleic acid (siNA). The siNA may comprise at least 5 nucleotides. The nucleotides may be modified nucleotides, non-modified nucleotides, or any combination thereof. The nucleotides may be ribonucleotides, deoxyribonucleotides, or any combination thereof. The siNA may be single-stranded. Alternatively, the siNA is double-stranded. The double-stranded siNA maycomprise one or more blunt ends. The double-stranded siNA may comprise one or more overhangs. The double-stranded siNA may comprise a blunt end and an overhang. Further disclosed herein are short interfering nucleic acid (siNA) molecules comprising (a) a conjugated moiety; and (b) a short interfering nucleic acid (siNA). The siNA may comprise at least 5 nucleotides. The nucleotides may be modified nucleotides, non-modified nucleotides, or any combination thereof. The nucleotides may be ribonucleotides, deoxyribonucleotides, or any combination thereof. The siNA may be single-stranded. Alternatively, the siNA is double-stranded. The double-stranded siNA may comprise one or more blunt ends. The double-stranded siNA may comprise one or more overhangs. The double-stranded siNA may comprise a blunt end and an overhang. Further disclosed herein are short interfering nucleic acid (siNA) molecules comprising (a) a 5’-stabilized end cap; and (b) a short interfering nucleic acid (siNA). The siNA may comprise at least 5 nucleotides. The nucleotides may be modified nucleotides, non-modified nucleotides, or any combination thereof. The nucleotides may be ribonucleotides, deoxyribonucleotides, or any combination thereof. The siNA may be single-stranded. Alternatively, the siNA is double-stranded. The double-stranded siNA may comprise one or more blunt ends. The double-stranded siNA may comprise one or more overhangs. The double-stranded siNA may comprise a blunt end and an overhang. Further disclosed herein are short interfering nucleic acid (siNA) molecules comprising (a) at least one phosphorylation blocker, conjugated moiety, or 5’-stabilized end cap; and (b) a short interfering nucleic acid (siNA). The siNA may comprise at least 5 nucleotides. The nucleotides may be modified nucleotides, non-modified nucleotides, or any combination thereof. The nucleotides may be ribonucleotides, deoxyribonucleotides, or any combination thereof. The siNA may be single-stranded. Alternatively, the siNA is double-stranded. The double-stranded siNA may comprise one or more blunt ends. The double-stranded siNA may comprise one or more overhangs. The double-stranded siNA may comprise a blunt end and an overhang. An exemplary siNA molecule of the present disclosure is shown in FIG.1. As shown in FIG.1, an exemplary siNA molecule comprises a sense strand (101) and an antisense strand (102). The sense strand (101) may comprise a first oligonucleotide sequence (103). The first oligonucleotide sequence (103) may comprise one or more phosphorothioate internucleoside linkages (109). The phosphorothioate internucleoside linkage (109) may be between the nucleotides at the 5’ or 3’ terminal end of the firstoligonucleotide sequence (103). The phosphorothioate internucleoside linkage (109) may be between the first three nucleotides from the 5’ end of the first oligonucleotide sequence (103). The first oligonucleotide sequence (103) may comprise one or more 2’-fluoro nucleotides (110). The first oligonucleotide sequence (103) may comprise one or more 2’- O-methyl nucleotides (111). The first oligonucleotide sequence (103) may comprise 15 or more modified nucleotides independently selected from 2’-fluoro nucleotides (110) and 2’- O-methyl nucleotides (111). The sense strand (101) may further comprise a phosphorylation blocker (105). The sense strand (101) may further comprise a galactosamine (106). The antisense strand (102) may comprise a second oligonucleotide sequence (104). The second oligonucleotide sequence (104) may comprise one or more phophorothioate internucleoside linkages (109). The phosphorothioate internucleoside linkage (109) may be between the nucleotides at the 5’ or 3’ terminal end of the second oligonucleotide sequence (104). The phosphorothioate internucleoside linkage (109) may be between the first three nucleotides from the 5’ end of the second oligonucleotide sequence (104). The phosphorothioate internucleoside linkage (109) may be between the first three nucleotides from the 3’ end of the second oligonucleotide sequence (104). The second oligonucleotide sequence (104) may comprise one or more 2’-fluoro nucleotides (110). The second oligonucleotide sequence (104) may comprise one or more 2’-O-methyl nucleotides (111). The second oligonucleotide sequence (104) may comprise 15 or more modified nucleotides independently selected from 2’-fluoro nucleotides (110) and 2’-O-methyl nucleotides (111). The antisense strand (102) may further comprise a 5’-stabilized end cap (107). The siNA may further comprise one or more blunt ends. Alternatively, or additionally, one end of the siNA may comprise an overhang (108). The overhang (108) may be part of the sense strand (101). The overhang (108) may be part of the antisense strand (102). The overhang (108) may be distinct from the first nucleotide sequence (103). The overhang (108) may be distinct from the second nucleotide sequence (104). The overhang (108) may be part of the first nucleotide sequence (103). The overhang (108) may be part of the second nucleotide sequence (104). The overhang (108) may comprise 1 or more nucleotides. The overhang (108) may comprise 1 or more deoxyribonucleotides. The overhang (108) may comprise 1 or more modified nucleotides. The overhang (108) may comprise 1 or more modified ribonucleotides. The sense strand (101) may be shorter than the antisense strand (102). The sense strand (101) may be the same length as the antisense strand (102). The sense strand (101) may be longer than the antisense strand (102).An exemplary siNA molecule of the present disclosure is shown in FIG.2. As shown in FIG.2, an exemplary siNA molecule comprises a sense strand (201) and an antisense strand (202). The sense strand (201) may comprise a first oligonucleotide sequence (203). The first oligonucleotide sequence (203) may comprise one or more phophorothioate internucleoside linkages (209). The phosphorothioate internucleoside linkage (209) may be between the nucleotides at the 5’ or 3’ terminal end of the first oligonucleotide sequence (203). The phosphorothioate internucleoside linkage (209) may be between the first three nucleotides from the 5’ end of the first oligonucleotide sequence (203). The first oligonucleotide sequence (203) may comprise one or more 2’-fluoro nucleotides (210). The first oligonucleotide sequence (203) may comprise one or more 2’- O-methyl nucleotides (211). The first oligonucleotide sequence (203) may comprise 15 or more modified nucleotides independently selected from 2’-fluoro nucleotides (210) and 2’- O-methyl nucleotides (211). The sense strand (201) may further comprise a phosphorylation blocker (205). The sense strand (201) may further comprise a galactosamine (206). The antisense strand (202) may comprise a second oligonucleotide sequence (204). The second oligonucleotide sequence (204) may comprise one or more phophorothioate internucleoside linkages (209). The phosphorothioate internucleoside linkage (209) may be between the nucleotides at the 5’ or 3’ terminal end of the second oligonucleotide sequence (204). The phosphorothioate internucleoside linkage (209) may be between the first three nucleotides from the 5’ end of the second oligonucleotide sequence (204). The phosphorothioate internucleoside linkage (209) may be between the first three nucleotides from the 3’ end of the second oligonucleotide sequence (204). The second oligonucleotide sequence (204) may comprise one or more 2’-fluoro nucleotides (210). The second oligonucleotide sequence (204) may comprise one or more 2’-O-methyl nucleotides (211). The second oligonucleotide sequence (204) may comprise 15 or more modified nucleotides independently selected from 2’-fluoro nucleotides (210) and 2’-O-methyl nucleotides (211). The antisense strand (202) may further comprise a 5’-stabilized end cap (207). The siNA may further comprise one or more overhangs (208). The overhang (208) may be part of the sense strand (201). The overhang (208) may be part of the antisense strand. (202). The overhang (208) may be distinct from the first nucleotide sequence (203). The overhang (208) may be distinct from the second nucleotide sequence (204). The overhang (208) may be part of the first nucleotide sequence (203). The overhang (208) may be part of the second nucleotide sequence (204). The overhang (208) may be adjacent to the 3’ end of the firstnucleotide sequence (203). The overhang (208) may be adjacent to the 5’ end of the first nucleotide sequence (203). The overhang (208) may be adjacent to the 3’ end of the second nucleotide sequence (204). The overhang (208) may be adjacent to the 5’ end of the second nucleotide sequence (204). The overhang (208) may comprise 1 or more nucleotides. The overhang (208) may comprise 1 or more deoxyribonucleotides. The overhang (208) may comprise a TT sequence. The overhang (208) may comprise 1 or more modified nucleotides. The overhang (208) may comprise 1 or more modified nucleotides disclosed herein (e.g., 2-fluoro nucleotide, 2’-O-methyl nucleotide, 2’-fluoro nucleotide mimic, 2’-O- methyl nucleotide mimic, or a nucleotide comprising a modified nucleobase). The overhang (208) may comprise 1 or more modified ribonucleotides. The sense strand (201) may be shorter than the antisense strand (202). The sense strand (201) may be the same length as the antisense strand (202). The sense strand (201) may be longer than the antisense strand (202). FIGs.3A-3G depict exemplary ds-siNA modification patterns. As shown in FIGs.3A-3G, an exemplary ds-siNA molecule may have the following formula: 5’-An1Bn2An3Bn4An5Bn6An7Bn8An9-3’ 3’-Cq1Aq2Bq3Aq4Bq5Aq6Bq7Aq8Bq9Aq10Bq11Aq12-5’ wherein: the top strand is a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence comprises 15 to 30 nucleotides; the bottom strand is an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises 15 to 30 nucleotides; each A is independently a 2’-O-methyl nucleotide or a nucleotide comprising a 5’ stabilized end cap or phosphorylation blocker; B is a 2’-fluoro nucleotide; C represents overhanging nucleotides and is a 2’-O-methyl nucleotide; n1= 1-4 nucleotides in length; each n2, n6, n8, q3, q5, q7, q9, q11, and q12is independently 0-1 nucleotides in length; each n3and n4is independently 1-3 nucleotides in length;n5is 1-10 nucleotides in length; n7is 0-4 nucleotides in length; each n9, q1, and q2is independently 0-2 nucleotides in length; q4is 0-3 nucleotides in length; q6is 0-5 nucleotides in length; q8is 2-7 nucleotides in length; and q10is 2-11 nucleotides in length. The ds-siNA may further comprise a conjugated moiety. The conjugated moiety may comprise any of the galactosamines disclosed herein. The ds-siNA may further comprise (i) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2 and positions 2 and 3 from the 5’ end of the sense strand; and (ii) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2; positions 2 and 3; positions 19 and 20; and positions 20 and 21 from the 5’ end of the antisense strand. The ds- siNA may further comprise a 5’-stabilizing end cap. The 5’-stabilizing end cap may be a vinyl phosphonate. The 5’-stabilizing end cap may be attached to the 5’ end of the antisense strand. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’- O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is further modified to contain a phosphorylation blocker. An exemplary ds-siNA molecule may have the following formula: 5’-A2-4B1A1-3B2-3A2-10B0-1A0-4B0-1A0-2-3’ 3’-C2A0-2B0-1A0-3B0-1A0-5B0-1A2-7B1A2-11B1A1-5’ wherein: the top strand is a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNAcorresponding to a target gene, wherein the first nucleotide sequence comprises 15 to 30 nucleotides; the bottom strand is an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises 15 to 30 nucleotides; each A is independently a 2’-O-methyl nucleotide or a nucleotide comprising a 5’ stabilized end cap or phosphorylation blocker; B is a 2’-fluoro nucleotide; C represents overhanging nucleotides and is a 2’-O-methyl nucleotide. The ds-siNA may further comprise a conjugated moiety. The conjugated moiety may comprise any of the galactosamines disclosed herein. The ds-siNA may further comprise (i) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2 and positions 2 and 3 from the 5’ end of the sense strand; and (ii) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2; positions 2 and 3; positions 19 and 20; and positions 20 and 21 from the 5’ end of the antisense strand. The ds- siNA may further comprise a 5’-stabilizing end cap. The 5’-stabilizing end cap may be a vinyl phosphonate. The vinyl phosphonate may be a deuterated vinyl phosphonate. The deuterated vinyl phosphonate may be a mono-deuterated vinyl phosphonate. The deuterated vinyl phosphonate may be a mono-di-deuterated vinyl phosphonate.The 5’-stabilizing end cap may be attached to the 5’ end of the antisense strand. The 5’-stabilizing end cap may be attached to the 3’ end of the antisense strand. The 5’-stabilizing end cap may be attached to the 5’ end of the sense strand. The 5’-stabilizing end cap may be attached to the 3’ end of the sense strand. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’- O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a phosphorylationblocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is further modified to contain a phosphorylation blocker. The exemplary ds-siNA shown in FIGs.3A-3G comprise (i) a sense strand comprising 19-21 nucleotides; and (ii) an antisense strand comprising 21-23 nucleotides. The ds-siNA may further comprise (iii) a conjugated moiety, wherein the conjugated moiety is attached to the 3’ end of the antisense strand. The ds-siNA may comprise a 2 nucleotide overhang consisting of nucleotides at positions 20 and 21 from the 5’ end of the antisense strand. The ds-siNA may comprise a 2 nucleotide overhang consisting of nucleotides at positions 22 and 23 from the 5’ end of the antisense strand. The ds-siNA may further comprise 1, 2, 3, 4, 5, 6 or more phosphorothioate (ps) internucleoside linkages. At least one phosphorothioate internucleoside linkage may be between the nucleotides at positions 1 and 2 or positions 2 and 3 from the 5’ end of the sense strand. At least one phosphorothioate internucleoside linkage may be between the nucleotides at positions 1 and 2 or positions 2 and 3 from the 5’ end of the antisense strand. At least one phosphorothioate internucleoside linkage may be between the nucleotides at positions 19 and 20, positions 20 and 21, positions 21 and 22, or positions 22 and 23 from the 5’ end of the antisense strand. As shown in FIGs.3A-3G, 4-6 nucleotides in the sense strand may be 2’-fluoro nucleotides. As shown in FIGs.3A-3G, 2-5 nucleotides in the antisense strand may be 2’-fluoro nucleotides. As shown in FIGs.3A-3G, 13-15 nucleotides in the sense strand may be 2’-O-methyl nucleotides. As shown in FIGs.3A-3G, 14-19 nucleotides in the antisense strand may be 2’- O-methyl nucleotides. As shown in FIGs.3A-3G, the ds-siNA does not contain a base pair between 2’-fluoro nucleotides on the sense and antisense strands. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is further modified to contain a phosphorylation blocker.As shown in FIG.3A, a ds-siNA may comprise (a) a sense strand consisting of 19 nucleotides, wherein 2’-fluoro nucleotides are at positions 3, 7-9, 12, and 17 from the 5’ end of the sense strand, and wherein 2’-O-methyl nucleotides are at positions 1, 2, 4-6, 10, 11, 13-16, 18, and 19 from the 5’ end of the sense strand; (b) an antisense strand consisting of 21 nucleotides, wherein nucleotides at positions 2 and 14 from the 5’ end of the antisense strand are 2’-fluoro nucleotides; and wherein nucleotides at positions 1, 3-13, and 15-21 are 2’-O-methyl nucleotides. The ds-siNA may further comprise a conjugated moiety attached to the 3’ end of the sense strand. The ds-siNA may further comprise (i) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2 and positions 2 and 3 from the 5’ end of the sense strand; and (ii) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2; positions 2 and 3; positions 19 and 20; and positions 20 and 21 from the 5’ end of the antisense strand. In some embodiments, the 2’-O- methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O- methyl nucleotide at position 1 from the 5’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a 2’-fluoro nucleotide mimic.In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a f4P, f2P, or fX nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-O-methyl nucleotide on the sense or antisense strand is a 2’-O-methyl nucleotide mimic.As shown in FIG.3B, a ds-siNA may comprise (a) a sense strand consisting of 19 nucleotides, wherein 2’-fluoro nucleotides are at positions 3, 7, 8, and 17 from the 5’ end of the sense strand, and wherein 2’-O-methyl nucleotides are at positions 1, 2, 4-6, 9-16, 18, and 19 from the 5’ end of the sense strand; (b) an antisense strand consisting of 21 nucleotides, wherein nucleotides at positions 2 and 14 from the 5’ end of the antisense strand are 2’-fluoro nucleotides; and wherein nucleotides at positions 1, 3-13, and 15-21 are 2’-O-methyl nucleotides. The ds-siNA may further comprise a conjugated moiety attached to the 3’ end of the sense strand. The ds-siNA may further comprise (i) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2 and positions 2 and 3 from the 5’ end of the sense strand; and (ii) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2; positions 2 and 3; positions 19 and 20; and positions 20 and 21 from the 5’ end of the antisense strand. In some embodiments, the 2’-O- methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O- methyl nucleotide at position 1 from the 5’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a 2’-fluoro nucleotide mimic. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a f4P, f2P, or fX nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-O-methyl nucleotide on the sense or antisense strand is a 2’-O-methyl nucleotide mimic.As shown in FIG.3C, a ds-siNA may comprise (a) a sense strand consisting of 19 nucleotides, wherein 2’-fluoro nucleotides are at positions 3, 7-9, 12 and 17 from the 5’ end of the sense strand, and wherein 2’-O-methyl nucleotides are at positions 1, 2, 4-6, 10, 11, 13-16, 18, and 19 from the 5’ end of the sense strand; (b) an antisense strand consisting of 21 nucleotides, wherein the nucleotides in the antisense strand comprise an alternating 1:3 modification pattern, and wherein 1 nucleotide is a 2’-fluoro nucleotide and 3 nucleotides are 2’-O-methyl nucleotides. The ds-siNA may further comprise a conjugated moiety attached to the 3’ end of the sense strand. The ds-siNA may further comprise (i) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2 and positions 2 and 3 from the 5’ end of the sense strand; and (ii) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2; positions 2 and 3; positions 19 and 20; and positions 20 and 21 from the 5’ end of the antisense strand. The ds- siNA may comprise 2-5 alternating 1:3 modification patterns on the antisense strand. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’- O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a 2’-fluoro nucleotide mimic. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand is a f4P, f2P, or fX nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotideson the antisense strand is a f4P, f2P, or fX nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-O-methyl nucleotide on the sense or antisense strand is a 2’-O-methyl nucleotide mimic. As shown in FIG.3D, a ds-siNA may comprise (a) a sense strand consisting of 19 nucleotides, wherein 2’-fluoro nucleotides are at positions 5 and 7-9 from the 5’ end of the sense strand, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6, and 10-19 from the 5’ end of the sense strand; (b) an antisense strand consisting of 21 nucleotides, wherein the nucleotides in the antisense strand comprise an alternating 1:3 modification pattern, and wherein 1 nucleotide is a 2’-fluoro nucleotide and 3 nucleotides are 2’-O- methyl nucleotides. The ds-siNA may further comprise a conjugated moiety attached to the 3’ end of the sense strand. The ds-siNA may further comprise (i) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2 and positions 2 and 3 from the 5’ end of the sense strand; and (ii) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2; positions 2 and 3; positions 19 and 20; and positions 20 and 21 from the 5’ end of the antisense strand. The ds-siNA may comprise 2-5 alternating 1:3 modification patterns on the antisense strand. The alternating 1:3 modification pattern may start at the nucleotide at any of positions 2, 6, 10, 14, and / or 18 from the 5’ end of the antisense strand. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 fromthe 3’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a 2’-fluoro nucleotide mimic. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand is a f4P, f2P, or fX nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the antisense strand is a f4P, f2P, or fX nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-O-methyl nucleotide on the sense or antisense strand is a 2’-O-methyl nucleotide mimic. As shown in FIG.3E, a ds-siNA may comprise (a) a sense strand consisting of 19 nucleotides, wherein 2’-fluoro nucleotides are at positions 5 and 7-9 from the 5’ end of the sense strand, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6, and 10-19 from the 5’ end of the sense strand; (b) an antisense strand consisting of 21 nucleotides, wherein the nucleotides in the antisense strand comprise an alternating 1:2 modification pattern, and wherein 1 nucleotide is a 2’-fluoro nucleotide and 2 nucleotides are 2’-O- methyl nucleotides. The ds-siNA may further comprise a conjugated moiety attached to the 3’ end of the sense strand. The ds-siNA may further comprise (i) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2 and positions 2 and 3 from the 5’ end of the sense strand; and (ii) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2; positions 2 and 3; positions 19 and 20; and positions 20 and 21 from the 5’ end of the antisense strand. The ds-siNA may comprise 2-5 alternating 1:2 modification patterns on the antisense strand. The alternating 1:2 modification pattern may start at the nucleotide at any of positions 2, 5, 8, 14, and / or 17 from the 5’ end of the antisense strand. In some embodiments, the ds-siNA comprises (a) a sense strand consisting of 19 nucleotides, wherein 2’-fluoro nucleotides are at positions 5 and 7-9 from the 5’ end of the sense strand, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6, and 10-19 from the 5’ end of the sense strand; (b) an antisense strand consisting of 21 nucleotides, wherein 2’-fluoro nucleotides are at positions 2, 5, 8, 14, and 17 from the 5’ end of the antisense strand, and wherein 2’-O-methyl nucleotides are at positions 1, 3, 4, 6, 7, 9-13, 15, 16, and 18-21 from the 5’ end of the sense strand. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a phosphorylation blocker.In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O- methyl nucleotide at position 1 from the 5’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a 2’-fluoro nucleotide mimic. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand is a f4P, f2P, or fX nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the antisense strand is a f4P, f2P, or fX nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-O-methyl nucleotide on the sense or antisense strand is a 2’-O-methyl nucleotide mimic. As shown in FIG.3F, a ds-siNA may comprise (a) a sense strand consisting of 19 nucleotides, wherein 2’-fluoro nucleotides are at positions 5 and 7-9 from the 5’ end of the sense strand, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6, and 10-19 from the 5’ end of the sense strand; (b) an antisense strand consisting of 21 nucleotides, wherein 2’-fluoro nucleotides are at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand, and wherein 2’-O-methyl nucleotides are at positions 1, 3-5, 7-13, 15, and 17-21 from the 5’ end of the antisense strand. The ds-siNA may further comprise a conjugated moiety attached to the 3’ end of the sense strand. The ds-siNA may further comprise (i) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2 and positions 2 and 3 from the 5’ end of the sense strand; and (ii) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2; positions 2 and 3; positions 19 and 20; and positions 20 and 21 from the 5’ end of the antisense strand. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a f4P, f2P, or fX nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a f4P nucleotide. In some embodiments, at least 1, 2, 3, or 4 of the 2’-fluoro-nucleotides at positions 2, 6, 14,and 16 from the 5’ end of the antisense strand is a f4P nucleotide. In some embodiments, at least one of the 2’-fluoro-nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a f4P nucleotide. In some embodiments, at least two of the 2’-fluoro- nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a f4P nucleotide. In some embodiments, less than or equal to 3 of the 2’-fluoro-nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a f4P nucleotide. In some embodiments, less than or equal to 2 of the 2’-fluoro-nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a f4P nucleotide. In some embodiments, the 2’-fluoro-nucleotide at position 2 from the 5’ end of the antisense strand is a f4P nucleotide. In some embodiments, the 2’-fluoro-nucleotide at position 6 from the 5’ end of the antisense strand is a f4P nucleotide. In some embodiments, the 2’-fluoro-nucleotide at position 14 from the 5’ end of the antisense strand is a f4P nucleotide. In some embodiments, the 2’-fluoro-nucleotide at position 16 from the 5’ end of the antisense strand is a f4P nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a f2P nucleotide. In some embodiments, at least 1, 2, 3, or 4 of the 2’-fluoro-nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a f2P nucleotide. In some embodiments, at least one of the 2’-fluoro- nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a f2P nucleotide. In some embodiments, at least two of the 2’-fluoro-nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a f2P nucleotide. In some embodiments, less than or equal to 3 of the 2’-fluoro-nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a f2P nucleotide. In some embodiments, less than or equal to 2 of the 2’-fluoro-nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a f2P nucleotide. In some embodiments, the 2’-fluoro-nucleotide at position 2 from the 5’ end of the antisense strand is a f2P nucleotide. In some embodiments, the 2’-fluoro-nucleotide at position 6 from the 5’ end of the antisense strand is a f2P nucleotide. In some embodiments, the 2’-fluoro-nucleotide at position 14 from the 5’ end of the antisense strand is a f2P nucleotide. In some embodiments, the 2’-fluoro-nucleotide at position 16 from the 5’ end of the antisense strand is a f2P nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a fX nucleotide. In some embodiments, at least 1, 2, 3, or 4 of the 2’- fluoro-nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a fX nucleotide. In some embodiments, at least one of the 2’-fluoro-nucleotides at positions 2,6, 14, and 16 from the 5’ end of the antisense strand is a fX nucleotide. In some embodiments, at least two of the 2’-fluoro-nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a fX nucleotide. In some embodiments, less than or equal to 3 of the 2’-fluoro-nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a fX nucleotide. In some embodiments, less than or equal to 2 of the 2’-fluoro- nucleotides at positions 2, 6, 14, and 16 from the 5’ end of the antisense strand is a fX nucleotide. In some embodiments, the 2’-fluoro-nucleotide at position 2 from the 5’ end of the antisense strand is a fX nucleotide. In some embodiments, the 2’-fluoro-nucleotide at position 6 from the 5’ end of the antisense strand is a fX nucleotide. In some embodiments, the 2’-fluoro-nucleotide at position 14 from the 5’ end of the antisense strand is a fX nucleotide. In some embodiments, the 2’-fluoro-nucleotide at position 16 from the 5’ end of the antisense strand is a fX nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O- methyl nucleotide at position 1 from the 3’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a 2’-fluoro nucleotide mimic. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand is a f4P, f2P, or fX nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the antisense strand is a f4P, f2P, or fX nucleotide. In someembodiments, at least 1, 2, 3, 4 or more 2’-O-methyl nucleotide on the sense or antisense strand is a 2’-O-methyl nucleotide mimic. As shown in FIG.3G, a ds-siNA may comprise (a) a sense strand consisting of 21 nucleotides, wherein 2’-fluoro nucleotides are at positions 5, 9-11, 14, and 19 from the 5’ end of the sense strand, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6-8, 12, 13, 15-18, 20, and 21 from the 5’ end of the sense strand; and (b) an antisense strand consisting of 23 nucleotides, wherein 2’-flouro nucleodies are at positions 2 and 14 from the 5’ end of the antisense strand, and wherein 2’-O-methyl nucleotides are at positions 1, 3-13, and 15-23 from the 5’ end of the antisense strand. The ds-siNA may further comprise a conjugated moiety attached to the 3’ end of the sense strand. The ds-siNA may further comprise (i) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2 and positions 2 and 3 from the 5’ end of the sense strand; and (ii) phosphorothioate internucleoside linkages between the nucleotides at positions 1 and 2; positions 2 and 3; positions 19 and 20; and positions 20 and 21 from the 5’ end of the antisense strand. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’- O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a 5’ stabilizing end cap. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is further modified to contain a phosphorylation blocker. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 5’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the sense strand is a d2vd3 nucleotide. In some embodiments, the 2’-O-methyl nucleotide at position 1 from the 3’ end of the antisense strand is a d2vd3 nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand or antisense strand is a 2’-fluoro nucleotide mimic. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the sense strand is a f4P,f2P, or fX nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-fluoro nucleotides on the antisense strand is a f4P, f2P, or fX nucleotide. In some embodiments, at least 1, 2, 3, 4 or more 2’-O-methyl nucleotide on the sense or antisense strand is a 2’-O-methyl nucleotide mimic. Any of the siNAs disclosed herein may comprise a sense strand and an antisense strand. The sense strand may comprise a first nucleotide sequence that is 15 to 30 nucleotides in length. The antisense strand may comprise a second nucleotide sequence that is 15 to 30 nucleotides in length. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and the nucleotide at position 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and the nucleotide at position 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to theRNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and the nucleotide at position 7 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O- methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and the nucleotide at position 7, 9, 10, and / or 11 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least onemodified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and the nucleotide at position 2, 5, 6, 8, 10, 14, 16, 17, and / or 18 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and the nucleotide at position 2 of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (a) a sense strand comprising a first nucleotide sequence that isat least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (iii) comprises 1 or more phosphorothioate internucleoside linkage; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (iii) comprises 1 or more phosphorothioate internucleoside linkage. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide, wherein the ds-siNA may further comprise a phosphorylation blocker, a galactosamine, or 5’-stabilized end cap. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (I) a sense strand comprising (A) a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (B) a phosphorylation blocker or a galactosamine; and (II) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (a) is 15 to 30 nucleotides in length; and (b) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (I) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (a) is 15 to 30 nucleotides in length; and (b) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (II) an antisense strand comprising (A) a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (B) a 5’-stabilized end cap. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (I) a sense strand comprising (A) a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (B) a phosphorylation blocker or a galactosamine; and (II) an antisense strand comprising (A) a second nucleotide sequence that is at least about 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (B) a 5’-stabilized end cap. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the double-stranded short interfering nucleic acid (ds-siNA) molecule comprises: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence comprises a nucleotide sequence as shown in Tables 1-3; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises a nucleotide sequence as shown in Tables 1-3. In some embodiments, the double-stranded short interfering nucleic acid (ds- siNA) molecule comprises: (a) a sense strand comprising a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415-444; and (b) an antisense strand comprising a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, the ds-siNA molecule comprises a double-stranded molecule as identified by the duplex ID (e.g., ds-siNA-001 to ds-siNA-0178) shown in Tables 6 and 10. Further disclosed herein are compositions comprising two or more of the siNA molecules described herein. Further disclosed herein are compositions comprising any of the siNA molecule described and a pharmaceutically acceptable carrier or diluent.Further disclosed herein are compositions comprising two or more of the siNA molecules described herein for use as a medicament. Further disclosed herein are compositions comprising any of the siNA molecule described and a pharmaceutically acceptable carrier or diluent for use as a medicament. Further disclosed herein are methods of treating a disease in a subject in need thereof, the method comprising administering to the subject any of the siNA molecules described herein. Further disclosed herein are uses of any of the siNA molecules described herein in the manufacture of a medicament for treating a disease. Short interfering nucleic acid (siNA) molecules As indicated above, the present disclosure provides siNA molecules comprising modified nucleotides. Any of the siNA molecules described herein may be double-stranded siNA (ds-siNA) molecules. The terms “siNA molecules” and “ds-siNA molecules” may be used interchangeably. In some embodiments, the ds-siNA molecules comprise a sense strand and an antisense strand. Further disclosed herein are siNA molecules comprising (a) at least one phosphorylation blocker, conjugated moiety, or 5’-stabilized end cap; and (b) a short interfering nucleic acid (siNA). In some embodiments, the phosphorylation blocker is a phosphorylation blocker disclosed herein. In some embodiments, the conjugated moiety is a galactosamine disclosed herein. In some embodiments, the 5’-stabilized end cap is a 5’- stabilized end cap disclosed herein. The siNA may comprise any of the first nucleotide, second nucleotide, sense strand, or antisense strand sequences disclosed herein. The siNA may comprise 5 to 100, 5 to 90, 10 to 100, 10 to 90, 10 to 80, 10 to 70, 10 to 60, 10 to 50, 10 to 30, 10 to 25, 15 to 100, 15 to 90, 15 to 80, 15 to 70, 15 to 60, 15 to 50, 15 to 30, or 15 to 25 nucleotides. The siNA may comprise at least 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 nucleotides. The siNA may comprise less than or equal to 50, 45, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, or 19 nucleotides. The nucleotides may be modified nucleotides. The siNA may be single stranded. The siNA may be double stranded. The siNA may comprise (a) a sense strand comprising 15 to 30, 15 to 25, 15 to 24, 15 to 23, 15 to 22, 15 to 21, 17 to 30, 17 to 25, 17 to 24, 17 to 23, 17 to 22, 17 to 21, 18 to 30, 18 to 25, 18 to 24, 18 to 23, 18 to 22, 18 to 21, 19 to 30, 19 to 25, 19 to 24, 19 to 23, 19 to 22, 19 to 21, 20 to 25, 20 to 24, 20 to 23, 21 to 25, 21 to 24, or 21 to 23 nucleotides; and(b) an antisense strand comprising 15 to 30, 15 to 25, 15 to 24, 15 to 23, 15 to 22, 15 to 21, 17 to 30, 17 to 25, 17 to 24, 17 to 23, 17 to 22, 17 to 21, 18 to 30, 18 to 25, 18 to 24, 18 to 23, 18 to 22, 18 to 21, 19 to 30, 19 to 25, 19 to 24, 19 to 23, 19 to 22, 19 to 21, 20 to 25, 20 to 24, 20 to 23, 21 to 25, 21 to 24, or 21 to 23 nucleotides. The siNA may comprise (a) a sense strand comprising about 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides; and (b) an antisense strand comprising about 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides. The siNA may comprise (a) a sense strand comprising about 19 nucleotides; and (b) an antisense strand comprising about 21 nucleotides. The siNA may comprise (a) a sense strand comprising about 21 nucleotides; and (b) an antisense strand comprising about 23 nucleotides. In some embodiments, any of the siNA molecules disclosed herein further comprise one or more linkers independently selected from a phosphodiester (PO) linker, phosphorothioate (PS) linker, phosphorodithioate linker, and PS-mimic linker. In some embodiments, the PS-mimic linker is a sulfur linker. In some embodiments, the linkers are internucleoside linkers.Alternatively, or additionally, the linkers connect a nucleotide of the siNA molecule to at least one phosphorylation blocker, conjugated moiety, or 5’-stabilized end cap. In some embodiments, the linkers connect a conjugated moiety to a phosphorylation blocker or 5’-stabilized end cap. siNA sense strand Any of the siNA molecules described herein may comprise a sense strand. The sense strand may comprise a first nucleotide sequence. The first nucleotide sequence may be 15 to 30, 15 to 25, 15 to 23, 17 to 23, 19 to 23, or 19 to 21 nucleotides in length. In some embodiments, the first nucleotide sequence is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, the first nucleotide sequence is at least 19 nucleotides in length. In some embodiments, the first nucleotide sequence is at least 21 nucleotides in length. In some embodiments, the sense strand is the same length as the first nucleotide sequence. In some embodiments, the sense strand is longer than the first nucleotide sequence. In some embodiments, the sense strand may further comprise 1, 2, 3, 4, or 5 or more nucleotides than the first nucleotide sequence. In some embodiments, the sense strand may further comprise a deoxyribonucleic acid (DNA). In some embodiments, the DNA is thymine (T). In some embodiments, the sense strand may further comprise a TT sequence. In some embodiments, the sense strand may further comprise one or more modifiednucleotides that are adjacent to the first nucleotide sequence. In some embodiments, the one or more modified nucleotides are independently selected from any of the modified nucleotides disclosed herein (e.g., 2’-fluoro nucleotide, 2’-O-methyl nucleotide, 2’-fluoro nucleotide mimic, 2’-O-methyl nucleotide mimic, or a nucleotide comprising a modified nucleobase). In some embodiments, the first nucleotide sequence comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2′-fluoro nucleotide. In some embodiments, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the nucleotides in the first nucleotide sequence are modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide. In some embodiments, 100% of the nucleotides in the first nucleotide sequence are modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide. In some embodiments, the 2’-O-methyl nucleotide is a 2’-O-methyl nucleotide mimic. In some embodiments, the 2’-fluoro nucleotide is a 2’-fluoro nucleotide mimic. In some embodiments, between about 15 to 30, 15 to 25, 15 to 24, 15 to 23, 15 to 22, 15 to 21, 17 to 30, 17 to 25, 17 to 24, 17 to 23, 17 to 22, 17 to 21, 18 to 30, 18 to 25, 18 to 24, 18 to 23, 18 to 22, 18 to 21, 19 to 30, 19 to 25, 19 to 24, 19 to 23, 19 to 22, 19 to 21, 20 to 25, 20 to 24, 20 to 23, 21 to 25, 21 to 24, or 21 to 23 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 2 to 20 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 5 to 25 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 10 to 25 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 12 to 25 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 12 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 13 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 14 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 15 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 16 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 17 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 18 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 19 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 21 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 20 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 19 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 18 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 17 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 16 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 15 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 14 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 13 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least one modified nucleotide of the first nucleotide sequence is a 2’-O- methyl pyrimidine. In some embodiments, at least 5, 6, 7, 8, 9, or 10 modified nucleotides of the first nucleotide sequence are 2’-O-methyl pyrimidines. In some embodiments, at least one modified nucleotide of the first nucleotide sequence is a 2’-O-methyl purine. In some embodiments, at least 5, 6, 7, 8, 9, or 10 modified nucleotides of the first nucleotide sequence are 2’-O-methyl purines. In some embodiments, the 2’-O-methyl nucleotide is a 2’-O-methyl nucleotide mimic. In some embodiments, between 2 to 15 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, between 2 to 10 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, between 2 to 6 modified nucleotides of the first nucleotide sequence are 2’- fluoro nucleotides. In some embodiments, 1 to 6, 1 to 5, 1 to 4, or 1 to 3 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In someembodiments, at least 1, 2, 3, 4, 5, or 6 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least 1 modified nucleotide of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, at least 2 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least 3 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least 4 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least 5 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least 6 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 10, 9, 8, 7, 6, 5, 4, 3 or fewer modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 10 or fewer modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 7 or fewer modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 6 or fewer modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 5 or fewer modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 4 or fewer modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 3 or fewer modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 2 or fewer modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least one modified nucleotide of the first nucleotide sequence is a 2’-fluoro pyrimidine. In some embodiments, 1, 2, 3, 4, 5, or 6 modified nucleotides of the first nucleotide sequence are 2’-fluoro pyrimidines. In some embodiments, at least one modified nucleotide of the first nucleotide sequence is a 2’-fluoro purine. In some embodiments, 1, 2, 3, 4, 5, or 6 modified nucleotides of the first nucleotide sequence are 2’-fluoro purines. In some embodiments, the 2’-fluoro nucleotide is a 2’-fluoro nucleotide mimic. In some embodiments, the nucleotide at position 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, at least two nucleotides at positions 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least three nucleotides at positions 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least four nucleotides at positions 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19from the 5’ end of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least five nucleotides at positions 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, the nucleotides at positions 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, the nucleotide at position 3 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 7 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 8 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 9 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 12 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 17 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the 2’-fluoro nucleotide is a 2’-fluoro nucleotide mimic. In some embodiments, at least 1, 2, 3, 4, 5, 6, or 7 nucleotides at position 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence is a 2’- fluoro nucleotide. In some embodiments, the nucleotide at positions 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, at least two nucleotides at positions 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least three nucleotides at positions 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, the nucleotides at positions 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, the nucleotide at position 3 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 5 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 7 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 8 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 9 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 10 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 11 from the 5’ end of the first nucleotidesequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 12 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 14 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 17 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 19 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 3, 7, 8, 9, 12, and / or 17 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 3, 7, 8, and / or 17 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 3, 7, 8, 9, 12, and / or 17 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 5, 7, 8, and / or 9 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 5, 9, 10, 11, 12, and / or 19 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the 2’-fluoro nucleotide is a 2’-fluoro nucleotide mimic. In some embodiments, the 2’-fluoro nucleotide or 2’-O-methyl nucleotide is a 2’-fluoro or 2’-O-methyl nucleotide mimic. In some embodiments, the 2’-fluoro or 2’-O- methyl nucleotide mimic is a nucleotide mimic of Formula (wherein R1is independently a nucleobase, aryl, heteroaryl, or H, Q1and Q2are independently S or O, R5is independently –OCD3, –F, or –OCH3, and R6and R7are independently H, D, or CD3. In some embodiments, the nucleobase is selected from cytosine, guanine, adenine, uracil, aryl, heteroaryl, and an analogue or derivative thereof. In some embodiments, the 2’-fluoro or 2’-O-methyl nucleotide mimic is a nucleotide mimic of Formula (16) – Formula (20):Formula (16) Formula (17) Formula (18) Formula (19) Formula (20) ,wherein R1is independently a nucleobase and R2is F or –OCH3. In some embodiments, the nucleobase is selected from cytosine, guanine, adenine, uracil, aryl, heteroaryl, and an analogue or derivative thereof. In some embodiments, the first nucleotide sequence comprises, consists of, or consists essentially of ribonucleic acids (RNAs). In some embodiments, the first nucleotide sequence comprises, consists of, or consists essentially of modified RNAs. In some embodiments, the modified RNAs are selected from a 2’-O-methyl RNA and 2’-fluoro RNA. In some embodiments, 15, 16, 17, 18, 19, 20, 21, 22, or 23 modified nucleotides of the first nucleotide sequence are independently selected from 2’-O-methyl RNA and 2’- fluoro RNA. In some embodiments, the sense strand may further comprise one or more internucleoside linkages independently selected from a phosphodiester (PO) internucleoside linkage, phosphorothioate (PS) internucleoside linkage, phosphorodithioate internucleoside linkage, and PS-mimic internucleoside linkage. In some embodiments, the PS-mimic internucleoside linkage is a sulfo internucleoside linkage. In some embodiments, the sense strand may further comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or more phosphorothioate internucleoside linkages. In some embodiments, the sense strand comprises 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3 or fewer phosphorothioate internucleoside linkages. In some embodiments, the sense strand comprises 2 to 10, 2 to 8, 2 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 phosphorothioate internucleoside linkages. In some embodiments, the sense strand comprises 1 to 2 phosphorothioate internucleoside linkages. In some embodiments, the sense strand comprises 2 to 4 phosphorothioate internucleoside linkages. In some embodiments, at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 1 and 2 from the 5’ end of the first nucleotide sequence. In some embodiments, at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 2 and 3 from the 5’ end of the first nucleotide sequence. In some embodiments, the sense strand comprises two phosphorothioate internucleoside linkages between the nucleotides at positions 1 to 3 from the 5’ end of the first nucleotide sequence. In some embodiments, any of the sense strands disclosed herein further comprise a monomer selected from Examples 21-32, 36, 37, 40-42, and 44-46 monomers. In some embodiments, any of the sense strands disclosed herein further comprise a 5’ end capmonomer. In some embodiments, the 5’ end cap monomer is selected from Examples 5-11, 33-35, 38, 39, 43, and 49-535’ end cap monomers. In some embodiments, any of the first nucleotide sequences disclosed herein further comprise a monomer selected from Examples 21-32, 36, 37, 40-42, and 44-46 monomers. In some embodiments, any of the first nucleotide sequences disclosed herein further comprise a 5’ end cap monomer. In some embodiments, the 5’ end cap monomer is selected from Examples 5-11, 33-35, 38, 39, 43, and 49-535’ end cap monomers. siNA antisense strand Any of the siNA molecules described herein may comprise an antisense strand. The antisense strand may comprise a second nucleotide sequence. The second nucleotide sequence may be 15 to 30, 15 to 25, 15 to 23, 17 to 23, 19 to 23, or 19 to 21 nucleotides in length. In some embodiments, the second nucleotide sequence is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, the second nucleotide sequence is at least 19 nucleotides in length. In some embodiments, the second nucleotide sequence is at least 21 nucleotides in length. In some embodiments, the antisense strand is the same length as the second nucleotide sequence. In some embodiments, the antisense strand is longer than the second nucleotide sequence. In some embodiments, the antisense strand may further comprise 1, 2, 3, 4, or 5 or more nucleotides than the second nucleotide sequence. In some embodiments, the antisense strand is the same length as the sense strand. In some embodiments, the antisense strand is longer than the sense strand. In some embodiments, the antisense strand may further comprise 1, 2, 3, 4, or 5 or more nucleotides than the sense strand. In some embodiments, the antisense strand may further comprise a deoxyribonucleic acid (DNA). In some embodiments, the DNA is thymine (T). In some embodiments, the antisense strand may further comprise a TT sequence. In some embodiments, the antisense strand may further comprise one or more modified nucleotides that are adjacent to the second nucleotide sequence. In some embodiments, the one or more modified nucleotides are independently selected from any of the modified nucleotides disclosed herein (e.g., 2’- fluoro nucleotide, 2’-O-methyl nucleotide, 2’-fluoro nucleotide mimic, 2’-O-methyl nucleotide mimic, or a nucleotide comprising a modified nucleobase). In some embodiments, the second nucleotide sequence comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide. In some embodiments, 70%, 75%, 80%, 85%, 90%,95% or 100% of the nucleotides in the second nucleotide sequence are modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide. In some embodiments, 100% of the nucleotides in the second nucleotide sequence are modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide. In some embodiments, between about 15 to 30, 15 to 25, 15 to 24, 15 to 23, 15 to 22, 15 to 21, 17 to 30, 17 to 25, 17 to 24, 17 to 23, 17 to 22, 17 to 21, 18 to 30, 18 to 25, 18 to 24, 18 to 23, 18 to 22, 18 to 21, 19 to 30, 19 to 25, 19 to 24, 19 to 23, 19 to 22, 19 to 21, 20 to 25, 20 to 24, 20 to 23, 21 to 25, 21 to 24, or 21 to 23 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 2 to 20 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 5 to 25 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 10 to 25 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, between about 12 to 25 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 12 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 13 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 14 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 15 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 16 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 17 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 18 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least about 19 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 21 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In someembodiments, less than or equal to 20 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 19 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 18 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 17 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 16 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 15 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 14 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, less than or equal to 13 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides. In some embodiments, at least one modified nucleotide of the second nucleotide sequence is a 2’-O-methyl pyrimidine. In some embodiments, at least 5, 6, 7, 8, 9, or 10 modified nucleotides of the second nucleotide sequence are 2’-O-methyl pyrimidines. In some embodiments, at least one modified nucleotide of the second nucleotide sequence is a 2’-O- methyl purine. In some embodiments, at least 5, 6, 7, 8, 9, or 10 modified nucleotides of the second nucleotide sequence are 2’-O-methyl purines. In some embodiments, the 2’-O- methyl nucleotide is a 2’-O-methyl nucleotide mimic. In some embodiments, between 2 to 15 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, between 2 to 10 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, between 2 to 6 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 1 to 6, 1 to 5, 1 to 4, or 1 to 3 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least 1, 2, 3, 4, 5, or 6 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least 1 modified nucleotide of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, at least 2 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least 3 modified nucleotides of the second nucleotide sequence are 2’- fluoro nucleotides. In some embodiments, at least 4 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least 5 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In someembodiments, 10, 9, 8, 7, 6, 5, 4, 3 or fewer modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 10 or fewer modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 7 or fewer modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 6 or fewer modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 5 or fewer modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 4 or fewer modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, 3 or fewer modified nucleotides of the second nucleotide sequence are 2’- fluoro nucleotides. In some embodiments, 2 or fewer modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least one modified nucleotide of the second nucleotide sequence is a 2’-fluoro pyrimidine. In some embodiments, 1, 2, 3, 4, 5, or 6 modified nucleotides of the second nucleotide sequence are 2’-fluoro pyrimidines. In some embodiments, at least one modified nucleotide of the second nucleotide sequence is a 2’-fluoro purine. In some embodiments, 1, 2, 3, 4, 5, or 6 modified nucleotides of the second nucleotide sequence are 2’-fluoro purines. In some embodiments, the 2’-fluoro nucleotide is a 2’-fluoro nucleotide mimic. In some embodiments, the 2’-fluoro nucleotide or 2’-O-methyl nucleotide is a 2’-fluoro or 2’-O-methyl nucleotide mimic. In some embodiments, the 2’-fluoro or 2’-O- methyl nucleotide mimic is a nucleotide mimic of Formula (wherein R1is independently a nucleobase, aryl, heteroaryl, or H, Q1and Q2are independently S or O, R5is independently –OCD3, –F, or –OCH3, and R6and R7are independently H, D, or CD3. In some embodiments, the nucleobase is selected from cytosine, guanine, adenine, uracil, aryl, heteroaryl, and an analogue or derivative thereof. In some embodiments, the 2’-fluoro or 2’-O-methyl nucleotide mimic is a nucleotide mimic of Formula (16) – Formula (20):Formula (16) Formula (17) Formula (18) Formula (19) Formula (20) , wherein R1is a nucleobase and R2is independently F or -OCH3. In some embodiments, the nucleobase is selected from cytosine, guanine, adenine, uracil, aryl, heteroaryl, and an analogue or derivative thereof. In some embodiments, at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 nucleotides at position 2, 5, 6, 8, 10, 14, 16, 17, and / or 18 from the 5’ end of the second nucleotide sequence is a 2’- fluoro nucleotide. In some embodiments, the nucleotide at position 2, 5, 6, 8, 10, 14, 16, 17, and / or 18 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, at least two nucleotides at positions 2, 5, 6, 8, 10, 14, 16, 17, and / or 18 from the 5’ end of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least three nucleotides at positions 2, 5, 6, 8, 10, 14, 16, 17, and / or 18 from the 5’ end of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least four nucleotides at positions 2, 5, 6, 8, 10, 14, 16, 17, and / or 18 from the 5’ end of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, at least five nucleotides at positions 2, 5, 6, 8, 10, 14, 16, 17, and / or 18 from the 5’ end of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, the nucleotides at positions 2 and / or 14 from the 5’ end of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, the nucleotides at positions 2, 6, and / or 16 from the 5’ end of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, the nucleotides at positions 2, 6, 14, and / or 16 from the 5’ end of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, the nucleotides at positions 2, 6, 10, 14, and / or 18 from the 5’ end of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, the nucleotides at positions 2, 5, 8, 14, and / or 17 from the 5’ end of the second nucleotide sequence are 2’-fluoro nucleotides. In some embodiments, the nucleotide at position 2 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 5 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 6 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 8 fromthe 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 10 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 14 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 16 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 17 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the nucleotide at position 18 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide. In some embodiments, the 2’-fluoro nucleotide is a 2’- fluoro nucleotide mimic. In some embodiments, the nucleotides in the second nucleotide sequence are arranged in an alternating 1:3 modification pattern, wherein 1 nucleotide is a 2’-fluoro nucleotide and 3 nucleotides are 2’-O-methyl nucleotides, and wherein the alternating 1:3 modification pattern occurs at least 2 times. In some embodiments, the alternating 1:3 modification pattern occurs 2-5 times. In some embodiments, at least two of the alternating 1:3 modification pattern occur consecutively. In some embodiments, at least two of the alternating 1:3 modification pattern occurs nonconsecutively. In some embodiments, at least 1, 2, 3, 4, or 5 alternating 1:3 modification pattern begins at nucleotide position 2, 6, 10, 14, and / or 18 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 2 from the 5’ end of the antisense strand. In some embodiments, wherein at least one alternating 1:3 modification pattern begins at nucleotide position 6 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 10 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 14 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:3 modification pattern begins at nucleotide position 18 from the 5’ end of the antisense strand. In some embodiments, the 2’-fluoro nucleotide is a 2’-fluoro nucleotide mimic. In some embodiments, the nucleotides in the second nucleotide sequence are arranged in an alternating 1:2 modification pattern, wherein 1 nucleotide is a 2’-fluoro nucleotide and 2 nucleotides are 2’-O-methyl nucleotides, and wherein the alternating 1:2 modification pattern occurs at least 2 times. In some embodiments, the alternating 1:2 modification pattern occurs 2-5 times. In some embodiments, at least two of the alternating1:2 modification pattern occurs consecutively. In some embodiments, at least two of the alternating 1:2 modification pattern occurs nonconsecutively. In some embodiments, at least 1, 2, 3, 4, or 5 alternating 1:2 modification pattern begins at nucleotide position 2, 5, 8, 14, and / or 17 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 2 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 5 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 8 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 14 from the 5’ end of the antisense strand. In some embodiments, at least one alternating 1:2 modification pattern begins at nucleotide position 17 from the 5’ end of the antisense strand. In some embodiments, the 2’-fluoro nucleotide is a 2’-fluoro nucleotide mimic. In some embodiments, the second nucleotide sequence comprises, consists of, or consists essentially of ribonucleic acids (RNAs). In some embodiments, the second nucleotide sequence comprises, consists of, or consists essentially of modified RNAs. In some embodiments, the modified RNAs are selected from a 2’-O-methyl RNA and 2’- fluoro RNA. In some embodiments, 15, 16, 17, 18, 19, 20, 21, 22, or 23 modified nucleotides of the second nucleotide sequence are independently selected from 2’-O-methyl RNA and 2’-fluoro RNA. In some embodiments, the 2’-fluoro nucleotide is a 2’-fluoro nucleotide mimic. In some embodiments, the sense strand may further comprise one or more internucleoside linkages independently selected from a phosphodiester (PO) internucleoside linkage, phosphorothioate (PS) internucleoside linkage, phosphorodithioate internucleoside linkage, and PS-mimic internucleoside linkage. In some embodiments, the PS-mimic internucleoside linkage is a sulfo internucleoside linkage. In some embodiments, the antisense strand may further comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or more phosphorothioate internucleoside linkages. In some embodiments, the antisense strand comprises 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3 or fewer phosphorothioate internucleoside linkages. In some embodiments, the antisense strand comprises 2 to 10, 2 to 8, 2 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 phosphorothioate internucleoside linkages. In some embodiments, the antisense strand comprises 2 to 10, 2 to 8, 2 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 phosphorothioateinternucleoside linkages. In some embodiments, the antisense strand comprises 2 to 8 phosphorothioate internucleoside linkages. In some embodiments, the antisense strand comprises 3 to 8 phosphorothioate internucleoside linkages. In some embodiments, the antisense strand comprises 4 to 8 phosphorothioate internucleoside linkages. In some embodiments, at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 1 and 2 from the 5’ end of the second nucleotide sequence. In some embodiments, at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 2 and 3 from the 5’ end of the second nucleotide sequence. In some embodiments, at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 1 and 2 from the 3’ end of the second nucleotide sequence. In some embodiments, at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 2 and 3 from the 3’ end of the second nucleotide sequence. In some embodiments, the antisense strand comprises two phosphorothioate internucleoside linkages between the nucleotides at positions 1 to 3 from the 5’ end of the first nucleotide sequence. In some embodiments, the antisense strand comprises two phosphorothioate internucleoside linkages between the nucleotides at positions 1 to 3 from the 3’ end of the first nucleotide sequence. In some embodiments, the antisense strand comprises (a) two phosphorothioate internucleoside linkages between the nucleotides at positions 1 to 3 from the 5’ end of the first nucleotide sequence; and (b) two phosphorothioate internucleoside linkages between the nucleotides at positions 1 to 3 from the 3’ end of the first nucleotide sequence. In some embodiments, at least one end of the ds-siNA is a blunt end. In some embodiments, at least one end of the ds-siNA comprises an overhang, wherein the overhang comprises at least one nucleotide. In some embodiments, both ends of the ds-siNA comprise an overhang, wherein the overhang comprises at least one nucleotide. In some embodiments, the overhang comprises 1 to 5 nucleotides, 1 to 4 nucleotides, 1 to 3 nucleotides, or 1 to 2 nucleotides. In some embodiments, the overhang consists of 1 to 2 nucleotides. In some embodiments, the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415-444. In someembodiments, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. In some embodiments, any of the antisense strands disclosed herein further comprise a monomer selected from Examples 21-32, 36, 37, 40-42, and 44-46 monomers. In some embodiments, any of the antisense strands disclosed herein further comprise a 5’ end cap monomer. In some embodiments, the 5’ end cap monomer is selected from Examples 5-11, 33-35, 38, 39, 43, and 49-535’ end cap monomers. In some embodiments, any of the secondnucleotide sequences disclosed herein further comprise a monomer selected from Examples 21-32, 36, 37, 40-42, and 44-46 monomers. In some embodiments, any of the second nucleotide sequences disclosed herein further comprise a 5’ end cap monomer. In some embodiments, the 5’ end cap monomer is selected from Examples 5-11, 33-35, 38, 39, 43, and 49-535’ end cap monomers. Modified Nucleotides Further disclosed herein are siNA molecules comprising one or more modified nucleotides. In some embodiments, any of the siNAs disclosed herein comprise one or more modified nucleotides. In some embodiments, any of the sense strands disclosed herein comprise one or more modified nucleotides. In some embodiments, any of the first nucleotide sequences disclosed herein comprise one or more modified nucleotides. In some embodiments, any of the antisense strands disclosed herein comprise one or more modified nucleotides. In some embodiments, any of the second nucleotide sequences disclosed herein comprise one or more modified nucleotides. In some embodiments, the one or more modified nucleotides is adjacent to the first nucleotide sequence. In some embodiments, at least one modified nucleotide is adjacent to the 5’ end of the first nucleotide sequence. In some embodiments, at least one modified nucleotide is adjacent to the 3’ end of the first nucleotide sequence. In some embodiments, at least one modified nucleotide is adjacent to the 5’ end of the first nucleotide sequence and at least one modified nucleotide is adjacent to the 3’ end of the first nucleotide sequence. In some embodiments, the one or more modified nucleotides is adjacent to the second nucleotide sequence. In some embodiments, at least one modified nucleotide is adjacent to the 5’ end of the second nucleotide sequence. In some embodiments, at least one modified nucleotide is adjacent to the 3’ end of the second nucleotide sequence. In some embodiments, at least one modified nucleotide is adjacent to the 5’ end of the second nucleotide sequence and at least one modified nucleotide is adjacent to the 3’ end of the second nucleotide sequence. In some embodiments, a 2’-O-methyl nucleotide in any of sense strands or first nucleotide sequences disclosed herein is replaced with a modified nucleotide. In some embodiments, a 2’-O-methyl nucleotide in any of antisense strands or second nucleotide sequences disclosed herein is replaced with a modified nucleotide. In some embodiments, any of the siNA molecules, siNAs, sense strands, first nucleotide sequences, antisense strands, and second nucleotide sequences disclosed herein comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more modified nucleotides. In some embodiments, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the nucleotides in the siNA molecule, siNA, sense strand, first nucleotide sequence, antisense strand, or second nucleotide sequence are modified nucleotides. In some embodiments, a modified nucleotide is selected from the group consisting of 2’-fluoro nucleotide, 2’-O-methyl nucleotide, 2’-fluoro nucleotide mimic, 2’- O-methyl nucleotide mimic, a locked nucleic acid, and a nucleotide comprising a modified nucleobase. In some embodiments, any of the siRNAs disclosed herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more 2’-fluoro or 2’-O-methyl nucleotide mimics. In some embodiments, any of the sense strands disclosed herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more 2’-fluoro or 2’-O-methyl nucleotide mimics. In some embodiments, any of the first nucleotide sequences disclosed herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more 2’-fluoro or 2’-O-methyl nucleotide mimics. In some embodiments, any of the antisense strand disclosed herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more 2’- fluoro or 2’-O-methyl nucleotide mimics. In some embodiments, any of the second nucleotide sequences disclosed herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more 2’-fluoro or 2’-O-methyl nucleotide mimics. In some embodiments, the 2’-fluoro or 2’-O- methyl nucleotide mimic is a nucleotide mimic of Formula (16) – Formula (20):Formula (16) Formula (17) Formula (18) Formula (19) Formula (20) ,wherein R1is a nucleobase and R2is independently F or -OCH3. In some embodiments, the nucleobase is selected from cytosine, guanine, adenine, uracil, aryl, heteroaryl, and an analogue or derivative thereof. In some embodiments, the siNA molecules disclosed herein comprise at least one 2’-fluoro nucleotide, at least one 2’-O-methyl nucleotide, and at least one 2’-fluoro or 2’-O-methyl nucleotide mimic. In some embodiments, the at least one 2’- fluoro or 2’-O-methyl nucleotide mimic is adjacent to the first nucleotide sequence. In some embodiments, the at least one 2’-fluoro or 2’-O-methyl nucleotide mimic is adjacent to the 5’ end of first nucleotide sequence. In some embodiments, the at least one 2’-fluoro or 2’- O-methyl nucleotide mimic is adjacent to the 3’ end of first nucleotide sequence. In some embodiments, the at least one 2’-fluoro or 2’-O-methyl nucleotide mimic is adjacent to the second nucleotide sequence. In some embodiments, the at least one 2’-fluoro or 2’-O- methyl nucleotide mimic is adjacent to the 5’ end of second nucleotide sequence. In some embodiments, the at least one 2’-fluoro or 2’-O-methyl nucleotide mimic is adjacent to the 3’ end of second nucleotide sequence. In some embodiments, the first nucleotide sequence does not comprise a 2’-fluoro nucleotide mimic. In some embodiments, the first nucleotide sequence does not comprise a 2’-O-methyl nucleotide mimic. In some embodiments, the second nucleotide sequence does not comprise a 2’-fluoro nucleotide mimic. In some embodiments, the second nucleotide sequence does not comprise a 2’-O-methyl nucleotide mimic. In some embodiments, any of the siRNAs disclosed herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more locked nucleic acids. In some embodiments, any of the sense strands disclosed herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more locked nucleic acids. In some embodiments, any of the first nucleotide sequences disclosed herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more locked nucleic acids. In some embodiments, any of the antisense strand disclosed herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more locked nucleic acids. In some embodiments, any of the second nucleotide sequences disclosed herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more locked nucleic acids. In some embodiments, the locked nucleic acid is selected fromR is H or alkyl (or AmNA(N-Me)) when R is alkyl)GuNA(N-R), R = Me, Et, iPr, tBu , wherein B is a nucleobase. In some embodiments, any of the siRNAs, sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein comprise at least modified nucleotide that issome embodiments, any of the siRNAs, sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein comprise at least modified nucleotide that isome embodiments, any of the siRNAs, sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein comprise at least modified nucleotide that i(or AmNA(N-Me)) when R is alkyl). In some embodiments, any of the siRNAs, sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein comprise at least modified nucleotide that isome embodiments, any of the siRNAs, sense strands, first nucleotide sequences, antisense strands, or secondnucleotide sequences disclosed herein comprise at least modified nucleotide that isGuNA(N-R), R = Me, Et, iPr, tBu , wherein B is a nucleobase. Phosphorylation blocker Further disclosed herein are siNA molecules comprising a phosphorylation blocker. In some embodiments, a 2’-O-methyl nucleotide in any of sense strands or first nucleotide sequences disclosed herein is replaced with a nucleotide containing a phosphorylation blocker. In some embodiments, a 2’-O-methyl nucleotide in any of antisense strands or second nucleotide sequences disclosed herein is replaced with a nucleotide containing a phosphorylation blocker. In some embodiments, a 2’-O-methyl nucleotide in any of sense strands or first nucleotide sequences disclosed herein is further modified to contain a phosphorylation blocker. In some embodiments, a 2’-O-methyl nucleotide in any of antisense strands or second nucleotide sequences disclosed herein is further modified to contain a phosphorylation blocker. In some embodiments, any of the siNA molecules disclosed herein comprise a phosphorylation blocker of Formula1 4wherein R is a nucleobase, R is –O-R30or –NR31R32, R30is C1-C8substituted or unsubstituted alkyl; and R31and R32together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring. In some embodiments, any of the siNA molecules disclosed herein comprise a 1 phosphorylation blocker of Formula1Formula (IV), wherein R is a nucleobase, and R4is –OCH3or –N(CH2CH2)2O.In some embodiments, a siNA molecule comprises (a) a phosphorylation blocker of Formula wherein R1is a nucleobase, R4 30 31 32 30is –O-R or –NR R , R is C1-C8substituted or unsubstituted alkyl; and R31and R32together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; and (b) a short interfering nucleic acid (siNA), wherein the phosphorylation blocker is conjugated to the siNA. In some embodiments, a siNA molecule comprises (a) a phosphorylation blocker of Formula1 4Formula (IV), wherein R is a nucleobase, and R is –OCH3or –N(CH2CH2)2O; and (b) a short interfering nucleic acid (siNA), wherein the phosphorylation blocker is conjugated to the siNA. In some embodiments, the phosphorylation blocker is attached to the 3’ end of the sense strand or first nucleotide sequence. In some embodiments, the phosphorylation blocker is attached to the 3’ end of the sense strand or first nucleotide sequence via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the phosphorylation blocker is attached to the 5’ end of the sense strand or first nucleotide sequence. In some embodiments, the phosphorylation blocker is attached to the 5’ end of the sense strand or first nucleotide sequence via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the phosphorylation blocker is attached to the 3’ end of the antisense strand or second nucleotide sequence. In some embodiments, the phosphorylation blocker is attached to the 3’ end of the antisense strand or second nucleotide sequence via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the phosphorylation blocker is attached to the 5’ end of the antisense strand or second nucleotide sequence. In some embodiments, the phosphorylation blocker is attached to the 5’ end of the antisense strand or second nucleotide sequence via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the one or more linkers are independently selected from the group consisting of a phosphodiester linker, phosphorothioate linker, and phosphorodithioate linker. Conjugated MoietyFurther disclosed herein are siNA molecules comprising a conjugated moiety. In some embodiments, the conjugated moiety is selected from galactosamine, peptides, proteins, sterols, lipids, phospholipids, biotin, phenoxazines, active drug substance, cholesterols, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes. In some embodiments, the conjugated moiety is attached to the 3’ end of the sense strand or first nucleotide sequence. In some embodiments, the conjugated moiety is attached to the 3’ end of the sense strand or first nucleotide sequence via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the conjugated moiety is attached to the 5’ end of the sense strand or first nucleotide sequence. In some embodiments, the conjugated moiety is attached to the 5’ end of the sense strand or first nucleotide sequence via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the conjugated moiety is attached to the 3’ end of the antisense strand or second nucleotide sequence. In some embodiments, the conjugated moiety is attached to the 3’ end of the antisense strand or second nucleotide sequence via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the conjugated moiety is attached to the 5’ end of the antisense strand or second nucleotide sequence. In some embodiments, the conjugated moiety is attached to the 5’ end of the antisense strand or second nucleotide sequence via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the one or more linkers are independently selected from the group consisting of a phosphodiester linker, phosphorothioate linker, and phosphorodithioate linker. In some embodiments, the conjugated moiety is galactosamine. In some embodiments, any of the siNAs disclosed herein are attached to a conjugated moiety that is galactosamine. In some embodiments, the galactosamine is N-acetylgalactosamine (GalNAc). In some embodiments, any of the siNA molecules disclosed herein comprise GalNAc. In some embodiments, the GalNAc is of Formula (VI):, wherein m is 1, 2, 3, 4, or 5; each n is independently 1 or 2; p is 0 or 1; each R is independently H or a first protecting group; each Y is independently selected from –O-P(=O)(SH) –, –O-P(=O)(O) –, –O- P(=O)(OH) –, –O-P(S)S–, and –O–; Z is H or a second protecting group; either L is a linker or L and Y in combination are a linker; and A is H, OH, a third protecting group, an activated group, or an oligonucleotide. In some embodiments, the first protecting group isacetyl. In some embodiments, the second protecting group is trimethoxytrityl (TMT). In some embodiments, the activated group is a phosphoramidite group. In some embodiments, the phosphoramidite group is a cyanoethoxy N,N-diisopropylphosphoramidite group. In some embodiments, the linker is a C6-NH2group. In some embodiments, A is a short interfering nucleic acid (siNA) or siNA molecule. In some embodiments, m is 3. In some embodiments, R is H, Z is H, and n is 1. In some embodiments, R is H, Z is H, and n is 2. In some embodiments, the GalNAc is of Formula (VII):, wherein each n is independently 1 or 2. In some embodiments, the galactosamine is attached to the 3’ end of the sense strand or first nucleotide sequence. In some embodiments, the galactosamine is attached to the 3’ end of the sense strand or first nucleotide sequence via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the galactosamine is attached to the 5’ end of the sense strand or first nucleotide sequence. In some embodiments, the galactosamine is attached to the 5’ end of the sense strand or first nucleotide sequence via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the galactosamine is attached to the 3’ end of the antisense strand or second nucleotide sequence. In some embodiments, the galactosamine is attached to the 3’ end of the antisense strand or second nucleotide sequence via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the galactosamine is attached to the 5’ end of the antisense strand or second nucleotide sequence. In some embodiments, the galactosamine is attached to the 5’ end of the antisense strand or second nucleotide sequence via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the one or more linkers are independently selected from the group consisting of a phosphodiester (p or po) linker, phosphorothioate (ps) linker,phosphoramidite (HEG) linker, triethylene glycol (TEG) linker, and / or phosphorodithioate linker. In some embodiments, the one or more linkers are independently selected from the group consisting of p-(PS)2, (PS)2-p-TEG-p, (PS)2-p-HEG-p, and (PS)2-p-(HEG-p)2. In some embodiments, the conjugated moiety is a lipid moiety. In some embodiments, any of the siNAs disclosed herein are attached to a conjugated moiety that is a lipid moiety. Examples of lipid moieties include, but are not limited to, a cholesterol moiety, a thioether, e.g., hexyl-S-tritylthiol, a thiocholesterol, an aliphatic chain, e.g., dodecandiol or undecyl residues a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1-di-O-hexadecyl-rac-glycero-S-H-phosphonate, a polyamine or a polyethylene glycol chain, adamantane acetic acid, a palmityl moiety, or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety. In some embodiments, the conjugated moiety is an active drug substance. In some embodiments, any of the siNAs disclosed herein are attached to a conjugated moiety that is an active drug substance. Examples of active drug substances include, but are not limited to, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (5)-(+)- pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indomethicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic. 5’-Stabilized End Cap Further disclosed herein are siNA molecules comprising a 5’-stabilized end cap. As used herein the terms “5’-stabilized end cap” and “5’ end cap” are used interchangeably. In some embodiments, a 2’-O-methyl nucleotide in any of sense strands or first nucleotide sequences disclosed herein is replaced with a nucleotide containing a 5’-stabilized end cap. In some embodiments, a 2’-O-methyl nucleotide in any of antisense strands or second nucleotide sequences disclosed herein is replaced with a nucleotide containing a 5’- stabilized end cap. In some embodiments, a 2’-O-methyl nucleotide in any of sense strands or first nucleotide sequences disclosed herein is further modified to contain a 5’-stabilized end cap. In some embodiments, a 2’-O-methyl nucleotide in any of antisense strands or second nucleotide sequences disclosed herein is further modified to contain a 5’-stabilized end cap. In some embodiments, the 5’-stabilized end cap is a 5’ phosphate mimic. In some embodiments, the 5’-stabilized end cap is a modified 5’ phosphate mimic. In some embodiments, the modified 5’ phosphate is a chemically modified 5’ phosphate. In someembodiments, the 5’-stabilized end cap is a 5’-vinyl phosphonate. In some embodiments, the 5’-vinyl phosphonate is a 5’-(E)-vinyl phosphonate or 5’-(Z)-vinyl phosphonate. In some embodiments, the 5’-vinyl phosphonate is a deuterated vinyl phosphonate. In some embodiments, the deuterated vinyl phosphonate is a mono-deuterated vinyl phosphonate. In some embodiments, the deuterated vinyl phosphonate is a di-deuterated vinyl phosphonate. In some embodiments, the 5’-stabilized end cap is a phosphate mimic. Examples of phosphate mimics are disclosed in Parmar et al., 2018, J Med Chem, 61(3):734-744, International Publication Nos. WO2018 / 045317 and WO2018 / 044350, and U.S. Patent No. 10,087,210, each of which is incorporated by reference in its entirety. In some embodiments, any of the siNA molecules, sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein comprise a 5’-stabilized end cap of Formula (Ia):, wherein R1is H, a nucleobase,Z, –CD=CD-Z, –(CR21R22)n-Z, or –(C2-C6alkenylene)-Z and R20is H; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n-Z or –(C2- C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, – OP(S)OH(CH2)mCO2R23, –P(O)(OH)2, -P(O)(OH)(OCH3), -P(O)(OH)(OCD3), – SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, –NR23SO2R24; either R21and R22are independently hydrogen or C1-C6alkyl, or R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or –C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl.In some embodiments, any of the siNA molecules, sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein comprise a 5’-stabilized end cap of Formula (Ib):, wherein R1is H, a nucleobase,Z, –CD=CD-Z, –(CR21R22)n-Z, or –(C2-C6alkenylene)-Z and R20is H; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n-Z or –(C2- C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, – OP(S)OH(CH2)mCO2R23, –P(O)(OH)2, -P(O)(OH)(OCH3), -P(O)(OH)(OCD3), – SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, –NR23SO2R24; either R21and R22are independently hydrogen or C1-C6alkyl, or R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or –C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl. In some embodiments, any of the siNA molecules, sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein comprise a 5’-stabilized end cap of Formula (Ic):, wherein R1is a nucleobase, aryl, heteroaryl, or H,(C2-C6alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n-Z or –(C2-C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, –OP(S)OH(CH2)mCO2R23, –P(O)(OH)2, - P(O)(OH)(OCH3), -P(O)(OH)(OCD3), –SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, or –NR23SO2R24; R21and R22either are independently hydrogen or C1-C6alkyl, or R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or –C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl. In some embodiments, any of the siNA molecules, sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein comprise a R2OR1O OCH35’-stabilized end cap of Formula (IIa): , wherein R1is a nucleobase, aryl,SO2CH3or –COCH3, is a double or single bond, R10= –CH2PO3H or –NHCH3, R11is –CH2– or –CO–, and R12is H and R13is CH3or R12and R13together form –CH2CH2CH2–. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl. In some embodiments, any of the siNA molecules, sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein comprise a5’-stabilized end cap of Formula (IIb), wherein R1is a nucleobase, aryl,SO2CH3or –COCH3, is a double or single bond, R10= –CH2PO3H or –NHCH3, R11is –CH2– or –CO–, and R12is H and R13is CH3or R12and R13together form –CH2CH2CH2–. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl. In some embodiments, any of the siNA molecules, sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein comprise a 5’-stabilized end cap of Formula (, wherein R1is a nucleobase, aryl, heteroaryl, or H, L is –CH2–, –CH=CH–, –CO–, or –CH2CH2–, and A is –ONHCOCH3, – ONHSO2CH3, –PO3H, –OP(SOH)CH2CO2H, –SO2CH2PO3H, –SO2NHCH3, –NHSO2CH3, or –N(SO2CH2CH2CH2). In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl. In some embodiments, any of the siNA molecules, sense strands, first nucleotide sequences, antisense strands, or second nucleotide sequences disclosed herein comprise a 5’-stabilized end cap selected from Examples 5-11, 33-35, 38, 39, 43, and 49-535’ end cap monomers. Further disclosed herein are siNA molecules comprising (a) a 5’-stabilized end cap of Formula (Ia):, wherein R1is a nucleobase, aryl, heteroaryl, or H;(CR21R22)n-Z, or –(C2-C6alkenylene)-Z and R20is H; or R2and R20together form a 3- to 7- membered carbocyclic ring substituted with –(CR21R22)n-Z or – (C2-C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, –OP(S)OH(CH2)mCO2R23, - P(O)(OH)2, -P(O)(OH)(OCH3), -P(O)(OH)(OCD3), –SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, –NR23SO2R24; either R21and R22are independently hydrogen or C1-C6alkyl, or R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or – C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4; and (b) a short interfering nucleic acid (siNA), wherein the 5’-stabilized end cap is conjugated to the siNA. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl. Further disclosed herein are siNA molecules comprising (a) a 5’-stabilized end cap of Formula (Ib):, wherein R1is a nucleobase, aryl, heteroaryl, or H; R2(C2-C6alkenylene)-Z and R20is H; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n-Z or – (C2-C6 alkenylene)-Z; n is 1, 2, 3, or 4;Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, –OP(S)OH(CH2)mCO2R23, -P(O)(OH)2, - P(O)(OH)(OCH3), -P(O)(OH)(OCD3), –SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, – NR23SO2R24; either R21and R22are independently hydrogen or C1-C6alkyl, or R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or –C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4; and (b) a short interfering nucleic acid (siNA), wherein the 5’-stabilized end cap is conjugated to the siNA. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl. Further disclosed herein are siNA molecules comprising (a) a 5’-stabilized end cap of Formula (Ic):, wherein R1is a nucleobase, aryl, heteroaryl, or H, R2(C2-C6 alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n-Z or –(C2-C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, –OP(S)OH(CH2)mCO2R23, –P(O)(OH)2, - P(O)(OH)(OCH3), -P(O)(OH)(OCD3), –SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, or –NR23SO2R24; R21and R22either are independently hydrogen or C1-C6alkyl, or R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or –C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4; and (b) a short interfering nucleic acid (siNA), wherein the 5’-stabilized end cap is conjugated to the siNA. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl.In some embodiments, a siNA molecule comprises (a) a 5’-stabilized end cap of Formula ( , wherein R1is a nucleobase, aryl, heteroaryl, o2r H, R isa double or single bond, R10= –CH2PO3H or –NHCH3, R11is –CH2– or –CO–, and R12is H and R13is CH3or R12and R13together form –CH2CH2CH2–; and (b) a short interfering nucleic acid (siNA), wherein the 5’-stabilized end cap is conjugated to the siNA. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl. In some embodiments, a siNA molecule comprises (a) a 5’-stabilized end cap of Formula (IIb), wherein R1is a nucleobase, aryl, heteroaryl, or H, R2isa double or single bond, R10= –CH2PO3H or –NHCH3, R11is –CH2– or –CO–, and R12is H and R13is CH3or R12and R13together form –CH2CH2CH2–; and (b) a short interfering nucleic acid (siNA), wherein the 5’-stabilized end cap is conjugated to the siNA. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl. In some embodiments, a siNA molecule comprises (a) a 5’-stabilized end cap of ALOR1O OCH3Formula (III): , wherein R1is a nucleobase, aryl, heteroaryl, or H, L is –CH2–, –CH=CH–, –CO–, or –CH2CH2–, and A is –ONHCOCH3, –ONHSO2CH3, –PO3H, – OP(SOH)CH2CO2H, –SO2CH2PO3H, –SO2NHCH3, –NHSO2CH3, or –N(SO2CH2CH2CH2); and (b) a short interfering nucleic acid (siNA), wherein the 5’-stabilized end cap is conjugated to the siNA. In some embodiments, R1is an aryl. In some embodiments, the aryl is phenyl. In some embodiments, any of the siNA molecules disclosed herein comprise a 5’-stabilized end cap selected from the group consisting of Formula (1) to Formula (15), Formula (9X) to Formula (12X), and Formula (9Y) to Formula (12Y):Formula (1) Formula (2) Formula (3) Formula (4)Formula (8) Formula (9) Formula (9X) Formula (9Y)Formula (11) Formula (11X) Formula (11Y)Formula (13) Formula (14) Formula (15) , wherein R1is a nucleobase, aryl, heteroaryl, or H. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl. In some embodiments, any of the siNA molecules disclosed herein comprise a 5’-stabilized end cap selected from the group consisting of Formulas (1A)-(15A), Formulas (9B)-(12B), Formulas (9AX)-(12AX), Formulas (9AY)-(12AY), Formulas (9BX)-(12BX), and Formulas (9BY)-(12BY):Formula (8A) Formula (9A) Formula (9AX) Formula (9AY)Formula (12A) Formula (12AX) Formula (12AY)Formula (13A) Formula (14A) Formula (15A) . In some embodiments, any of the siNA molecules disclosed herein comprise a 5’-stabilized end cap selected from the group consisting of Formula (21) to Formula (35):Formula (21) Formula (22) Formula (23) Formula (24)Formula (25) Formula (26) Formula (27)Formula (28) Formula (29) Formula (30)Formula (34) Formula (35) , wherein R1is a nucleobase, aryl, heteroaryl, or H. In some embodiments, R1is an aryl. In some embodiments, the aryl is a phenyl. In some embodiments, any of the siNA molecules disclosed herein comprise a 5’-stabilized end cap selected from the group consisting of Formulas (21A)-(35A), Formulas (29B)-(32B), Formulas (29AX)-(32AX), Formulas (29AY)-(32AY), Formulas (29BX)-(32BX), and Formulas (29BY)-(32BY):Formula (21A) Formula (22A) Formula (23A) Formula (24A)Formula (25A) Formula (26A) Formula (27A)Formula (31B) Formula (31BX) Formula (31BY)Formula (33A) Formula (34A) Formula (35A) . In some embodiments, the 5’-stabilized end cap is attached to the 5’ end of the antisense strand. In some embodiments, the 5’-stabilized end cap is attached to the 5’ end of the antisense strand via 1, 2, 3, 4, or 5 or more linkers. In some embodiments, the one or more linkers are independently selected from the group consisting of a phosphodiester (p or po) linker, phosphorothioate (ps) linker (ps), phosphoramidite (HEG) linker, triethylene glycol (TEG) linker, and / or phosphorodithioate linker. In some embodiments, the one or more linkers are independently selected from the group consisting of p-(PS)2, (PS)2-p- TEG-p, (PS)2-p-HEG-p, and (PS)2-p-(HEG-p)2. Linker In some embodiments, any of the siRNAs, sense strands, first nucleotide sequences, antisense strands, and / or second nucleotide sequences disclosed herein comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or more internucleoside linkers. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more internucleoside linkers are independently selected from the group consisting of a phosphodiester (p or po) linker, phosphorothioate (ps) linker, or phosphorodithioate linker. In some embodiments, any of the siRNAs, sense strands, first nucleotide sequences, antisense strands, and / or second nucleotide sequences disclosed herein furthercomprise 1, 2, 3, 4 or more linkers that attach a conjugated moiety, phosphorylation blocker, and / or 5’ end cap to the siRNA, sense strand, first nucleotide sequence, antisense strand, and / or second nucleotide sequences. In some embodiments, the 1, 2, 3, 4 or more linkers are independently selected from the group consisting of a phosphodiester (p or po) linker, phosphorothioate (ps) linker, phosphoramidite (HEG) linker, triethylene glycol (TEG) linker, and / or phosphorodithioate linker. In some embodiments, the one or more linkers are independently selected from the group consisting of p-(PS)2, (PS)2-p-TEG-p, (PS)2-p-HEG-p, and (PS)2-p-(HEG-p)2. Target Gene Without wishing to be bound by theory, upon entry into a cell, any of the ds- siNA molecules disclosed herein may interact with proteins in the cell to form a RNA- Induced Silencing Complex (RISC). Once the ds-siNA is part of the RISC, the ds-siNA may be unwound to form a single-stranded siNA (ss-siNA). The ss-siNA may comprise the antisense strand of the ds-siNA. The antisense strand may bind to a complementary messenger RNA (mRNA), which results in silencing of the gene that encodes the mRNA. The target gene may be any gene in a cell. In some embodiments, the target gene is a viral gene. In some embodiments, the viral gene is from a DNA virus. In some embodiments, the DNA virus is a double-stranded DNA (dsDNA) virus. In some embodiments, the dsDNA virus is a hepadnavirus. In some embodiments, the hepadnavirus is a hepatitis B virus (HBV). In some embodiments, the HBV is selected from HBV genotypes A-J. In some embodiments, the target gene is selected from the S gene or X gene of the HBV. In some embodiments, the HBV has a genome sequence shown in the nucleotide sequence of SEQ ID NO: 410, which corresponds to the nucleotide sequence of GenBank Accession No. U95551.1, which is incorporated by reference in its entirety. An exemplary HBV genome sequence is shown in SEQ ID NO: 415, corresponding to Genbank Accession No. KC315400.1, which is incorporated by reference in its entirety. Nucleotides 2307..3215,1..1623 of SEQ ID NO: 415 correspond to the polymerase / RT gene sequence, which encodes for the polymerase protein. Nucleotides 2848..3215,1..835 of SEQ ID NO: 415 correspond to the PreS1 / S2 / S gene sequence, which encodes for the large S protein. Nucleotides 3205..3215,1..835 of SEQ ID NO: 415 correspond to the PreS2 / S gene sequence, which encodes for the middle S protein. Nucleotides 155..835 of SEQ ID NO: 415 correspond to the S gene sequence, whichencodes the small S protein. Nucleotides 1374..1838 of SEQ ID NO: 415 correspond to the X gene sequence, which encodes the X protein. Nucleotides 1814..2452 of SEQ ID NO: 415 correspond to the PreC / C gene sequence, which encodes the precore / core protein. Nucleotides 1901..2452 of SEQ ID NO: 415 correspond to the C gene sequence, which encodes the core protein. The HBV genome further comprises viral regulatory elements, such as viral promoters (preS2, preS1, Core, and X) and enhancer elements (ENH1 and ENH2). Nucleotides 1624..1771 of SEQ ID NO: 415 correspond to ENH2. Nucleotides 1742..1849 of SEQ ID NO: 415 correspond to the Core promoter. Nucleotides 1818...3215,1..1930 of SEQ ID NO: 415 correspond to the pregenomic RNA (pgRNA), which encodes the core and polymerase proteins. In some embodiments, the ASO is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary or hybridizes to a viral target RNA sequence that begins in an X region of HBV or in an S region of HBV. The viral target may, e.g., begin at the 5'-end of target-site in acc. KC315400.1 (genotype B, “gt B”), or in any one of genotypes A, C, or D. The skilled person would understand the HBV position, e.g., as described in Wing-Kin Sung, et al., Nature Genetics 44:765 (2012). In some embodiments, the S region is defined as from the beginning of small S protein (in genotype B KC315400.1 isolate, position #155) to before beginning of X protein (in genotype B KC315400.1 isolate, position #1373). In some embodiments, the X region is defined as from the beginning X protein (in genotype B KC315400.1 isolate, position #1374) to end of DR2 site (in genotype B KC315400.1 isolate, position #1603). In some embodiments, the second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30, 15 to 25, 15 to 23, 15 to 22, 15 to 21, 17 to 25, 17 to 23, 17 to 22, 17 to 21, or 19 to 21 nucleotides within positions 200-720 or 1100-1700 of SEQ ID NO: 410. In some embodiments, the second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30, 15 to 25, 15 to 23, 15 to 22, 15 to 21, 17 to 25, 17 to 23, 17 to 22, 17 to 21, or 19 to 21 nucleotides within positions 200-280, 300-445, 460-510, 650-720, 1170-1220, 1250-1300, or 1550-1630 of SEQ ID NO: 410. In some embodiments, the second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30, 15 to 25, 15 to 23, 15 to 22, 15 to 21, 17 to 25, 17 to 23, 17 to 22, 17 to 21, or 19 to 21 nucleotides within positions 200-230, 250-280, 300- 330, 370-400, 405-445, 460-500, 670-700, 1180-1210, 1260-1295, 1520-1550, or 1570-1610 of SEQ ID NO: 410. In some embodiments, the second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30, 15 to 25, 15 to 23, 15 to 22, 15 to 21, 17 to 25, 17 to 23, 17 to 22, 17 to 21, or 19 to 21 nucleotides starting at position 203, 206, 254, 305, 375, 409, 412, 415, 416, 419, 462, 466, 467, 674, 676, 1182, 1262, 1263, 1268, 1526, 1577, 1578, 1580, 1581, 1583, or 1584 of SEQ ID NO: 410. In some embodiments, the first nucleotide is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to a nucleotide region within SEQ ID NO: 410, with the exception that the thymines (Ts) in SEQ ID NO: 410 are replaced with uracil (U). In some embodiments, the first nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to 15 to 30, 15 to 25, 15 to 23, 15 to 22, 15 to 21, 17 to 25, 17 to 23, 17 to 22, 17 to 21, or 19 to 21 nucleotides within positions 200- 720 or 1100-1700 of SEQ ID NO: 410. In some embodiments, the first nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to 15 to 30, 15 to 25, 15 to 23, 15 to 22, 15 to 21, 17 to 25, 17 to 23, 17 to 22, 17 to 21, or 19 to 21 nucleotides within positions 200-280, 300-445, 460-510, 650-720, 1170-1220, 1250-1300, or 1550-1630 of SEQ ID NO: 410. In some embodiments, the first nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to 15 to 30, 15 to 25, 15 to 23, 15 to 22, 15 to 21, 17 to 25, 17 to 23, 17 to 22, 17 to 21, or 19 to 21 nucleotides within positions 200-230, 250-280, 300-330, 370-400, 405-445, 460-500, 670- 700, 1180-1210, 1260-1295, 1520-1550, or 1570-1610 of SEQ ID NO: 410. In some embodiments, the first nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to 15 to 30, 15 to 25, 15 to 23, 15 to 22, 15 to 21, 17 to 25, 17 to 23, 17 to 22, 17 to 21, or 19 to 21 nucleotides starting at position 203, 206, 254, 305, 375, 409, 412, 415, 416, 419, 462, 466, 467, 674, 676, 1182, 1262, 1263, 1268, 1526, 1577, 1578, 1580, 1581, 1583, or 1584 of SEQ ID NO: 410. In some embodiments, the target gene is involved in liver metabolism. In some embodiments, the target gene is an inhibitor of the electron transport chain. In some embodiments, the target gene encodes the MCJ protein (MCJ / DnaJC15 or Methylation- Controlled J protein). In some embodiments, the MCJ protein is encoded by the mRNA sequence of SEQ ID NO: 411, which corresponds to the nucleotide sequence of GenBank Accession No. NM_013238.3, which is incorporated by reference in its entirety.In some embodiments, the target gene is TAZ. In some embodiments, TAZ comprises the nucleotide sequence of SEQ ID NO: 412, which corresponds to the nucleotide sequence of GenBank Accession No. NM_000116.5, which is incorporated by reference in its entirety. In some embodiments, the target gene is angiopoietin like 3 (ANGPTL3). In some embodiments, ANGPTL3 comprises the nucleotide sequence of SEQ ID NO: 413, which corresponds to the nucleotide sequence of GenBank Accession No. NM_014495.4, which is incorporated by reference in its entirety. In some embodiments, the target gene is diacylglycerol acyltransferase 2 (DGAT2). In some embodiments, DGAT2 comprises the nucleotide sequence of SEQ ID NO: 414, which corresponds to the nucleotide sequence of GenBank Accession No. NM_001253891.1, which is incorporated by reference in its entirety. Compositions As indicated above, the present disclosure provides compositions comprising any of the siNA molecules, sense strands, antisense strands, first nucleotide sequences, or second nucleotide sequences described herein. The compositions may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more siNA molecules described herein. The compositions may comprise a first nucleotide sequence comprising a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260. In some embodiments, the composition comprises a second nucleotide sequence comprising a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261-306. In some embodiments, the composition comprises a sense strand comprising a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415-444. In some embodiments, the composition comprises an antisense strand comprising a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539. Alternatively, the compositions may comprise (a) a phosphorylation blocker; and (b) a short interfering nucleic acid (siNA). In some embodiments, the phosphorylation blocker is any of the phosphorylation blockers disclosed herein. In some embodiments, the siNA is any of the siNAs disclosed herein. In some embodiments, the siNA comprises any of the sense strands, antisense strands, first nucleotide sequences, or second nucleotide sequences described herein. In some embodiments, the siNA comprises any of the sense strands, antisense strands, first nucleotide sequences, or second nucleotide sequences described herein. In some embodiments, the siNA comprises one or more modified nucleotides. In some embodiments, the one or more modified nucleotides are independentlyselected from a 2’-fluoro nucleotide and a 2’-O-methyl nucleotide. In some embodiments, the 2’-fluoro nucleotide or the 2’-O-methyl nucleotide is independently selected from any of the 2’-fluoro or 2’-O-methyl nucleotide mimics disclosed herein. In some embodiments, the siNA comprises a nucleotide sequence comprising any of the modification patterns disclosed herein. In some embodiments, the composition comprises (a) a conjugated moiety; and (b) a short interfering nucleic acid (siNA). In some embodiments, the conjugated moiety is any of the galactosamines disclosed herein. In some embodiments, the siNA is any of the siNAs disclosed herein. In some embodiments, the siNA comprises any of the sense strands, antisense strands, first nucleotide sequences, or second nucleotide sequences described herein. In some embodiments, the siNA comprises any of the sense strands, antisense strands, first nucleotide sequences, or second nucleotide sequences described herein. In some embodiments, the siNA comprises one or more modified nucleotides. In some embodiments, the one or more modified nucleotides are independently selected from a 2’- fluoro nucleotide and a 2’-O-methyl nucleotide. In some embodiments, the 2’-fluoro nucleotide or the 2’-O-methyl nucleotide is independently selected from any of the 2’-fluoro or 2’-O-methyl nucleotide mimics disclosed herein. In some embodiments, the siNA comprises a nucleotide sequence comprising any of the modification patterns disclosed herein. In some embodiments, the composition comprises (a) a 5’-stabilized end cap; and (b) a short interfering nucleic acid (siNA). In some embodiments, the 5’-stabilized end cap is any of the 5-stabilized end caps disclosed herein. In some embodiments, the siNA is any of the siNAs disclosed herein. In some embodiments, the siNA comprises any of the sense strands, antisense strands, first nucleotide sequences, or second nucleotide sequences described herein. In some embodiments, the siNA comprises one or more modified nucleotides. In some embodiments, the one or more modified nucleotides are independently selected from a 2’-fluoro nucleotide and a 2’-O-methyl nucleotide. In some embodiments, the 2’-fluoro nucleotide or the 2’-O-methyl nucleotide is independently selected from any of the 2’-fluoro or 2’-O-methyl nucleotide mimics disclosed herein. In some embodiments, the siNA comprises a nucleotide sequence comprising any of the modification patterns disclosed herein. In some embodiments, the composition comprises (a) at least one phosphorylation blocker, conjugated moiety, or 5’-stabilized end cap; and (b) a shortinterfering nucleic acid (siNA). In some embodiments, the phosphorylation blocker is any of the phosphorylation blockers disclosed herein. In some embodiments, the conjugated moiety is any of the galactosamines disclosed herein. In some embodiments, the 5’- stabilized end cap is any of the 5-stabilized end caps disclosed herein. In some embodiments, the siNA is any of the siNAs disclosed herein. In some embodiments, the siNA comprises any of the sense strands, antisense strands, first nucleotide sequences, or second nucleotide sequences described herein. In some embodiments, the siNA comprises one or more modified nucleotides. In some embodiments, the one or more modified nucleotides are independently selected from a 2’-fluoro nucleotide and a 2’-O-methyl nucleotide. In some embodiments, the 2’-fluoro nucleotide or the 2’-O-methyl nucleotide is independently selected from any of the 2’-fluoro or 2’-O-methyl nucleotide mimics disclosed herein. In some embodiments, the siNA comprises a nucleotide sequence comprising any of the modification patterns disclosed herein. The composition may be a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an amount of one or more of the siNA molecules described herein formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. The phrase “therapeutically-effective amount” as used herein means that amount of a compound, material, or composition comprising a siNA of the present disclosure which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit / risk ratio applicable to any medical treatment. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings andanimals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Formulations of the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound (e.g., siNA molecule) which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. In certain embodiments, a formulation of the present disclosure comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound (e.g., siNA molecule) of the present disclosure. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound (e.g., siNA molecule) of the present disclosure. Methods of preparing these formulations or compositions include the step of bringing into association a compound (e.g., siNA molecule) of the present disclosure withthe carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound (e.g., siNA molecule) of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Formulations of the disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound (e.g., siNA molecule) of the present disclosure as an active ingredient. A compound (e.g., siNA molecule) of the present disclosure may also be administered as a bolus, electuary or paste. In solid dosage forms of the disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. Liquid dosage forms for oral administration of the compounds (e.g., siNA molecules) of the disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (I particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the active compounds (e.g., siNA molecules), may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations of the pharmaceutical compositions of the disclosure for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds (e.g., siNA molecules) of the disclosure with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound (e.g., siNA molecule). Formulations of the present disclosure which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for the topical or transdermal administration of a compound (e.g., siNA molecule) of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound (e.g., siNA molecule) may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to an active compound (e.g., siNA molecule) of this disclosure, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to a compound (e.g., siNA molecule) of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the added advantage of providing controlled delivery of a compound (e.g., siNA molecule) of the present disclosure to the body. Such dosageforms can be made by dissolving or dispersing the compound (e.g., siNA molecule) in the proper medium. Absorption enhancers can also be used to increase the flux of the compound (e.g., siNA molecule) across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound (e.g., siNA molecule) in a polymer matrix or gel. Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise one or more compounds (e.g., siNA molecules) of the disclosure in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material havingpoor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the subject compounds (e.g., siNA molecules) in biodegradable polymers such as polylactide- polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue. When the compounds (e.g., siNA molecules) of the present disclosure are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier. Methods of Treatment and Administration The siNA molecules of the present disclosure may be used to treat a disease in a subject in need thereof. In some embodiments, a method of treating a disease in a subject in need thereof comprises administering to the subject any of the siNA molecules disclosed herein. In some embodiments, a method of treating a disease in a subject in need thereof comprises administering to the subject any of the compositions disclosed herein. The preparations (e.g., siNA molecules or compositions) of the present disclosure may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred. The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually. Regardless of the route of administration selected, the compounds (e.g., siNA molecules) of the present disclosure, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound (e.g., siNA molecule) of the present disclosure employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds (e.g., siNA molecules) of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.In general, a suitable daily dose of a compound (e.g., siNA molecule) of the disclosure is the amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose generally depends upon the factors described above. Preferably, the compounds are administered at about 0.01 mg / kg to about 200 mg / kg, more preferably at about 0.1 mg / kg to about 100 mg / kg, even more preferably at about 0.5 mg / kg to about 50 mg / kg. In some embodiments, the compound is administered at a dose equal to or greater than 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1 mg / kg. In some embodiments, the compound is administered at a dose equal to or less than 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, or 15 mg / kg. In some embodiments, the total daily dose of the compound is equal to or greater than 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 100 mg. When the compounds (e.g., siNA molecules) described herein are co- administered with another, the effective amount may be less than when the compound is used alone. If desired, the effective daily dose of the active compound (e.g., siNA molecule) may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day. In some embodiments, the compound is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 times a week. In some embodiments, the compound is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 times a month. In some embodiments, the compound is administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days. In some embodiments, the compound is administered once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. Diseases The siNA molecules and compositions described herein may be administered to a subject to treat a disease. Further disclosed herein are uses of any of the siNA molecules or compositions disclosed herein in the manufacture of a medicament for treating a disease.In some embodiments, the disease is a viral disease. In some embodiments, the viral disease is caused by a DNA virus. In some embodiments, the DNA virus is a double stranded DNA (dsDNA virus). In some embodiments, the dsDNA virus is a hepadnavirus. In some embodiments, the hepadnavirus is a hepatitis B virus (HBV). In some embodiments, the disease is a liver disease. In some embodiments, the liver disease is nonalcoholic fatty liver disease (NAFLD). In some embodiments, the NAFLD is nonalcoholic steatohepatitis (NASH). In some embodiments, the liver disease is hepatocellular carcinoma (HCC). Administration of siNA Administration of any of the siNAs disclosed herein may be conducted by methods known in the art. In some embodiments, the siNA is administered by subcutaneous (SC) or intravenous (IV) delivery. The preparations (e.g., siNAs or compositions) of the present disclosure may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. In some embodiments, subcutaneous administration is preferred. The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.Regardless of the route of administration selected, the compounds (e.g., siNAs) of the present disclosure, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound (e.g., siNA) of the present disclosure employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds (e.g., siNAs) of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound (e.g., siNA) of the disclosure is the amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose generally depends upon the factors described above. Preferably, the compounds are administered at about 0.01 mg / kg to about 200 mg / kg, more preferably at about 0.1 mg / kg to about 100 mg / kg, even more preferably at about 0.5 mg / kg to about 50 mg / kg. In some embodiments, the compound is administered at about 1 mg / kg to about 40 mg / kg, about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, or 1 mg / kg to about 10 mg / kg. In some embodiments, the compound is administered at a dose equal to or greater than 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24,0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1 mg / kg. In some embodiments, the compound is administered at a dose equal to or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg / kg. In some embodiments, the compound is administered at a dose equal to or less than 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, or 15 mg / kg. In some embodiments, the total daily dose of the compound is equal to or greater than 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 100 mg. If desired, the effective daily dose of the active compound (e.g., siNA) may be administered as two, three, four, five, six, seven, eight, nine, ten or more doses or sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In some embodiments, the compound is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times. Preferred dosing is one administration per day. In some embodiments, the compound is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 times a week. In some embodiments, the compound is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 times a month. In some embodiments, the compound is administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days. In some embodiments, the compound is administered every 3 days. In some embodiments, the compound is administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 weeks. In some embodiments, the compound is administered every month. In some embodiments, the compound is administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 months. In some embodiments, the compound is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, or 53 times over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 days. In some embodiments, the compound is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, or 53 times over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, or 53 weeks. In some embodiments, the compound is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, or 53 times over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, or 53 months. In some embodiments, the compound is administered at least once a week for a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 weeks. In some embodiments, the compound is administered at least once a week for a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 months. In some embodiments, the compound is administered at least twice a week for a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 weeks. In some embodiments, the compound is administered at least twice a week for a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 months. In some embodiments, the compound is administered at least once every two weeks for a period of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 weeks. In some embodiments, the compound is administered at least once every two weeks for a period of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 months. In some embodiments, the compound is administered at least once every four weeks for a period of at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 weeks. In some embodiments, the compound is administered at least once every four weeks for a period of at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 months. In some embodiments, any one of the siNAs or compositions disclosed herein is administered in a particle or viral vector. In some embodiments, the viral vector is a vector of adenovirus, adeno-associated virus (AAV), alphavirus, flavivirus, herpes simplex virus, lentivirus, measles virus, picornavirus, poxvirus, retrovirus, or rhabdovirus. In some embodiments, the viral vector is a recombinant viral vector. In some embodiments, the viral vector is selected from AAVrh.74, AAVrh.10, AAVrh.20, AAV-1, AAV-2, AAV-3, AAV- 4, AAV-5, AAV-6, AAV-7, AAV-8, AAV-9, AAV-10, AAV-11, AAV-12 and AAV-13. The subject of the described methods may be a mammal, and it includes humans and non-human mammals. In some embodiments, the subject is a human, such as an adult human. Some embodiments include a method for treating an HBV virus in a subject infected with the virus comprising administering a therapeutically effective amount of one or more siNA of the present disclosure or a composition of the present disclosure to the subject in need thereof thereby reducing the viral load of the virus in the subject and / or reducing a level of a virus antigen in the subject. The siNA may be complementary or hybridize to a portion of the target RNA in the virus, e.g., an X region and / or an S region of HBV. Combination Therapies Any of the methods disclosed herein may further comprise administering to the subject an additional HBV treatment agent. Any of the compositions disclosed herein may further comprise an additional HBV treatment agent. In some embodiments, the additional HBV treatment agent is selected from a nucleotide analog, nucleoside analog, a capsid assembly modulator (CAM), a recombinant interferon, an entry inhibitor, a small molecule immunomodulator and oligonucleotide therapy. In some embodiments, the additional HBV treatment agent is selected from HBV STOPSTMALG-010133, HBV CAM ALG-000184, ASO 1, recombinant interferon alpha 2b, IFN-a, PEG-IFN-a-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil, NVR3-778, BAY41-4109, JNJ-632, JNJ-3989 (ARO-HBV), RG6004, GSK3228836, REP-2139, REP-2165, AB-729, VIR-2218, RG6346 (DCR-HBVS), JNJ-6379, GLS4, ABI-HO731, JNJ-440, NZ-4, RG7907, EDP-514, AB-423, AB-506, ABI-H03733 and ABI-H2158. In some embodiments, the oligonucleotide therapy is selected from Nucleic Acid Polymers or S-Antigen Transport-inhibiting Oligonucleotide Polymers (NAPs or STOPS), siRNA, and ASO. In some embodiments, the oligonucleotide therapy is an additional siNA. In some embodiments, the additional siNA is selected from any of ds-siNA-001 to ds-siNA-0178. In some embodiments, the oligonucleotide therapy is an antisense oligonucleotide (ASO). In some embodiments, the ASO is ASO 1. In some embodiments, any of the siNAs disclosed herein are co-administered with STOPS. Exemplary STOPS are described in International Publication No. WO2020 / 097342 and U.S. Publication No.2020 / 0147124, both of which are incorporated by reference in their entirety. In some embodiments, the STOPS is ALG- 010133. In some embodiments, any of the siNAs disclosed herein are co-administered with tenofovir. In some embodiments, any of the siNAs disclosed herein are co-administered with a CAM. Exemplary CAMs are described in Berke et al., Antimicrob Agents Chemother, 2017, 61(8):e00560-17, Klumpp, et al., Gastroenterology, 2018, 154(3):652- 662.e8, International Application Nos. PCT / US2020 / 017974, PCT / US2020 / 026116, and PCT / US2020 / 028349 and U.S. Application Nos.16 / 789,298, 16 / 837,515, and 16 / 849,851, each which is incorporated by reference in its entirety. In some embodiments, the CAM is ALG-000184, ALG-001075, ALG-001024, JNJ-632, BAY41-4109, or NVR3-778. In some embodiments, the siNA and the HBV treatment agent are administered simultaneously. In some embodiments, the siNA and the HBV treatment agent are administered concurrently. In some embodiments, the siNA and the HBV treatment agent are administered sequentially. In some embodiments, the siNA is administered prior to administering the HBV treatment agent. In some embodiments, the siNA is administered after administering the HBV treatment agent. In some embodiments, the siNA and the HBV treatment agent are in separate containers. In some embodiments, the siNA and the HBV treatment agent are in the same container. Any of the methods disclosed herein may further comprise administering to the subject a liver disease treatment agent. Any of the compositions disclosed herein may further comprise a liver disease treatment agent. In some embodiments, the liver disease treatment agent is selected from a peroxisome proliferator-activator receptor (PPAR) agonist, farnesoid X receptor (FXR) agonist, lipid-altering agent, and incretin-basedtherapy. In some embodiments, the PPAR agonist is selected from a PPARα agonist, dual PPARα / δ agonist, PPARγ agonist, and dual PPARα / γ agonist. In some embodiments, the dual PPARα agonist is a fibrate. In some embodiments, the PPARα / δ agonist is elafibranor. In some embodiments, the PPARγ agonist is a thiazolidinedione (TZD). In some embodiments, TZD is pioglitazone. In some embodiments, the dual PPARα / γ agonist is saroglitazar. In some embodiments, the FXR agonist is obeticholic acis (OCA). In some embodiments, the lipid-altering agent is aramchol. In some embodiments, the incretin-based therapy is a glucagon-like peptide 1 (GLP-1) receptor agonist or dipeptidyl peptidase 4 (DPP-4) inhibitor. In some embodiments, the GLP-1 receptor agonist is exenatide or liraglutide. In some embodiments, the DPP-4 inhibitor is sitagliptin or vildapliptin. In some embodiments, the siNA and the liver disease treatment agent are administered concurrently. In some embodiments, the siNA and the liver disease treatment agent are administered sequentially. In some embodiments, the siNA is administered prior to administering the liver disease treatment agent. In some embodiments, the siNA is administered after administering the liver disease treatment agent. In some embodiments, the siNA and the liver disease treatment agent are in separate containers. In some embodiments, the siNA and the liver disease treatment agent are in the same container. Definitions Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed.1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al., (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate. As used herein, the terms “patient” and “subject” refer to organisms to be treated by the methods of the present disclosure. Such organisms are preferably mammals (e.g.,marines, simians, equines, bovines, porcinis, canines, felines, and the like), and more preferably humans. As used herein, the term “effective amount” refers to the amount of a compound (e.g., a siNA of the present disclosure) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. As used herein, the terms “alleviate” and “alleviating” refer to reducing the severity of the condition, such as reducing the severity by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] . The term “about” as used herein when referring to a measurable value (e.g., weight, time, and dose) is meant to encompass variations, such as ±10%, ±5% , ±1% , or ±0.1% of the specified value. As used herein, the term “nucleobase” refers to a nitrogen-containing biological compound that forms a nucleoside. Examples of nucleobases include, but are not limited to, thymine, uracil, adenine, cytosine, guanine, aryl, heteroaryl, and an analogue or derivative thereof. Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present disclosure that consist essentially of, orconsist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps. As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates that may need to be independently confirmed. EXAMPLES Example 1. siNA Synthesis This example describes an exemplary method for synthesizing ds-siNAs, such as the siNAs disclosed in Table 6 (as identified by the ds-siNA ID). The 2’-OMe phosphoramidite 5’-O-DMT-deoxy Adenosine (NH-Bz), 3’-O-(2- cyanoethyl-N,N-diisopropyl phosphoramidite, 5’-O-DMT-deoxy Guanosine (NH-ibu), 3’- O-(2-cyanoethyl-N,N-diisopropyl phosphoramidite, 5’-O-DMT-deoxy Cytosine (NH-Bz), 3’-O-(2-cyanoethyl-N,N-diisopropyl phosphoramidite, 5’-O-DMT-Uridine 3’-O-(2- cyanoethyl-N,N-diisopropyl phosphoramidite and solid supports were purchased from Chemgenes Corp. MA.The 2’-F -5’-O-DMT-(NH-Bz) Adenosine-3’-O-(2-cyanoethyl-N,N-diisopropyl phosphoramidite, 2’-F -5’-O-DMT-(NH-ibu)- Guanosine, 3’-O-(2-cyanoethyl-N,N- diisopropyl phosphoramidite, 5’-O-DMT-(NH-Bz)- Cytosine, 2’-F-3’-O-(2-cyanoethyl- N,N-diisopropyl phosphoramidite, 5’-O-DMT-Uridine, 2’-F-3’-O-(2-cyanoethyl-N,N- diisopropyl phosphoramidite and solid supports were purchased from Thermo Fischer Milwaukee WI, USA.All the monomers were dried in vacuum desiccator with desiccants (P2O5, RT 24h). The solid supports (CPG) attached to the nucleosides and universal supports was obtained from LGC and Chemgenes. The chemicals and solvents for post synthesis workflow were purchased from commercially available sources like VWR / Sigma and used without any purification or treatment. Solvent (Acetonitrile) and solutions (amidite and activator) were stored over molecular sieves during synthesis.The oligonucleotides were synthesized on a DNA / RNA Synthesizers (Expedite 8909 or ABI-394) using standard oligonucleotide phosphoramidite chemistry starting from the 3′ residue of the oligonucleotide preloaded on CPG support. An extended coupling of 0.1M solution of phosphoramidite in CH3CN in the presence of 5-(ethylthio)-1H-tetrazole activator to a solid bound oligonucleotide followed by standard capping, oxidation and deprotection afforded modified oligonucleotides. The 0.1M I2, THF:Pyridine;Water-7:2:1 was used as oxidizing agent while DDTT ((dimethylamino-methylidene) amino)-3H-1,2,4- dithiazaoline-3-thione was used as the sulfur-transfer agent for the synthesis of oligoribonucleotide phosphorothioates. The stepwise coupling efficiency of all modified phosphoramidites was more than 98%. Reagents Detailed Description Deblock Solution 3% Dichloroacetic acid (DCA) in Dichloromethane (DCM) Amidite Concentration 0.1 M in Anhydrous Acetonitrile Activator 0.25 M Ethyl-thio-Tetrazole (ETT) Cap-A solution Acetic anhydride in Pyridine / THF Cap-B Solution 16% 1-Methylimidazole in THF Oxidizing Solution 0.02M I2, THF: Pyridine; Water-7:2:1 Sulfurizing Solution 0.2 M DDTT in Pyridine / Acetonitrile 1:1 Cleavage and Deprotection: Deprotection and cleavage from the solid support was achieved with mixture of ammonia methylamine (1:1, AMA) for 15 min at 65 °C, when the universal linker was used, the deprotection was left for 90 min at 65oC or solid supports were heated with aqueous ammonia (28%) solution at 55 °C for 16 h to deprotect the base labile protecting groups. Quantitation of Crude SiNA or Raw Analysis Samples were dissolved in deionized water (1.0mL) and quantitated as follows: Blanking was first performed with water alone (2 ul) on Nanodrop then Oligo sample reading obtained at 260 nm. The crude material is dried down and stored at -20oC. Crude HPLC / LC-MS analysis The 0.1 OD of the crude samples were analyzed for crude HPLC and LC-MS analysis. After Confirming the crude LC-MS data then purification step was performed. HPLC Purification The unconjugated and GalNac modified oligonucleotides were purified by anion-exchange HPLC. The buffers were 20 mM sodium phosphate in 10 % CH3CN, pH8.5 (buffer A) and 20 mM sodium phosphate in 10% CH3CN, 1.0 M NaBr, pH 8.5 (buffer B). Fractions containing full-length oligonucleotides were pooled. Desalting of Purified SiNA The purified dry siNA was then desalted using Sephadex G-25 M (Amersham Biosciences). The cartridge was conditioned with 10 mL of deionized water thrice. Finally, the purified siNA dissolved thoroughly in 2.5mL RNAse free water was applied to the cartridge with very slow drop wise elution. The salt free siNA was eluted with 3.5 ml deionized water directly into a screw cap vial. IEX HPLC and Electrospray LC / MS Analysis Approximately 0.10 OD of siNA is dissolved in water and then pipetted in special vials for IEX-HPLC and LC / MS analysis. Analytical HPLC and ES LC-MS established the integrity of the compounds. Duplex Preparation: Single strand oligonucleotides (Sense and Antisense strands) were annealed (1:1 by molar equivalents, heat 90oC for 3 min followed by room temperature, 20 min) to give the duplex ds-siNA. The final compounds were analyzed on size exclusion chromatography (SEC). Example 2. ds-siNA Activity This example investigates the activity of the ds-siNAs synthesized in Example 1. Homo sapiens HepG2.2.15 cells were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) (ATCC 30-2002) supplemented to also contain 10% fetal calf serum (FCS). Cells were incubated at 37°C in an atmosphere with 5% CO2 in a humidified incubator. For transfection of HepG2.2.15 cells with HBV targeting siRNAs, cells were seeded at a density of 15000 cells / well in 96-well regular tissue culture plates. Transfection of cells was carried out using RNAiMAX (Invitrogen / Life Technologies) according to the manufacturer’s instructions. Dose-response experiments were done with oligo concentrations of 40, 20, 10, 5, 2.5, 1.25, 0.625, 0.3125, 0.15625 and 0.07813nM. For each HBV targeting siRNA treatment (e.g., ds-siRNA, as identified by the ds-siNA ID in Table 6), four wells were transfected in parallel, and individual data points were collected from each well. After 24h of incubation with siRNA, media was removed, and cells were lysed and analyzed with a QuantiGene2.0 branched DNA (bDNA) probe set specific for HBV genotype D (also called Hepatitis B virus subtype ayw, complete genome of 3182 base- pairs) as present in cell line HepG2.2.15.For each well, the HBV on-target mRNA levels were normalized to the GAPDH mRNA level. As shown in Table 6, the activity of the HBV targeting ds-siRNAs was expressed as EC50, 50% reduction of normalized HBV RNA level from no drug control. As shown in Table 6, the cytotoxicity of the HBV targeting ds-siRNAs was expressed by CC50 of 50% reduction of GAPDH mRNA from no drug control. Example 3. Use of ds-siNAs to treat hepatitis B virus infection In this example, the ds-siNAs synthesized in Example 1 are used to treat a hepatitis B virus infection in a subject. Generally, a composition comprising a ds-siNA from Table 6 (as identified by the ds-siNA ID) and a pharmaceutically acceptable carrier is administered to the subject suffering from hepatitis B virus. The ds-siNA from Table 6 is conjugated to N-acetylgalactosamine. The ds-siNA is administered at a dose of 0.3 to 5 mg / kg every three weeks by subcutaneous injection or intra...

Claims

WHAT IS CLAIMED IS:

1. A short interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and the nucleotide at position 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide.

2. A short interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementaryto the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and the nucleotide at position 2, 5, 6, 8, 10, 14, 16, 17, and / or 18 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide.

3. The siNA of claim 1 or 2, wherein the first nucleotide sequence comprises 16, 17, 18, 19, 20, 21, 22, 23, or more modified nucleotides independently selected from a 2’-O- methyl nucleotide and a 2′-fluoro nucleotide.

4. The siNA of claim 1 or 2, wherein 70%, 75%, 80%, 85%, 90%, 95% or 100% of the nucleotides in the first nucleotide sequence are modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2′-fluoro nucleotide.

5. The siNA of any one of claims 1-4, wherein: (i) at least 2, 3, 4, 5, or 6 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides; (ii) no more than 10, 9, 8, 7, 6, 5, 4, 3, or 2 modified nucleotides of the first nucleotide sequence are 2’-fluoro nucleotides; (iii) at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides; and / or (iv) no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 modified nucleotides of the first nucleotide sequence are 2’-O-methyl nucleotides.

6. The siRNA of any one of claims 1-5, wherein the second nucleotide sequence comprises 16, 17, 18, 19, 20, 21, 22, 23, or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2′-fluoro nucleotide.

7. The siNA of any one of claims 1-6, wherein 70%, 75%, 80%, 85%, 90%, 95% or 100% of the nucleotides in the second nucleotide sequence are modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide.

8. The siNA of any one of claims 1-7, wherein: (i) at least 2, 3, 4, 5, or 6 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides; (ii) less than or equal to 10, 9, 8, 7, 6, 5, 4, 3, or 2 modified nucleotides of the second nucleotide sequence are 2’-fluoro nucleotides; (iii) at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides; and / or (iv) less than or equal to 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 modified nucleotides of the second nucleotide sequence are 2’-O-methyl nucleotides.

9. A short interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (iii) comprises 1 or more phosphorothioate internucleoside linkage; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (iii) comprises 1 or more phosphorothioate internucleoside linkage.

10. A short interfering nucleic acid (siNA) molecule comprising:(a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide; and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence: (i) is 15 to 30 nucleotides in length; and (ii) comprises 15 or more modified nucleotides independently selected from a 2’-O-methyl nucleotide and a 2’-fluoro nucleotide, wherein at least one modified nucleotide is a 2’-O-methyl nucleotide and at least one modified nucleotide is a 2’-fluoro nucleotide, wherein the siNA further comprises a phosphorylation blocker, a galactosamine, or 5’-stabilized end cap.

11. The siNA according to any preceding claim, wherein at least 1, 2, 3, 4, 5, 6, or 7 nucleotides at position 3, 5, 7, 8, 9, 10, 11, 12, and / or 17 from the 5’ end of the first nucleotide sequence is a 2’-fluoro nucleotide.

12. The siNA according to any preceding claim, wherein at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 nucleotides at position 2, 5, 6, 8, 10, 14, 16, 17, and / or 18 from the 5’ end of the second nucleotide sequence is a 2’-fluoro nucleotide.

13. The siNA according to any preceding claim, wherein the nucleotides in the second nucleotide sequence are arranged in an alternating 1:3 modification pattern, and wherein 1 nucleotide is a 2’-fluoro nucleotide and 3 nucleotides are 2’-O-methyl nucleotides.

14. The siNA of claim 13, wherein the alternating 1:3 modification pattern occurs 2-5 times.

15. The siNA according to claim 13 or 14, wherein: (i) at least two of the alternating 1:3 modification pattern occur consecutively; (ii) at least two of the alternating 1:3 modification pattern occurs nonconsecutively; and / or (iii) at least 1, 2, 3, 4, or 5 alternating 1:3 modification pattern begins at nucleotide position 2, 6, 10, 14, and / or 18 from the 5’ end of the antisense strand.

16. The siNA according to any one of claims 1-12, wherein: (i) the nucleotides in the second nucleotide sequence are arranged in an alternating 1:2 modification pattern, and (ii) 1 nucleotide is a 2’-fluoro nucleotide and 2 nucleotides are 2’-O-methyl nucleotides.

17. The siNA of claim 16, wherein the alternating 1:2 modification pattern occurs 2-5 times.

18. The siNA according to claim 16 or 17, wherein: (i) at least two of the alternating 1:2 modification pattern occurs consecutively; (ii) at least two of the alternating 1:2 modification pattern occurs nonconsecutively; and / or (iii) at least 1, 2, 3, 4, or 5 alternating 1:2 modification pattern begins at nucleotide position 2, 5, 8, 14, and / or 17 from the 5’ end of the antisense strand.

19. A short interfering nucleic acid (siNA) molecule represented by Formula (VIII): 5’-An1Bn2An3Bn4An5Bn6An7Bn8An9-3’ 3’-Cq1Aq2Bq3Aq4Bq5Aq6Bq7Aq8Bq9Aq10Bq11Aq12-5’ wherein: the top strand is a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence comprises 15 to 30 nucleotides; the bottom strand is an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises 15 to 30 nucleotides;each A is independently a 2’-O-methyl nucleotide or a nucleotide comprising a 5’- stabilized end cap or a phosphorylation blocker; B is a 2’-fluoro nucleotide; C represents overhanging nucleotides and is a 2’-O-methyl nucleotide; n1= 1-4 nucleotides in length; each n2, n6, n8, q3, q5, q7, q9, q11, and q12is independently 0-1 nucleotides in length; each n3and n4is independently 1-3 nucleotides in length; n5is 1-10 nucleotides in length; n7is 0-4 nucleotides in length; each n9, q1, and q2is independently 0-2 nucleotides in length; q4is 0-3 nucleotides in length; q6is 0-5 nucleotides in length; q8is 2-7 nucleotides in length; and q10is 2-11 nucleotides in length.

20. A short interfering nucleic acid (siNA) molecule represented by Formula (IX): 5’-A2-4B1A1-3B2-3A2-10B0-1A0-4B0-1A0-2-3’ 3’-C2A0-2B0-1A0-3B0-1A0-5B0-1A2-7B1A2-11B1A1-5’ wherein: the top strand is a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence comprises 15 to 30 nucleotides; the bottom strand is an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises 15 to 30 nucleotides; each A is independently a 2’-O-methyl nucleotide or a nucleotide comprising a 5’- stabilized end cap or a phosphorylation blocker; B is a 2’-fluoro nucleotide; C represents overhanging nucleotides and is a 2’-O-methyl nucleotide.

21. A short interfering nucleic acid (siNA) molecule comprising(a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 3, 7-9, 12, and 17 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1, 2, 4-6, 10, 11, and 13-16 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 2 and 14 from the 5’ end of the second nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1, 3-13, and 15-17 from the 5’ end of the second nucleotide sequence.

22. The siNA molecule of claim 21, wherein the first nucleotide sequence consists of 19 nucleotides.

23. The siNA molecule of claim 22, wherein 2’-O-methyl nucleotides are at positions 18 and 19 from the 5’ end of the first nucleotide sequence.

24. The siNA molecule according to any one of claims 21-23, wherein the second nucleotide sequence consists of 21 nucleotides.

25. The siNA molecule of claim 24, wherein 2’-O-methyl nucleotides are at positions 18-21 from the 5’ end of the second nucleotide sequence.

26. A short interfering nucleic acid (siNA) molecule comprising (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 3, 7, 8, and 17 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1, 2, 4-6, and 9-16 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 2 and 14 from the 5’ end of the first nucleotide sequence; and wherein 2’-O-methyl nucleotides are at positions 1, 3-13, and 15-17 from the 5’ end of the first nucleotide sequence.

27. The siNA molecule of claim 26, wherein the first nucleotide sequence consists of 19 nucleotides.

28. The siNA molecule of claim 27, wherein 2’-O-methyl nucleotides are at positions 18 and 19 from the 5’ end of the first nucleotide sequence.

29. The siNA molecule according to any one of claims 26-28, wherein the second nucleotide sequence consists of 21 nucleotides.

30. The siNA molecule of claim 29, wherein 2’-O-methyl nucleotides are at positions 18-21 from the 5’ end of the second nucleotide sequence.

31. A short interfering nucleic acid (siNA) molecule comprising (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 3, 7-9, 12 and 17 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1, 2, 4-6, 10, 11, and 13-16 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein the nucleotides in the second nucleotide sequence are arranged in an alternating 1:3 modification pattern, and wherein 1 nucleotide is a 2’-fluoro nucleotide and 3 nucleotides are 2’-O-methyl nucleotides.

32. The siNA molecule of claim 31, wherein the first nucleotide sequence consists of 19 nucleotides.

33. The siNA molecule of claim 32, wherein 2’-O-methyl nucleotides are at positions 18 and 19 from the 5’ end of the first nucleotide sequence.

34. The siNA molecule according to any one of claims 31-33, wherein the second nucleotide sequence consists of 21 nucleotides.

35. The siNA molecule of claim 34, wherein 2’-O-methyl nucleotides are at positions 19-21 from the 5’ end of the second nucleotide sequence.

36. The siRNA molecule according to any one of claims 31-35, wherein:(i) the alternating 1:3 modification pattern occurs 2-5 times; (ii) at least two of the alternating 1:3 modification pattern occur consecutively; (iii) at least two of the alternating 1:3 modification pattern occurs nonconsecutively; and / or (iv) at least 1, 2, 3, 4, or 5 alternating 1:3 modification pattern begins at nucleotide position 2, 6, 10, 14, and / or 18 from the 5’ end of the antisense strand.

37. A short interfering nucleic acid (siNA) molecule comprising (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 5 and 7-9 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6, and 10-17 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein the nucleotides in the second nucleotide sequence are arranged in an alternating 1:3 modification pattern, and wherein 1 nucleotide is a 2’-fluoro nucleotide and 3 nucleotides are 2’-O-methyl nucleotides.

38. The siNA molecule of claim 37, wherein the first nucleotide sequence consists of 19 nucleotides.

39. The siNA molecule of claim 38, wherein 2’-O-methyl nucleotides are at positions 18 and 19 from the 5’ end of the first nucleotide sequence.

40. The siNA molecule according to any one of claims 37-39, wherein the second nucleotide sequence consists of 21 nucleotides.

41. The siNA molecule of claim 40, wherein 2’-O-methyl nucleotides are at positions 19-21 from the 5’ end of the second nucleotide sequence.

42. The siRNA molecule according to any one of claims 37-41, wherein: (i) the alternating 1:3 modification pattern occurs 2-5 times; (ii) at least two of the alternating 1:3 modification pattern occur consecutively;(iii) at least two of the alternating 1:3 modification pattern occurs nonconsecutively; and / or (iv) at least 1, 2, 3, 4, or 5 alternating 1:3 modification pattern begins at nucleotide position 2, 6, 10, 14, and / or 18 from the 5’ end of the antisense strand.

43. A short interfering nucleic acid (siNA) molecule comprising (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 5 and 7-9 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6, and 10-17 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein the nucleotides in the second nucleotide sequence are arranged in an alternating 1:2 modification pattern, and wherein 1 nucleotide is a 2’-fluoro nucleotide and 2 nucleotides are 2’-O-methyl nucleotides.

44. The siNA molecule of claim 43, wherein the first nucleotide sequence consists of 19 nucleotides.

45. The siNA molecule of claim 44, wherein 2’-O-methyl nucleotides are at positions 18 and 19 from the 5’ end of the first nucleotide sequence.

46. The siNA molecule according to any one of claims 43-45, wherein the second nucleotide sequence consists of 21 nucleotides.

47. The siNA molecule of claim 46, wherein 2’-O-methyl nucleotides are at positions 18-21 from the 5’ end of the second nucleotide sequence.

48. The siRNA molecule according to any one of claims 43-47, wherein: (i) the alternating 1:2 modification pattern occurs 2-5 times; (ii) at least two of the alternating 1:2 modification pattern occur consecutively; (iii) at least two of the alternating 1:2 modification pattern occurs nonconsecutively; and / or(iv) at least 1, 2, 3, 4, or 5 alternating 1:2 modification pattern begins at nucleotide position 2, 5, 8, 14, and / or 17 from the 5’ end of the antisense strand.

49. A short interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 5 and 7-9 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6, and 10-17 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 2, 6, 14, and 16 from the 5’ end of the second nucleotide sequence, and wherein 2’-O- methyl nucleotides are at positions 1, 3-5, 7-13, 15, and 17 from the 5’ end the second nucleotide sequence.

50. The siNA molecule of claim 49, wherein the first nucleotide sequence consists of 19 nucleotides.

51. The siNA molecule of claim 50, wherein 2’-O-methyl nucleotides are at positions 18 and 19 from the 5’ end of the first nucleotide sequence.

52. The siNA molecule according to any one of claims 49-51, wherein the second nucleotide sequence consists of 21 nucleotides.

53. The siNA molecule of claim 52, wherein 2’-O-methyl nucleotides are at positions 18-21 from the 5’ end of the second nucleotide sequence.

54. A short interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 5, 9-11, and 14 from the 5’ end of the first nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1-4, 6-8, and 12-17 from the 5’ end of the first nucleotide sequence; and (b) an antisense strand comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2’-fluoro nucleotides are at positions 2 and 14from the 5’ end of the second nucleotide sequence, and wherein 2’-O-methyl nucleotides are at positions 1, 3-13, and 15-17 from the 5’ end the second nucleotide sequence.

55. The siNA molecule of claim 54, wherein the first nucleotide sequence consists of 21 nucleotides.

56. The siNA molecule of claim 55, wherein 2’-O-methyl nucleotides are at positions 18-21 from the 5’ end of the first nucleotide sequence.

57. The siNA molecule according to any one of claims 53-55, wherein the second nucleotide sequence consists of 23 nucleotides.

58. The siNA molecule of claim 57, wherein 2’-O-methyl nucleotides are at positions 18-23 from the 5’ end of the second nucleotide sequence.

59. The siNA according to any preceding claim, wherein the sense strand further comprises TT sequence adjacent to the first nucleotide sequence.

60. The siNA according to any preceding claim, wherein the sense strand further comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more phosphorothioate internucleoside linkages.

61. The siNA of claim 60, wherein: (i) at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 1 and 2 from the 5’ end of the first nucleotide sequence; (ii) at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 2 and 3 from the 5’ end of the first nucleotide sequence.

62. The siNA according to any preceding claim, wherein the antisense strand further comprises TT sequence adjacent to the second nucleotide sequence.

63. The siNA according to any preceding claim, wherein the antisense strand further comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more phosphorothioate internucleoside linkages.

64. The siNA of claim 63, wherein:(i) at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 1 and 2 from the 5’ end of the second nucleotide sequence; (ii) at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 2 and 3 from the 5’ end of the second nucleotide sequence; (iii) at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 1 and 2 from the 3’ end of the second nucleotide sequence; and / or (iv) at least one phosphorothioate internucleoside linkage is between the nucleotides at positions 2 and 3 from the 3’ end of the second nucleotide sequence.

65. The siNA according to any preceding claim, wherein: (i) the first nucleotide from the 5’ end of the first nucleotide sequence comprises a 5’ stabilizing end cap; (ii) the first nucleotide from the 5’ end of the second nucleotide sequence comprises a 5’ stabilizing end cap; (iii) the first nucleotide from the 5’ end of the first nucleotide sequence comprises a phosphorylation blocker; and / or (iv) the first nucleotide from the 5’ end of the second nucleotide sequence comprises a phosphorylation blocker.

66. The siNA according to any preceding claim, wherein the first nucleotide sequence or second nucleotide sequence comprises at least one modified nucleotide selected fromR is H or alkyl (or AmNA(N-Me)) when R is alkyl)GuNA(N-R), R = Me, Et, iPr, tBu , wherein B is a nucleobase.

67. A short-interfering nucleic acid (siNA) molecule comprising: (a) a phosphorylation blocker of Formulawherein R1is a nucleobase, R4is –O-R30or –NR31R32, R30is C1-C8substituted or unsubstituted alkyl; and R31and R32together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; and (b) a short interfering nucleic acid (siNA).

68. A short-interfering nucleic acid (siNA) molecule comprising: (a) a 5’-stabilized end cap of Formula (Ia):, wherein R1is a nucleobase, aryl, heteroaryl, or H,CD=CH-Z, –CD=CD-Z, –(CR21R22)n-Z, or -(C2-C6alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with – (CR21R22)n-Z or -(C2-C6alkenylene)-Z; n is 1, 2, 3, or 4;Z is –ONR23R24, -OP(O)OH(CH2)mCO2R23, -OP(S)OH(CH2)mCO2R23, -P(O)(OH)2, -P(O)(OH)(OCH3), -P(O)(OH)(OCD3), -SO2(CH2)mP(O)(OH)2, -SO2NR23R25, - NR23R24, R21and R22are independently hydrogen or C1-C6alkyl; R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or -C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4; and (b) a short interfering nucleic acid (siNA).

69. A short-interfering nucleic acid (siNA) molecule comprising: (a) a 5’-stabilized end cap of Formula (Ib):, wherein R1is a nucleobase, aryl, heteroaryl, or H,CD=CH-Z, –CD=CD-Z, –(CR21R22)n-Z, or -(C2-C6alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with – (CR21R22)n-Z or -(C2-C6alkenylene)-Z; n is 1, 2, 3, or 4;Z is –ONR23R24, -OP(O)OH(CH2)mCO2R23, -OP(S)OH(CH2)mCO2R23, -P(O)(OH)2, -P(O)(OH)(OCH3), -P(O)(OH)(OCD3), -SO2(CH2)mP(O)(OH)2, -SO2NR23R25, - NR23R24, R21and R22are independently hydrogen or C1-C6alkyl; R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or -C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4; and (b) a short interfering nucleic acid (siNA).

70. A short-interfering nucleic acid (siNA) molecule comprising: (a) a 5’-stabilized end cap selected from the group consisting of Formula (1) to Formula (15), Formula (9X) to Formula (12X), and Formula (9Y) to Formula (12Y):Formula (1) Formula (2) Formula (3) Formula (4)Formula (8) Formula (9) Formula (9X) Formula (9Y), wherein R1is anucleobase, aryl, heteroaryl, or H; and (b) a short interfering nucleic acid (siNA).

71. A short-interfering nucleic acid (siNA) molecule comprising: (a) a 5’-stabilized end cap selected from the group consisting of Formulas (1A)- (15A), Formulas (9B)-(12B), Formulas (9AX)-(12AX), Formulas (9AY)- (12AY), Formulas (9BX)-(12BX), and Formulas (9BY)-(12BY):Formula (5A) Formula (6A) Formula (7A)(b) a short interfering nucleic acid (siNA).

72. The siNA molecule according to any one of claims 67-71, wherein the siNA comprises the sense strand of any one of claims 1-66.

73. The siNA molecule according to any one of claims 67-72, wherein the siNA comprises the antisense strand of any one of claims 1-66.

74. A short interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a first nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to an RNA corresponding to a target gene, wherein the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260; and(b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57- 102, 159-204, and 261-306.

75. A interfering nucleic acid (siNA) molecule comprising: (a) a sense strand comprising a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415-444; and (b) an antisense strand comprising a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539.

76. The siNA according to any one of claims 1-66 and 68-75, wherein the siNA further comprises a phosphorylation blocker.

77. The siNA according to any one of claims 10, 65, and 76, wherein the phosphorylation blocker has the structure of Formulawherein R1is a nucleobase, R4is –O-R30or –NR31R32, R30is C1-C8substituted or unsubstituted alkyl; and R31and R32together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring.

78. The siNA of claim 67 or 77, wherein R4is –OCH3or –N(CH2CH2)2O.

79. The siNA according to any one of claims 10, 65, 67, and 76-78, wherein: (i) the phosphorylation blocker is attached to the 5’ end of the sense strand; (ii) the phosphorylation blocker is attached to the 3’ end of the sense strand; (iii) the phosphorylation blocker is attached to the 5’ end of the antisense strand; or (iv) the phosphorylation blocker is attached to the 3’ end of the antisense strand.

80. The siNA of claim 78, wherein:(i) the phosphorylation blocker is attached to the 5’ end of the sense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, and phosphorodithioate linker; (ii) the phosphorylation blocker is attached to the 3’ end of the sense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, and phosphorodithioate linker; (iii) the phosphorylation blocker is attached to the 5’ end of the antisense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, and phosphorodithioate linker; or (iv) the phosphorylation blocker is attached to the 3’ end of the antisense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, and phosphorodithioate linker.

81. The siNA according to any preceding claim, wherein the siNA further comprises a galactosamine.

82. The siNA of claim 10 or 81, wherein the galactosamine is N-acetylgalactosamine (GalNAc) of Formula (VII):, wherein each n is independently 1 or 2.

83. The siNA of claim 10 or 81, wherein the galactosamine is N-acetylgalactosamine (GalNAc) of Formula (wherein m is 1, 2, 3, 4, or 5; each n is independently 1 or 2; p is 0 or 1; each R is independently H; each Y is independently selected from –O-P(=O)(SH)–, –O-P(=O)(O)–, –O-P(=O)(OH)–, and -O-P(S)S-; Z is H or a second protecting group; either L is a linker or L and Y in combination are a linker; and A is H, OH, a third protecting group, an activated group, or an oligonucleotide.

84. The siNA of claim 83, wherein: (i) A is an oligonucleotide; or (ii) A is 1-2 oligonucleotides.

85. The siNA of any one of claim 84, wherein the oligonucleotide is dTdT.

86. The siNA according to any one of claims 10, 84, and 85, wherein the galactosamine is attached to (i) the 3’ end of the sense strand; (ii) the 5’ end of the sense strand; (iii) the 3’ end of the antisense strand; or (iv) the 5’ end of the antisense strand.

87. The siNA of claim 86, wherein the galactosamine is attached to: (i) the 3’ end of the sense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, or phosphorodithioate linker; (ii) the 5’ end of the sense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, or phosphorodithioate linker; (iii) the 3’ end of the atnisense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, or phosphorodithioate linker; or(iv) the 5’ end of the atnisense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, or phosphorodithioate linker.

88. The siNA according to any one of claims 1-67 and 70-87, wherein the siNA further comprises a 5’-stabilized end cap.

89. The siNA according to any one of claims 10, 65, and 88, wherein the 5’-stabilized end cap is a 5’ vinyl phosphonate or deuterated 5’ vinyl phosphonate.

90. The siNA according to any one of claims 10, 65, and 88, wherein the 5’-stabilized end cap has the structure of Formula (Ia):, wherein R1is a nucleobase, aryl, heteroaryl, or H,, , , - , - , - ,n- , –(C2-C6alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n- Z or –(C2-C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, –OP(S)OH(CH2)mCO2R23, –P(O)(OH)2, - P(O)(OH)(OCH3), -P(O)(OH)(OCD3), –SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, or –NR23SO2R24; R21and R22either are independently hydrogen or C1-C6alkyl, or R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or –C(O)R25; orR23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4.

91. The siNA according to any one of claims 65 and 88, wherein the 5’-stabilized end cap has the structure of Formula (Ib):, wherein R1is a nucleobase, aryl, heteroaryl, or H,(C2-C6alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n- Z or –(C2-C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, –OP(S)OH(CH2)mCO2R23, –P(O)(OH)2, - P(O)(OH)(OCH3), -P(O)(OH)(OCD3), –SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, or –NR23SO2R24; R21and R22either are independently hydrogen or C1-C6alkyl, or R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or –C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6 alkyl; and m is 1, 2, 3, or 4.

92. The siNA of claim 90 or 91, wherein R1is an aryl.

93. The siNA of claim 92, wherein the aryl is a phenyl.

94. The siNA according to any one of claims 10, 65, and 88, wherein the 5’-stabilized end cap is selected from the group consisting of Formula (1) to Formula (15), Formula (9X) to Formula (12X), and Formula (9Y) to Formula (12Y):Formula (1) Formula (2) Formula (3) Formula (4)Formula (8) Formula (9) Formula (9X) Formula (9Y)Formula (11) Formula (11X) Formula (11Y)Formula (13) Formula (14) Formula (15) , wherein R1is a nucleobase, aryl, heteroaryl, or H.

95. The siNA according to any one of claims 10, 65, and 88, wherein the 5’-stabilized end cap is selected from the group consisting of Formulas (1A)-(15A), Formulas (9B)- (12B), Formulas (9AX)-(12AX), Formulas (9AY)-(12AY), Formulas (9BX)-(12BX), and Formulas (9BY)-(12BY): O O O O NH NH NHNHO NONOO ON S O OOS OSN O O O O O O O N N N S H H N H O OOCH3 OOCH3 OOCH3 OOCH3Formula (1A) Formula (2A) Formula (3A) Formula (4A) O O O NH NH O NH OON HO P O S OO ON N O SOO HO SOO HN HN O OOCH3 OOCH3 OOCH3Formula (5A) Formula (6A) Formula (7A) O NH HOSNHOOH COO OHO P O O P O3P OD3COP O O HO HO HO O O OCH3O OCH3O OCH3O OCH3Formula (8A) Formula (9A) Formula (9AX) Formula (9AY)Formula (12A) Formula (12AX) Formula (12AY)Formula (13A) Formula (14A) Formula (15A) .

96. The siNA according to any one of claims 65 and 88, wherein the 5’-stabilized end cap has the structure of Formula (Ic):, wherein R1is a nucleobase, aryl, heteroaryl, or H,(C2-C6alkenylene)-Z and R20is hydrogen; or R2and R20together form a 3- to 7-membered carbocyclic ring substituted with –(CR21R22)n- Z or –(C2-C6alkenylene)-Z; n is 1, 2, 3, or 4; Z is –ONR23R24, –OP(O)OH(CH2)mCO2R23, –OP(S)OH(CH2)mCO2R23, –P(O)(OH)2, - P(O)(OH)(OCH3), -P(O)(OH)(OCD3), –SO2(CH2)mP(O)(OH)2, –SO2NR23R25, –NR23R24, or –NR23SO2R24;R21and R22either are independently hydrogen or C1-C6alkyl, or R21and R22together form an oxo group; R23is hydrogen or C1-C6alkyl; R24is –SO2R25or –C(O)R25; or R23and R24together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclic ring; R25is C1-C6alkyl; and m is 1, 2, 3, or 4.

97. The siNA of claim 96, wherein R1is an aryl.

98. The siNA of claim 97, wherein the aryl is a phenyl.

99. The siNA according to any one of claims 10, 65, and 88, wherein the 5’-stabilized end cap is selected from the group consisting of Formula (21) to Formula (35):Formula (21) Formula (22) Formula (23) Formula (24)Formula (25) Formula (26) Formula (27)Formula (34) Formula (35) , wherein R1is a nucleobase, aryl, heteroaryl, or H.

100. The siNA according to any one of claims 10, 65, and 88, wherein the 5’-stabilized end cap is selected from the group consisting of Formulas (21A)-(35A), Formulas (29B)- (32B), Formulas (29AX)-(32AX), Formulas (29AY)-(32AY), Formulas (29BX)-(32BX), and Formulas (29BY)-(32BY):Formula (25A) Formula (26A) Formula (27A)Formula (31B) Formula (31BX) Formula (31BY)Formula (33A) Formula (34A) Formula (35A) , wherein R1is a nucleobase, aryl, heteroaryl, or H.

101. The siNA according to any one of claims 1-100, wherein the antisense strand, sense strand, first nucleotide sequence, and / or second nucleotide sequence comprises at least one thermally destabilizing nucleotide selected from:,102. The siNA according to any one of claims 10, 65, and 88-101, wherein the 5’- stabilized end cap is attached to (i) the 5’ end of the antisense strand; or (ii) the 5’ end of the sense strand.

103. The siNA of claim 102, wherein the 5’-stabilized end cap is attached to: (i) the 5’ end of the antisense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, or phosphorodithioate linker; or (ii) the 5’ end of the sense strand via one or more linkers independently selected from a phosphodiester linker, phosphorothioate linker, or phosphorodithioate linker.

104. The siNA according to any preceding claim, wherein; (i) the target gene is a viral gene; (ii) the target gene is a gene is from a DNA virus. (iii) the target gene is a gene from a double-stranded DNA (dsDNA) virus; . (iv) the target gene is a gene from a hepadnavirus; (v) the target gene is a gene from a a hepatitis B virus (HBV); (vi) the target gene is a gene from a HBV of any one of genotypes A-J; or (vii) the target gene is selected from the S gene or X gene of a HBV.

105. The siNA according to any one of claims 1-104, wherein: (i) the second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30 nucleotides within positions 200-720 or 1100-1700 of SEQ ID NO: 410; (ii) the second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30 nucleotides within positions 200-280, 300-445, 460-510, 650-720, 1170-1220, 1250-1300, or 1550-1630 of SEQ ID NO: 410; (iii) the second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30 nucleotides within positions 200-230, 250-280, 300-330, 370-400, 405-445, 460-500, 670-700, 1180-1210, 1260- 1295, 1520-1550, or 1570-1610 of SEQ ID NO: 410; (iv) the second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30 nucleotides starting at position 203, 206, 254, 305, 375, 409, 412, 415, 416, 419, 462, 466, 467, 674, 676, 1182, 1262, 1263, 1268, 1526, 1577, 1578, 1580, 1581, 1583, or 1584 of SEQ ID NO: 410;(v) the first nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to 15 to 30 nucleotides within positions 200-720 or 1100-1700 of SEQ ID NO: 410; (vi) the first nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to 15 to 30 nucleotides within positions 200-280, 300- 445, 460-510, 650-720, 1170-1220, 1250-1300, or 1550-1630 of SEQ ID NO: 410; (vii) the first nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to 15 to 30 nucleotides within positions 200-230, 250- 280, 300-330, 370-400, 405-445, 460-500, 670-700, 1180-1210, 1260-1295, 1520- 1550, or 1570-1610 of SEQ ID NO: 410; and / or (viii) the first nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to 15 to 30 nucleotides starting at position 203, 206, 254, 305, 375, 409, 412, 415, 416, 419, 462, 466, 467, 674, 676, 1182, 1262, 1263, 1268, 1526, 1577, 1578, 1580, 1581, 1583, or 1584 of SEQ ID NO:

410.

106. The siNA according to any preceding claim, wherein: (i) the first nucleotide sequence comprises a nucleotide sequence of any one SEQ ID NOs: 1-56, 103-158, and 205-260; (ii) the second nucleotide sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 57-102, 159-204, and 261-306; (iii) the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 307-362 and 415-444; and / or (iv) the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 363-409, 445-533, and 536-539.

107. The siNA according to any preceding claim, wherein: (i) at least one end of the siNA is a blunt end; (ii) at least one end of the siNA comprises an overhang, wherein the overhang comprises at least one nucleotide; or (iii) both ends of the siNA comprise an overhang, wherein the overhang comprises at least one nucleotide.

108. The siNA according to any preceding claim, wherein the siNA is selected from ds- siNA-001 to ds-siNA-0178.

109. The siNA according to any preceding claim, wherein at least one 2’-fluoro nucleotide or 2’-O-methyl nucleotide is a 2’-fluoro or 2-O-methyl nucleotide mimic of Formula (V):, wherein R1is independently a nucleobase, aryl, heteroaryl, or H, Q1and Q2are independently S or O, R5is independently –OCD3, –F, or –OCH3, and R6and R7are independently H, D, or CD3.

110. The siNA of claim 109, wherein the 2’-fluoro or 2’-O-methyl nucleotide mimic is a nucleotide mimic of Formula (16) – Formula (20):Formula (16) Formula (17) Formula (18) Formula (19) Formula (20) , wherein R1is a nucleobase and R2is independently F or –OCH3.

111. The siNA according to any preceding claim, wherein at least one 2’-fluoro nucleotide is a 2’-fluoro nucleotide mimic.

112. The siNA according to claim 111, wherein: (i) at least 1, 2, 3, 4, 5, or more 2’-fluoro nucleotides on the antisense strand or the second nucleotide sequence is a 2’-fluoro nucleotide mimic; (ii) the nucleotide at position 2, 5, 6, 8, 10, 14, 16, and / or 17 from the 5’ end of the antisense strand or the second nucleotide sequence is a 2’-fluoro nucleotide mimic; (iii) at least 1, 2, 3, 4, 5, or more 2’-fluoro nucleotides on the sense strand or the first nucleotide sequence is a 2’-fluoro nucleotide mimic; and / or (iv) the nucleotide at position 3, 5, 7, 8, 9, 10, 11,12, 14, and / or 17 from the 5’ end of the sense strand or the first nucleotide sequence is a 2’-fluoro nucleotide mimic.

113. The siNA according to any one of claims 111-112, wherein:(i) at least 1, 2, 3, 4, 5, 6, or more 2’-fluoro nucleotide mimics is a f4P nucleotide ((ii) less than or equal to 10, 9, 8, 7, 6, 5, 4, 3, or 22’-fluoro nucleotide mimics is a f4P nucleotide(iii) 1, 2, 3, 4, 5, 6, or more 2’-fluoro nucleotide mimics is a f2P nucleotide ((iv) less than or equal to 10, 9, 8, 7, 6, 5, 4, 3, or 22’-fluoro nucleotide mimics is a f2P nucleotide(v) 1, 2, 3, 4, 5, 6, or more 2’-fluoro nucleotide mimics is a fX nucleotide (); and / or (vi) less than or equal to 10, 9, 8, 7, 6, 5, 4, 3, or 22’-fluoro nucleotide mimics is a fX nucleotide ().

114. The siNA according to any preceding claim, wherein: (i) the first nucleotide from the 5’ end of the antisense strand or second nucleotide sequence is a d2vd3 nucleotide); and / or (ii) the first nucleotide from the 3’ end of the antisense strand or second nucleotide sequence is a d2vd3 nucleotide).

115. A composition comprising: (I) (a) the siNA according to any one of claims 1-114; and (b) a pharmaceutically acceptable excipient; (II) 2, 3, 4, 5, 6, 7, 8, 9, 10 or more siNAs according to any one of claims 1-114; or (III) (a) 2, 3, 4, 5, 6, 7, 8, 9, 10 or more siNAs according to any one of claims 1-114; and (b) a pharmaceutically acceptable excipient; 116. The composition of claim 115, wherein: (i) at least 1, 2, 3, 4, 5, or more siNAs target an S gene of HBV; and / or (ii) at least 1, 2, 3, 4, 5, or more siNAs target an X gene of HBV.

117. The composition according to any one of claims 115-116, further comprising: (i) an additional HBV treatment agent; (ii) an additional HBV treatment agent selected from a nucleotide analog, nucleoside analog, a capsid assembly modulator (CAM), a recombinant interferon, an entry inhibitor, a small molecule immunomodulator and oligonucleotide therapy; (iii) an additional siNA; (iv) an additional siNA selected from any of ds-siNA-001 to ds-siNA-0178; (v) an oligonucleotide therapy selected from an antisense oligonucleotide (ASO), NAPs, or STOPs; (vi) an ASO selected from ASO 1 or ASO 2; and / or(vii) an additional HBV treatment agent selected from HBV STOPSTMALG- 010133, HBV CAM ALG-000184, ASO 1, recombinant interferon alpha 2b, IFN-a, PEG-IFN-a-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil, NVR3-778, BAY41-4109, JNJ-632, JNJ-3989 (ARO-HBV), RG6004, GSK3228836, REP-2139, REP-2165, AB-729, VIR-2218, RG6346 (DCR-HBVS), JNJ-6379, GLS4, ABI-HO731, JNJ-440, NZ-4, RG7907, EDP-514, AB-423, AB-506, ABI-H03733 and ABI-H2158.

118. Use of the siNA according to any one of claims 1-114 or the composition according to any one of claims 115-117 in the manufacture of a medicament for treating a disease.

119. The use of claim 118, wherein: (i) the disease is a viral disease; (ii) the disease is caused by a DNA virus; (iii) the disease is caused by a double stranded DNA (dsDNA virus); (iv) the disease is caused by a hepadnavirus; (v) the disease is caused by a hepatitis B virus (HBV); or (vi) the disease is caused by a HBV of any one of HBV genotypes A-J.

120. The use of any of one of claims 118-119, further comprising: (i) an additional HBV treatment agent in the manufacture of the medicament; (ii) an additional HBV treatment agent selected from a nucleotide analog, nucleoside analog, a capsid assembly modulator (CAM), a recombinant interferon, an entry inhibitor, a small molecule immunomodulator and oligonucleotide therapy; (iii) an additional siNA; (iv) an additional siNA selected from any of ds-siNA-001 to ds-siNA-0178; (v) an oligonucleotide therapy selected from an antisense oligonucleotide (ASO), NAPs, or STOPs; (vi) an ASO selected from ASO 1 and ASO 2; and / or (vii) an additional HBV treatment agent selected from HBV STOPSTMALG- 010133, HBV CAM ALG-000184, ASO 1, recombinant interferon alpha 2b, IFN-a, PEG-IFN-a-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil, NVR3-778, BAY41-4109, JNJ-632, JNJ-3989 (ARO-HBV), RG6004, GSK3228836, REP-2139, REP-2165, AB-729,VIR-2218, RG6346 (DCR-HBVS), JNJ-6379, GLS4, ABI-HO731, JNJ-440, NZ-4, RG7907, EDP-514, AB-423, AB-506, ABI-H03733 and ABI-H2158.

121. The use of claim 118, wherein: (i) the disease is a liver disease; (ii) the disease is a nonalcoholic fatty liver disease (NAFLD) or hepatocellular carcinoma (HCC); or (iii) the disease is nonalcoholic steatohepatitis (NASH).

122. The use of any of claims 118 and 121, further comprising a liver disease treatment agent in the manufacture of the medicament.

123. The use of claim 122, wherein: (i) the liver disease treatment agent is selected from a peroxisome proliferator- activator receptor (PPAR) agonist, farnesoid X receptor (FXR) agonist, lipid- altering agent, and incretin-based therapy; (ii) the liver disease treatment agent is a PPAR agonist is selected from a PPARα agonist, dual PPARα / δ agonist, PPARγ agonist, and dual PPARα / γ agonist; or (iii) the liver disease treatment agent is selected from a fibrate, elafibranor, thiazolidinedione (TZD), pioglitazone, saroglitazar, obeticholic acis (OCA), aramchol, glucagon-like peptide 1 (GLP-1) receptor agonist, dipeptidyl peptidase 4 (DPP-4) inhibitor, exenatide,liraglutide sitagliptin, and vildapliptin.

124. The siNA according to any one of claims 1-114 for use as a medicament.

125. The composition according to any one of claims 115-117 for use as a medicament.

126. The siNA according to any one of claims 1-114 for use in the treatment of a disease.

127. The siNA of claim 126, wherein: (i) the disease is a viral disease. (ii) the disease is caused by a DNA virus; (iii) the disease is caused by a double stranded DNA (dsDNA virus); (iv) the disease is caused by hepadnavirus; (v) the disease is caused by a hepatitis B virus (HBV); (vi) the disease is caused by a HBV of any one of HBV genotypes A-J;(vii) the disease is a liver disease; (viii) the disease is a nonalcoholic fatty liver disease (NAFLD) or hepatocellular carcinoma (HCC); or (ix) the disease is nonalcoholic steatohepatitis (NASH).

128. The composition according to any one of claims 115-117, for use in the treatment of a disease.

129. The composition of claim 128, wherein: (i) the disease is a viral disease. (ii) the disease is caused by a DNA virus; (iii) the disease is caused by a double stranded DNA (dsDNA virus); (iv) the disease is caused by hepadnavirus; (v) the disease is caused by a hepatitis B virus (HBV); (vi) the disease is caused by a HBV of any one of HBV genotypes A-J; (vii) the disease is a liver disease; (viii) the disease is a nonalcoholic fatty liver disease (NAFLD) or hepatocellular carcinoma (HCC); or (ix) the disease is nonalcoholic steatohepatitis (NASH).