Nucleic acid-polypeptide compositions and uses thereof

1. A pharmaceutical composition comprising:

a molecule of Formula (I):

A-X—B—Y—C   Formula I

wherein,

A is an antibody or its binding fragments thereof;

B consists of a double-stranded siRNA consisting of a passenger strand and a guide strand;

C consists of a polymer; and

X and Y are each independently a linker selected from the group consisting of a heterobifunctional linker, a homobifunctional linker, a maleimide group, a dipeptide moiety, a benzoic acid group or derivatives thereof, a C 1 -C 6 alkyl group, and a combination thereof; and

a pharmaceutically acceptable excipient;

wherein:

the double-stranded siRNA comprises at least one 2′ modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety;

A and C are attached in the same strand, but not at the same terminus; and

A-X and Y—C are conjugated to the passenger strand.

2. The pharmaceutical composition of claim 1 , wherein the guide strand hybridizes to a target region of a gene selected from the group consisting of KRAS, EGFR, AR, CTNNB1, PIK3CA, PIK3CB, MYC, and HPRT1.

3. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for the treatment of a solid tumor.

4. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for the treatment of breast cancer, lung cancer, ovarian cancer, prostate cancer, or skin cancer.

5. The pharmaceutical composition of claim 1 , wherein the at least one 2′ modified nucleotide comprises 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl, 2′-deoxy, 2'-deoxy-2′-fluoro, 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2'-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), or 2′-O—N-methylacetamido (2′-O-NMA) modified nucleotide.

6. The pharmaceutical composition of claim 1 , wherein the at least one 2′ modified nucleotide comprises locked nucleic acid (LNA) or ethylene nucleic acid (ENA).

7. The pharmaceutical composition of claim 1 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.

8. The pharmaceutical composition of claim 1 , wherein the at least one inverted abasic moiety is at at least one terminus.

9. The pharmaceutical composition of claim 1 , wherein the guide strand comprises a sequence having at least 80% sequence identity to SEQ ID NOs: 16-75, 452-1955, 1956-1962, 1967-2002, 2013-2032, 2082-2109, or 2117.

10. The pharmaceutical composition of claim 1 , wherein the antibody or binding fragment thereof comprises a humanized antibody or binding fragment thereof, chimeric antibody or binding fragment thereof, monoclonal antibody or binding fragment thereof, monovalent Fab′, divalent Fab2, single-chain variable fragment (scFv), diabody, minibody, nanobody, single-domain antibody (sdAb), or camelid antibody or binding fragment thereof.

11. The pharmaceutical composition of claim 1 , wherein the antibody or binding fragment thereof is an anti-transferrin receptor antibody or binding fragment thereof.

12. The pharmaceutical composition of claim 1 , wherein C is polyethylene glycol.

13. The pharmaceutical composition of claim 12 , wherein C has a molecular weight from about 1000 Da to about 5000 Da.

14. The pharmaceutical composition of claim 12 , wherein C has a molecular weight of about 1000 Da, 2000 Da, or 5000 Da.

15. The pharmaceutical composition of claim 1 , wherein A-X is conjugated to the 5′ end of the passenger strand and Y—C is conjugated to the 3′ end of the passenger strand.

16. The pharmaceutical composition of claim 1 , wherein Y—C is conjugated to the 5′ end of the passenger strand and A-X is conjugated to the 3′ end of the passenger strand.