MUSCLE-TARGETED COMPLEXES AND THEIR USES FOR THE TREATMENT OF DYSTROPHINOPATHIES.

Abstract

The present invention relates to a complex characterized in that it comprises an anti-transferrin receptor antibody covalently linked to a dystrophin-targeting oligonucleotide (DMD) in a muscle cell, wherein the oligonucleotide is configured to promote DMD expression or activity, has a length of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 35 nucleotides, and comprises a region complementary to a DMD sequence, wherein the complementary region has a length of at least 12 nucleotides; wherein the oligonucleotide is a phosphorodiamidate (PMO) morpholino oligomer; wherein the oligonucleotide is covalently linked to the anti-transferrin receptor antibody via a cleavable linker, wherein the cleavable linker comprises a valine-citrulline sequence;and wherein the anti-transferrin receptor antibody binds in the C89 to F760 range of the transferrin receptor 1 (TfR1) protein having an amino acid sequence established in any of SEQ ID NO: 1-3, permits the binding of transferrin to TfR1, and cross-reacts with extracellular epitopes of two or more of a human, non-human primate, and rodent transferrin receptor.

Description

MUSCLE TARGETED COMPLEXES AND THEIR USES FOR THE TREATMENT OF DYSTROPHINOPATHIES RELATED REQUESTS This application claims the benefit of the U.S. Provisional Application filing date. No. 62 / 714,031, entitled MUSCLE TARGETING COMPLEXES AND USES THEREOF FOR TREATING DYSTROPHINOPATHIES, filed August 2, 2018; and the U.S. Provisional Application No. 62 / 855,766, entitled MUSCLE TARGETING COMPLEXES AND USES THEREOF FOR TREATING DYSTROPHINOPATHIES, filed May 31, 2019; the contents of each of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION The present application relates to targeting complexes for the delivery of molecular payloads (eg, oligonucleotides) to cells and uses thereof, particularly uses related to the treatment of diseases. REFERENCE TO SEQUENCE LISTING This application is being submitted together with the Sequence Listing in electronic format. The Sequence Listing is provided as a file titled D082470008WO00-SEQ.txt created on July 31, 2019 that is 102 kilobytes in size. The information in electronic format of the sequence listing is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION Dystrophinopathies are a group of different neuromuscular diseases that result from mutations in the dystrophin gene. Dystrophinopathies include Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked dilated cardiomyopathy. Dystrophin (DMD) is a large gene, containing 79 exons and ~2.6 million base pairs in total. Numerous DMD mutations, including exonic frameshift, deletion, substitution, and duplicative mutations, are capable of decreasing functional dystrophin expression, leading to dystrophinopathies. An agent that targets exon 51 of human DMD, eteplirsen, has Garran / Lznz / q / YiAi has been preliminarily approved by the US Food and Drug Administration (FDA) however its efficacy is still being evaluated. BRIEF DESCRIPTION OF THE INVENTION In accordance with some aspects, the disclosure provides targeting complexes to muscle cells for purposes of delivering molecular payloads to those cells. In some embodiments, the complexes provided herein are particularly useful for the delivery of molecular payloads that increase or restore functional DMD expression or activity. In some embodiments, the complexes comprise oligonucleotide-based molecular payloads that promote normal expression of functional DMD through an in-frame exon skipping or stop codon suppression mechanism. In other embodiments, the complexes are configured for delivery of a dystrophin minigene or synthetic mRNA that increases or restores functional dystrophin activity. Accordingly, in some embodiments, the complexes provided herein comprise muscle-targeting agents (eg, muscle-targeting antibodies) that specifically bind to receptors on the surface of muscle cells for purposes of delivering molecular payloads. to muscle cells. In some embodiments, the complexes are taken up into cells via receptor-mediated internalization, after which the molecular payload can be released to perform a function within the cells. For example, complexes designed to deliver oligonucleotides can deliver the oligonucleotides so that the oligonucleotides can promote expression of functional DMD (eg, through an exon skipping mechanism) in muscle cells. In some embodiments, the oligonucleotides are released by endosomal cleavage of covalent linkers connecting the oligonucleotides and muscle targeting agents from the complexes. Aspects of the disclosure comprise a complex comprising a muscle-targeting agent covalently linked to a molecular payload configured to promote the expression or activity of a DMD, wherein the muscle-targeting agent specifically binds to an internalizing receptor. cell surface area in muscle cells. In some embodiments, the muscle-targeting agent is a muscle-targeting antibody. In some embodiments, a muscle-targeting antibody is an antibody that specifically binds to an extracellular epitope of a transferrin receptor (eg, a transferrin receptor apical domain epitope). A muscle-targeting antibody can specifically bind to an epitope of a sequence in the aarrbn / i 7n7 / 3i / υιλι range from C89 to F760 of SEQ ID NO: 1-3. In some embodiments, the equilibrium dissociation constant (Kd) of binding of a muscle-targeting antibody to a transferrin receptor ranges from 10'11M to ΙΟ'6M. In some embodiments, a muscle-targeting antibody in a complex competes for specific binding to a transferrin receptor epitope with an antibody listed in Table 1 (eg, competes for specific binding to a transferrin receptor epitope). transferrin with a Kd of less than or equal to ΙΟ'6M, eg, in a range of 10'11M to ΙΟ'6M). In some embodiments, a muscle-targeting antibody of a complex does not specifically bind to the transferrin binding site of a transferrin receptor and / or does not inhibit transferrin binding to a transferrin receptor. In some embodiments, a muscle-targeting antibody of a complex cross-reacts with extracellular epitopes of two or more of a human, non-human primate, and rodent transferrin receptor. In some embodiments, a muscle-targeting antibody of a complex is configured to promote transferrin receptor-mediated internalization of the molecular payload into a muscle cell. A muscle-targeting antibody (eg, the muscle-targeting antibody is an antibody that specifically binds to an extracellular epitope of a transferrin receptor) is a chimeric antibody, optionally where the chimeric antibody is a humanized monoclonal antibody. A muscle-targeting antibody may be in the form of a ScFv, Fab fragment, Fab' fragment, F(ab')2 fragment, or Fv fragment. In some embodiments, a molecular payload of a complex is an oligonucleotide. In some embodiments, an oligonucleotide comprises a sequence listed in Table 2. In some embodiments, an oligonucleotide comprises a sequence as provided in any of SEQ ID NO: 15-266. In some embodiments, an oligonucleotide comprises a region of complementarity to a mutated DMD allele. In some embodiments, an oligonucleotide is configured to delete a truncating mutation in a single- or multi-exon skipping DMD allele. In some embodiments, an oligonucleotide promotes antisense mediated exon skipping to produce dystrophin mRNA in frame. In some embodiments, an oligonucleotide promotes DMD exon skipping in the exon 8 to exon 55 range (eg, exon 23 to exon 53). In some embodiments, an oligonucleotide promotes skipping of exon 8, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, and / or exon 55. In some embodiments, an oligonucleotide promotes skipping of multiple exons in the range of exon 44 to exon 53. QQPPbn / l 7Π7 / Σ1 / ΥΙΛΙ An oligonucleotide of the disclosure may comprise at least one modified internucleotide linkage (eg, a phosphorothioate linkage). In some embodiments, an oligonucleotide comprises phosphorothioate linkages in the Rp stereochemical conformation and in the Sp stereochemical conformation. In some embodiments, an oligonucleotide comprises phosphorothioate linkages all of which are in the Rp stereochemical conformation. In other embodiments, an oligonucleotide comprises phosphorothioate linkages all of which are in the Sp stereochemical conformation. An oligonucleotide of the disclosure may comprise one or more modified nucleotides (eg, 2' modified nucleotides). In some embodiments, a modified nucleotide is a 2'-O-methyl, 2'-fluoro (2'-F), 2'-O-methoxyethyl (2'-MOE), or 2',4' bridged nucleotide. In some embodiments, a modified nucleotide is a bridged nucleotide (eg, selected from: 2',4'-restricted 2'-O-ethyl (cEt) and locked nucleic acid (LNA) nucleotides). In some embodiments, an oligonucleotide is a gapmer oligonucleotide that directs the seRNAH-mediated cleavage of a miRNA that negatively regulates DMD expression in a cell, optionally where the miRNA is m¡R-31. A gapmer oligonucleotide may comprise a central portion of 5 to 15 deoxyribonucleotides flanked by wings of 2 to 8 modified nucleotides (eg, 2' modified nucleotides). In some embodiments, an oligonucleotide is a mixmer oligonucleotide. In some embodiments, a mixmer oligonucleotide promotes exon skipping. A mixmer oligonucleotide can comprise two or more different 2' modified nucleotides. In some embodiments, an oligonucleotide is an RNAi oligonucleotide that promotes RNAi-mediated cleavage of a miRNA that downregulates DMD expression in a cell, optionally where the miRNA is miR-31. An RNAi oligonucleotide can be a double-stranded oligonucleotide from 19 to 25 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises at least one 2' modified nucleotide. In some embodiments, an oligonucleotide comprises a guide sequence for a genome-editing nuclease. In some embodiments, an oligonucleotide is a morpholino phosphorodiamidate (PMO) oligomer. In other embodiments, a molecular payload is a polypeptide. In some embodiments, a molecular payload is a polypeptide that is a functional fragment of dystrophin protein. In some embodiments, a muscle-targeting agent is covalently linked to a molecular payload via a cleavable linker (for example, a protease-sensitive aarrbn / i 7η7 / =ι / γΐΛΐ linker, pH-sensitive linker, or pH-sensitive linker). glutathione). A protease sensitive linker may comprise a sequence cleavable by a lysosomal protease and / or an endosomal protease. In some embodiments, a protease sensitive linker comprises a valine-citrulline dipeptide sequence. A pH sensitive linker can be cleaved at a pH in the range of 4 to 6. In some embodiments, a muscle-targeting agent is covalently linked to a molecular payload via a non-cleavable linker (eg, an alkane linker). In some embodiments, a muscle-targeting antibody comprises an unnatural amino acid to which an oligonucleotide can be covalently linked. In some embodiments, a muscle-targeting antibody is covalently linked to an oligonucleotide via conjugation to a lysine residue or a cysteine ​​residue of the antibody. In some embodiments, an oligonucleotide is conjugated to a cysteine ​​residue of the antibody via a maleimide-containing linker, optionally wherein the maleimide-containing linker comprises a maleimidocaproyl or maleimidomethyl cyclohexane-1-carboxylate group. In some embodiments, a muscle-targeting antibody is a glycosylated antibody comprising at least one sugar moiety to which an oligonucleotide is covalently linked. In some embodiments, a glycosylated antibody comprises at least one sugar moiety that is a branched mannose. In some embodiments, a muscle-targeting antibody is a glycosylated antibody comprising one to four sugar moieties each of which is covalently linked to a separate oligonucleotide. In some embodiments, a muscle-targeting antibody is a fully glycated antibody or a partially glycated antibody. A partially glycosylated antibody can be produced via chemical or enzymatic means. In some embodiments, a partially glycosylated antibody is produced in a cell that is deficient in an enzyme in the N- or O-glycosylation pathway. Some aspects of the disclosure comprise a method of delivering a molecular payload to a cell expressing the transferrin receptor. In some embodiments, methods of delivering a molecular payload to a cell expressing the transferrin receptor comprise contacting the cell with a complex comprising a muscle-targeting agent covalently linked to a molecular payload configured to promote expression. or activity of a DMD. Some aspects of the disclosure comprise a method of promoting the expression or activity of a DMD protein in a cell. In some embodiments, methods of promoting the expression or activity of a DMD protein in a cell comprise contacting αοΓΓπη / ι 7η7 / =ι / γΐΛΐ the cell with a complex comprising a muscle targeting agent covalently linked to a molecular payload configured to promote the expression or activity of a DMD in an amount effective to promote internalization of the molecular payload into the cell. In some embodiments, the cell is in vitro. In some embodiments, the cell is in a subject. In some embodiments, the subject is a human. Additional aspects of the disclosure comprise a method of treating a subject having a mutated DMD allele that is associated with a dystrophinopathy. In some embodiments, methods of treating a subject having a mutated DMD allele that is associated with a dystrophinopathy comprise administering to the subject an effective amount of a complex comprising a muscle-targeting agent covalently linked to a configured molecular payload. to promote the expression or activity of a DMD. Still further aspects of the disclosure comprise a method of promoting exon skipping of a DMD mRNA transcript in a cell. In some embodiments, methods of promoting exon skipping of a DMD mRNA transcript comprise administering to the cell an effective amount of the complex comprising a muscle-targeting agent covalently linked to a configured molecular payload to promote expression. or activity of a DMD. In some embodiments, the methods promote skipping of exon 8, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, and / or exon 55 of the DMD mRNA transcript. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 represents a non-limiting scheme showing the effect of transfecting cells with an siRNA. Figure 2 represents a non-limiting schematic showing the activity of a muscle targeting complex comprising a siRNA. Figures 3A to 3B represent non-limiting schematics showing the activity of a muscle targeting complex comprising an siRNA in mouse muscle tissues (gastrocnemius and heart) in vivo, relative to control experiments. (N=4 C57BL / 6 WT mice) Figures 4A to 4E represent non-limiting schematics showing the tissue selectivity of a muscle targeting complex comprising a siRNA. aarrbn / i 7Π7 / =ι / υιλι DETAILED DESCRIPTION OF THE INVENTION Aspects of the disclosure relate to a recognition that although certain molecular payloads (eg, oligonucleotides, peptides, small molecules) may have beneficial effects on muscle cells, effectively targeting such cells has proven challenging. As described herein, the present disclosure provides complexes comprising muscle-targeting agents covalently linked to molecular payloads to overcome such challenges. In some embodiments, the complexes are particularly useful for the delivery of molecular payloads that modulate (eg, promote) the expression or activity of target genes in muscle cells, eg, in a subject having or suspected of having a rare muscle disease. For example, in some embodiments, DMD targeting complexes are provided, eg, a mutated DMD allele. In some embodiments, the complexes provided herein may comprise oligonucleotides that promote the normal expression and activity of DMD. As another example, the complexes can comprise oligonucleotides that induce exon skipping of DMD mRNA. In some embodiments, synthetic nucleic acid payloads (eg, DNA or RNA payloads) may be used that express one or more proteins that promote normal expression and activity of DMD. In some embodiments, the complexes may comprise molecular payloads of synthetic cDNA and / or synthetic mRNA, eg, expressing dystrophin or fragments thereof (eg, a dystrophin minigene). In some embodiments, the complexes may comprise molecular payloads such as guide molecules (eg, guide RNA) that are capable of targeting programmable nucleic acid nucleases (eg, Cas9) to a sequence at or near a disease-associated DMD mutation, eg, a mutated DMD exon. In some embodiments, such programmable nucleic acid nucleases could be used to excise part or all of a disease-associated DMD mutation, eg, a mutated DMD exon, to promote expression of functional DMD. In some embodiments, the complexes may comprise molecular payloads that upregulate the expression and / or activity of genes that can replace dystrophin function, such as utrophin. Other aspects of the description, including a description of defined terms, are provided below. Qorrbn / iznz / q / YiAi Definitions Administration: As used herein, the terms "administer" or "administration" mean providing a complex to a subject in a manner that is physiologically and / or pharmacologically useful (eg, to treat a condition in the subject). Approximately As used herein, the term approximately or close to, as applied to one or more values ​​of interest, refers to a value that is similar to an established reference value. In certain embodiments, the term approximately or close to refers to a range of values ​​that falls within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%. , 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) from the stated reference value unless otherwise stated or otherwise apparent from the context (except when such a number could exceed 100% of a possible value). Antibody: As used herein, the term "antibody" refers to a polypeptide that includes at least one immunoglobulin variable domain or at least one antigenic determinant, eg, paratope that specifically binds to an antigen. In some embodiments, an antibody is a full length antibody. In some embodiments, an antibody is a chimeric antibody. In some embodiments, an antibody is a humanized antibody. However, in some embodiments, an antibody is a Fab fragment, F(ab')2 fragment, Fv fragment, or scFv fragment. In some embodiments, an antibody is a camelid antibody-derived nanobody or a shark antibody-derived nanobody. In some embodiments, an antibody is a diabody. In some embodiments, an antibody comprises a framework having a human germ line sequence. In another embodiment, an antibody comprises a heavy chain constant domain selected from the group consisting of IgG, IgGl, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgAl, IgA2, IgD, IgM, and IgE constant domains. In some embodiments, an antibody comprises a heavy (H) chain variable region (abbreviated herein as VH), and / or a light (L) chain variable region (abbreviated herein as VL). In some embodiments, an antibody comprises a constant domain, eg, an Fe region. An immunoglobulin constant domain refers to a heavy or light chain constant domain. The human IgG heavy chain and light chain constant domain amino acid sequences and their functional variations are known. With respect to the heavy chain, in some embodiments, the heavy chain of an antibody described herein may be an alpha (a), delta (Δ), epsilon (e), gamma (y), or mu (μ) heavy chain. . In some embodiments, the heavy chain of an antibody described herein may comprise a human alpha (a), delta (Δ), epsilon (ε), gamma (y) or mu (μ) heavy chain. In a particular embodiment, an antibody described herein comprises a human CH1, CH2, and / or CH3 gamma 1 domain. In some embodiments, the amino acid sequence of the VH domain comprises the amino acid sequence of a human gamma (y) heavy chain constant region such as any known in the art. aarrbn / i 7Π7 / 3 / ΥΙΛΙ Non-limiting examples of human constant region sequences have been described in the art, for example, see US Pat. from the U.S.A. No. 5,693,780 and Kabat E A et al., (1991) supra. In some embodiments, the VH domain comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identical to any of the variable chain constant regions that are provided herein. In some embodiments, an antibody is modified, eg, modified via glycosylation, phosphorylation, sumoylation, and / or methylation. In some embodiments, an antibody is a glycosylated antibody, which is conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and / or phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glucans. In some embodiments, the one or more sugar or carbohydrate molecules is a branched oligosaccharide or a branched glucan. In some embodiments, the one or more sugar or carbohydrate molecules include a mannose unit, a glucose unit, a N-acetylglucosamine unit, an N-acetylgalactosamine unit, a galactose unit, a fucose unit, or a N-acetylgalactosamine unit. phospholipid. In some embodiments, an antibody is a construct comprising a polypeptide comprising one or more antigen-binding fragments of the disclosure linked to a linker polypeptide or immunoglobulin constant domain. Linker polypeptides comprise two or more amino acid residues linked by peptide bonds and are used to link one or more antigen-binding moieties. Examples of linker polypeptides have been reported (see for example, Holliger, P., et al. (1993) Proc. Nati. Acad. Sci. USA 90:6444-6448; Poljak, R. 1, et al. (1994) Structure 2:1121-1123). Furthermore, an antibody may be part of a larger immunoadhesion molecule, formed by covalent or non-covalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include the use of the streptavidin core region to form a tetrameric scFv molecule (Kipriyanov, S.M., et al. (1995) Human Antibodies and Hybridomas 6:93-101) and the use of a residue cysteine, a marker peptide and a C-terminal polyhistidine tag to form bivalent and biotinylated scFv molecules (Kipriyanov, S.M., et al. (1994) Mol. Immunol. 31:1047-1058). CDR: As used herein, the term CDR refers to the complementarity determining region within the variable sequences of the antibody. There are three CDRs in each of the heavy chain and light chain variable regions, designated CDR1, CDR2 and CDR3, for each of the variable regions. The term "CDR pool" as used herein refers to a group of three CDRs that exist in a single variable region capable of binding antigen. The exact boundaries of these CDRs have been defined differently than Qorrbn / iznz / q / YiAi according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries that define the three CDRs. These CDRs may be referred to as Kabat CDRs. Subportions of the CDRs may be designated L1, L2, and L3 or H1, H2, and H3 where the L and H designate the light chain and heavy chain regions, respectively.These regions can be referred to as Chothia CDRs, which have boundaries that overlap with the Kabat CDRs.Other boundaries that define the overlapping CDRs with Kabat CDRs have been described by Padlan (FASEB 1 9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)).Even other CDR boundary definitions may do not strictly follow one of the above systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even CDRs complete cells do not significantly impact antigen binding. The methods used herein can use the CDRs defined according to any of these systems, although preferred embodiments use the CDRs defined by Kabat or Chothia. CDR-grafted antibody: The term "CDR-grafted antibody" refers to antibodies comprising heavy and light chain variable region sequences from one species but in which the sequences of one or more of the VH and / or VL CDR regions are replaced with CDR sequences from another species, such as antibodies having heavy and light chain variable regions in which one or more of the murine CDRs (eg, CDR3) have been replaced with human CDR sequences. Chimeric antibody: The term "chimeric antibody" refers to antibodies comprising heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions. Complementary As used herein, the term "complementary" refers to the ability of precise matching between two nucleotides or two sets of nucleotides. In particular, complementary is a term that characterizes an extension of the hydrogen bond pairing that causes the union between two nucleotides or two sets of nucleotides. For example, if a base at one position in an oligonucleotide is capable of hydrogen bonding with a base at the corresponding position in a target nucleic acid (eg, an mRNA), then the bases are considered to be complementary to each other in that position. Base pairings can include both canonical Watson-Crick base pairing as well as non-Watson-Crick base pairing (for example, Wobble base pairing and ΟΟΓΓΠη / I 7Π7 / 3 / ΥΙΛΙ Hoogsteen base pairing). For example, in some embodiments, for complementary base pairings, adenosine (A)-like bases are complementary to thymidine (T)-like bases or uracil (U)-like bases, those cytosine (C)-like bases are complementary. to guanosine (G)-like bases, and such universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize to and are considered complementary to any of A, C, U, or T. Inosine (I) has also been considered in technique as a universal basis and is considered complementary to any of A, C, U or T. Conservative Amino Acid Substitution: As used herein, a conservative amino acid substitution refers to an amino acid substitution that does not alter the charge- or size-related characteristics of the protein in which the amino acid substitution is made. Variants may be prepared according to methods for altering the sequence of the polypeptide known to one of ordinary skill in the art as found in references compiling such methods, for example Molecular Cloning: A Laboratory Manual, 1 Sambrook, et al. al., eds., Fourth Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2012, or Current Protocols in Molecular Biology, F.M. Ausubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative amino acid substitutions include substitutions made between amino acids within the following groups: (a) Μ, I, L, V; (b) F,Y,W; (c) K, R, H; (d) A, G; (its T; (f) Q,N; and (g) E, D. Covalently Linked: As used herein, the term "covalently linked" refers to a characteristic of two or more molecules that are linked together via at least one covalent bond. In some embodiments, two molecules can be covalently linked together by a single bond, eg, a disulfide bond or disulfide bridge, which serves as a linker between the molecules. However, in some embodiments, two or more molecules can be covalently linked together via a molecule that serves as a linker that joins the two or more molecules together through multiple covalent bonds. In some embodiments, a linker may be a cleavable linker. However, in some embodiments, a linker may be a non-cleavable linker. Cross-reactivity: As used herein and in the context of a targeting agent (eg, antibody), the term cross-reactivity refers to a property of the agent that it is capable of specifically binding to more than one antigen of a similar type or class (eg, multiple homologous, parologous, or orthologous antigens) with similar affinity or avidity. For example, in some embodiments, an antibody that cross-reacts against human and non-human primate antigens of a similar type or class (for example, a human transferrin receptor and a non-human primate transferrin receptor) is capable of binding to human antigen and non-human primate antigens with a similar affinity or avidity. In QQPPbn / l 7Π7 / Σ1 / ΥΙΛΙ In some embodiments, an antibody cross-reacts against a human antigen and a rodent antigen of a similar type or class. In some embodiments, an antibody cross-reacts against a rodent antigen and a non-human primate antigen of a similar type or class. In some embodiments, an antibody cross-reacts against a human antigen, a non-human primate antigen, and a rodent antigen of a similar type or class. DMD: As used herein, the term DMD refers to a gene that encodes the protein dystrophin, a key component of the dystrophin-glycoprotein complex, which bridges the inner cytoskeleton and extracellular matrix in muscle cells, particularly muscle fibers. Deletions, duplications, and point mutations in DMD can cause dystrophinopathies, such as Duchenne muscular dystrophy, Becker muscular dystrophy, or cardiomyopathy. The use of alternative promoter and alternative splicing results in numerous different transcript variants and protein isoforms for this gene. In some embodiments, a dystrophin gene can be a human (gene ID: 1756), non-human primate (eg, gene ID: 465559), or rodent (eg, gene ID: 13405; ID of gene: 24907). In addition, multiple human transcript variants (for example, as annotated under GenBank RefSeq Accession Numbers: NM_000109.3, NM_004006.2, NM_004009.3, NM_004010.3, and NM_004011.3) have been characterized as encoding different isoforms of protein. DMD allele: As used herein, the term DMD allele refers to any of the alternative forms (eg, wild-type or mutant forms) of a DMD gene. In some modalities, a DMD allele can code for dystrophin which retains its normal and typical functions. In some embodiments, a DMD allele may comprise one or more mutations that result in muscular dystrophy. Common mutations leading to Duchenne muscular dystrophy involve frameshift, deletion, substitution, and duplicative mutations of one or more of the 79 exons present in a dystrophin allele, eg, exon 8, exon 23, exon 41 , exon 44, exon 50, exon 51, exon 52, exon 53, or exon 55. Additional examples of DMD mutations are described, for example, in Flanigan KM, et al., Mutational spectrum of DMD mutations in dystrophinopathy patients : application of modern diagnostic techniques to a large cohort. Hum Mutat. 2009 Dec; 30(12):1657-66, the contents of which are incorporated herein by reference in their entirety. Dystrophinopathy: As used herein, the term dystrophinopathy refers to a muscle disease resulting from one or more mutated alleles of DMD. Dystrophinopathies include a spectrum of conditions (ranging from mild to severe) including Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM). In some forms, at one end of the spectrum, dystrophinopathy is phenotypically associated with aarrbn / i 7Π7 / 3 / ΥΙΛΙ with an asymptomatic increase in serum creatine phosphokinase (CK) concentration and / or muscle cramps with myoglobinuria. In some modalities, at the other end of the spectrum, dystrophinopathy is phenotypically associated with progressive muscular diseases that are generally classified as Duchenne or Becker muscular dystrophy when skeletal muscle is primarily affected and as DMD-associated dilated cardiomyopathy (DCM) when It mainly affects the heart. Symptoms of Duchenne muscular dystrophy include muscle wasting or wasting, decreased muscle function, pseudohypertrophy of the tongue and calf muscles, increased risk of neurological abnormalities, and decreased life expectancy. Duchenne muscular dystrophy is associated with Online Mendelian Inheritance in Males (OMIM) Entry # 310200. Becker muscular dystrophy is associated with OMIM Entry # 300376. Dilated cardiomyopathy is associated with OMIM Entry X# 302045. Setting: How to use as used herein, the term framework or framework sequence refers to the remaining sequences of a variable region minus the CDRs. Since the exact definition of a CDR sequence can be determined by different systems, the meaning of a frame sequence is correspondingly subject to different interpretations. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 for the light chain and CDR-H1, CDR-H2, and CDR-H3 for the heavy chain) also divide the framework regions into the light chain and heavy chain. into four sub-regions (FR1, FR2, FR3 and FR4) on each chain, in which CDR1 is positioned between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without specifying the particular sub-regions as FR1, FR2, FR3 or FR4, a framework region, as referred to by others, represents the combined FRs within the variable region of a single natural immunoglobulin chain. As used herein, an FR represents one of the four sub-regions, and FRs represent two or more of the four sub-regions that make up a framework region. Human heavy chain and light chain acceptor sequences are known in the art. In one embodiment, acceptor sequences known in the art can be used in the antibodies described herein. Human Antibody: The term human antibody, as used herein, is intended to include antibodies having variable and constant regions derived from human germ-line immunoglobulin sequences. Human antibodies of the disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (for example, mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and particularly in CDR3. However, the term human antibody, as used herein, is not intended to include antibodies in which the germline-derived CDR sequences of another mammalian species (such as mouse) have been grafted onto human framework sequences. QQPPbn / l 7Γ>7 / =1 / ΥΙΛΙ Humanized Antibody: The term "humanized antibody" refers to antibodies comprising heavy and light chain variable region sequences from a non-human species (eg, a mouse) but in which at least a portion of the VH sequence and / or or VL has been altered to be more human-like, ie, more similar to human germline variable sequences. One type of humanized antibody is a CDR-grafted antibody, in which human CDR sequences are inserted into non-human VH and VL sequences to replace the corresponding non-human CDR sequences. In one embodiment, humanized anti-transferrin receptor antibodies and antigen binding moieties are provided. Such antibodies can be generated by obtaining murine anti-transferrin receptor monoclonal antibodies using traditional hybridoma technology followed by humanization using in vitro genetic engineering, such as those described in Kasaian et al PCT publication No. WO 2005 / 123126 A2 . Cell Surface Internalization Receptor: As used herein, the term cell surface internalization receptor refers to a cell surface receptor that is internalized by cells, for example, following external stimulation, by example, binding of the ligand to the receptor. In some embodiments, a cell surface internalization receptor is internalized by endocytosis. In some embodiments, a cell surface internalization receptor is internalized by clathrin-mediated endocytosis. However, in some embodiments, a cell surface internalizing receptor is internalized by a clathrin-independent pathway, such as, for example, phagocytosis, macropinocytosis, caveolae and raft-mediated uptake, or clathrin-independent constitutive endocytosis. In some embodiments, the cell surface internalizing receptor comprises an intracellular domain, a transmembrane domain, and / or an extracellular domain, which may optionally comprise a ligand-binding domain. In some embodiments, a cell surface receptor becomes internalized by a cell after ligand binding. In some embodiments, a ligand may be a muscle-targeting agent or a muscle-targeting antibody. In some embodiments, a cell surface internalizing receptor is a transferrin receptor. Isolated antibody: An isolated antibody, as used herein, is intended to refer to an antibody that is substantially free of other antibodies that are substantially free of other antibodies that have different antigenic specificities (for example, an isolated antibody that is specifically binds to the transferrin receptor is substantially free of antibodies that specifically bind to antigens other than the transferrin receptor). An isolated antibody that specifically binds to the transferrin receptor complex may, however, cross-react with other antigens, such as molecules Qorrbn / iznz / q / YiAi of the transferrin receptor from other species. On the other hand, an isolated antibody can be substantially free of other cellular material and / or chemicals. Kabat Numbering: The terms Kabat numbering, Kabat definitions, and Kabat marking are used interchangeably herein. These terms, which are recognized in the art, refer to a numbering system of amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or a antigen-binding portion thereof (Kabat et al. (1971) Ann. NY Acad, Sci. 190:382-391 and, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3. Molecular Payload: As used herein, the term molecular payload refers to a molecule or species that functions to modulate a biological outcome. In some embodiments, a molecular payload is linked to, or otherwise associated with, a muscle-targeting agent. In some embodiments, the molecular payload is a small molecule, protein, peptide, nucleic acid, or oligonucleotide. In some embodiments, the molecular payload functions to modulate the transcription of a DNA sequence, to modulate the expression of a protein, or to modulate the activity of a protein. In some embodiments, the molecular payload is an oligonucleotide comprising a strand having a region of complementarity to a target gene. Muscle Targeting Agent: As used herein, the term, muscle targeting agent, refers to a molecule that specifically binds to an antigen expressed on muscle cells. The antigen in or on muscle cells can be a membrane protein, for example an integral membrane protein or a peripheral membrane protein. Typically, a muscle-targeting agent specifically binds to an antigen on muscle cells which facilitates internalization of the muscle-targeting agent (and any associated molecular payloads) into muscle cells. In some embodiments, a muscle-targeting agent specifically binds to a muscle-taking, cell-surface receptor and is capable of being taken up into muscle cells via receptor-mediated take-up. In some embodiments, the muscle targeting agent is a small molecule, protein, peptide, nucleic acid (eg, aptamer), or antibody. In some modalities, the agent of QQrrbn / ΙΖΠΖ / ^ / ΥΙΛΙ muscle targeting is linked to a molecular payload. Muscle-targeting antibody: As used herein, the term, muscle-targeting antibody, refers to a muscle-targeting agent that is an antibody that specifically binds to an antigen found in or on muscle cells. In some embodiments, a muscle-targeting antibody specifically binds to an antigen on muscle cells facilitating internalization of the muscle-targeting antibody (and any associated molecular payload) into muscle cells. In some embodiments, the muscle-targeting antibody specifically binds to an internalizing cell surface receptor present on muscle cells. In some embodiments, the muscle-targeting antibody is an antibody that specifically binds to a transferrin receptor. Oligonucleotide As used herein, the term "oligonucleotide" refers to an oligomeric nucleic acid compound up to 200 nucleotides in length. Examples of oligonucleotides include, but are not limited to, RNAi oligonucleotides (eg, siRNA, shRNA), microRNAs, gapmers, mixmers, phosphorodiamidite morpholinos, peptide nucleic acids, aptamers, guide nucleic acids (eg, Cas9 RNA, guide), etc Oligonucleotides can be single-stranded or double-stranded. In some embodiments, an oligonucleotide may comprise one or more modified nucleotides (eg 2'-O-methyl sugar modifications, purine or pyrimidine modifications). In some embodiments, an oligonucleotide may comprise one or more modified internucleotide linkages. In some embodiments, an oligonucleotide may comprise one or more phosphorothioate linkages, which may be in the Rp or Sp stereochemical conformation. Recombinant Antibody: The term human recombinant antibody, as used herein, is intended to include all human antibodies that are prepared, expressed, created, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell. (described in more detail in this disclosure), antibodies isolated from a combinatorial human, recombinant antibody library (Hoogenboom H.R., (1997) TIB Tech. 15:62-70; Azzazy H., and Highsmith W.E., (2002) Clin. Biochem 35:425-445, Gavilondo 1 V., and Larrick 1 W. (2002) BioTechniques 29:128-145, Hoogenboom H., and Chames R (2000) Immunology Today 21:371-378), antibodies isolated from an animal {for example, a mouse) that is transgenic for human immunoglobulin genes (see for example, Taylor, L.D., et al. (1992) Nucí. Acids Res. 20:62876295; Kellermann S-A., and Green L.L. ( 2002) Current Opinion in Biotechnology 13:593-597 Little M. et al (2000) Immunology Today 21:364-370) or antibodies prepared, expressed, created, or isolated by any other means involving splicing of gene sequences from human aarrbn / i immunoglobulin 7Π7 / =ι / υιλι to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germ line immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using a transgenic animal for human Ig sequences, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions Most of the recombinant antibodies are sequences which, although derived from and related to the human germline VH and VL sequences, may not naturally exist within the human germline antibody repertoire in vivo. One embodiment of the disclosure provides fully human antibodies capable of binding to the human transferrin receptor which can be generated using techniques well known in the art, such as, without limitation, using human Ig phage libraries such as those described in Jermutus. et al., PCT Publication No. WO 2005 / 007699 A2. Region of Complementarity: As used herein, the term "region of complementarity" refers to a nucleotide sequence, eg, of an oligonucleotide, that is sufficiently complementary to a cognate nucleotide sequence, eg, of a target nucleic acid. , such that the two nucleotide sequences are capable of annealing to each other under physiological conditions (eg, in a cell). In some embodiments, a region of complementarity is completely complementary to a cognate nucleotide sequence of the target nucleic acid. However, in some embodiments, a region of complementarity is partially complementary to a target nucleic acid cognate nucleotide sequence (eg, at least 80%, 90%, 95%, or 99% complementarity). In some embodiments, a region of complementarity contains 1, 2, 3, or 4 mismatches compared to a cognate nucleotide sequence of a target nucleic acid. Binds Specifically: As used herein, the term "binds specifically" refers to the ability of a molecule to bind to a binding partner with a degree of affinity or avidity that enables the molecule to be used to distinguish to the binding partner of an appropriate control in a binding assay or other binding context. With respect to an antibody, the term "binds specifically" refers to the ability of the antibody to bind to a specific antigen with a degree of affinity or avidity, as compared to an appropriate reference antigen(s), that enables the antibody. to be used to distinguish the specific antigen from others, eg, to a degree that allows preferential targeting to certain cells, eg, muscle cells, through antigen binding, as described herein. In some embodiments, an antibody specifically binds to a target if the antibody has a Kd for target binding of at least near ΙΟ'4Μ, ΙΟ'5Μ, ΙΟ'6M, aarrbn / i 7n7 / 3i / υιλι ΙΟ'7Μ, ΙΟ’8Μ, ΙΟ-9Μ, ΙΟ-10Μ, ΙΟ-11Μ, ΙΟ-12Μ, ΙΟ’13Μ, or less. In some embodiments, an antibody specifically binds to the transferrin receptor, eg, a transferrin receptor apical domain epitope. Subject As used herein, the term "subject" refers to a mammal. In some embodiments, a subject is a non-human primate, or rodent. In some embodiments, a subject is a human. In some embodiments, a subject is a patient, eg, a human patient who has or is suspected of having a disease. In some embodiments, the subject is a human patient who has or is suspected of having a disease resulting from a mutated DMD gene sequence, eg, a mutation in an exon of a DMD gene sequence. In some embodiments, a subject has a dystrophinopathy, eg, Duchenne muscular dystrophy. Transferrin Receptor: As used herein, the term, transferrin receptor (also known as TFRC, CD71, p90, or TFR1) refers to a cell surface internalizing receptor that binds transferrin to facilitate uptake of iron by endocytosis. In some embodiments, a transferrin receptor can be of human (NCBI gene ID 7037), non-human primate (eg, NCBI gene ID 711568 or NCBI gene ID 102136007), or rodent (eg, gene ID 711568) origin. NCBI 22042). In addition, multiple human transcript variants have been characterized that encode different isoforms of the receptor (for example, as noted under GenBank RefSeq Accession Numbers: NP_001121620.1, NP_003225.2, NP_001300894.1, and NP_001300895.1). . complexes Provided herein are complexes comprising a targeting agent, eg an antibody, covalently linked to a molecular payload. In some embodiments, a complex comprises a muscle-targeting antibody covalently linked to an oligonucleotide. A complex can comprise an antibody that specifically binds to a single antigenic site or that binds to at least two antigenic sites that may exist on the same or different antigens. A complex can be used to modulate the activity or function of at least one gene, protein, and / or nucleic acid. In some embodiments, the molecular payload present with a complex is responsible for the modulation of a gene, protein, and / or nucleic acid. A molecular payload can be a small molecule, protein, nucleic acid, oligonucleotide, or any molecular entity capable of modulating the activity or function of a gene, protein, and / or nucleic acid in a cell. In some embodiments, a molecular payload is an oligonucleotide that targets disease-associated repeats in muscle cells. αοΓΓπη / ι 7Π7 / =ι / υιλι In some embodiments, a complex comprises a muscle-targeting agent, eg, an anti-transferrin receptor antibody, covalently linked to a molecular payload, eg, an antisense mixmer oligonucleotide that targets a mutated allele of DMD to promote jumping. of exon. Muscle targeting agents Some aspects of the disclosure provide muscle targeting agents, eg, for the delivery of a molecular payload to a muscle cell. In some embodiments, such muscle-targeting agents are capable of binding to a muscle cell, eg, via specifically binding to an antigen on the muscle cell, and delivery of a muscle cell-associated molecular payload. In some embodiments, the molecular payload is attached (eg, covalently linked) to the muscle-targeting agent and is internalized into the muscle cell following binding of the muscle-targeting agent to an antigen on the muscle cell, eg, , via endocytosis. It should be appreciated that various types of muscle targeting agents may be used in accordance with the disclosure. For example, the muscle-targeting agent can comprise, or consist of, a nucleic acid (eg, DNA or RNA), a peptide (eg, an antibody), a lipid (eg, a microvesicle), or a sugar portion (eg, a polysaccharide). Exemplary muscle targeting agents are described in greater detail herein, however, it should be appreciated that the exemplary muscle targeting agents provided herein are not intended to be limiting. Some aspects of the disclosure provide muscle-targeting agents that specifically bind to an antigen in muscle, such as skeletal muscle, smooth muscle, or cardiac muscle. In some embodiments, any of the muscle-targeting agents provided herein binds (eg, specifically binds to) an antigen on a skeletal muscle cell, a smooth muscle cell, and / or a cell of heart muscle. By interacting with muscle-specific cell surface recognition elements (eg, cell membrane proteins), both tissue localization as well as selective uptake into muscle cells can be achieved. In some embodiments, molecules that are substrates for muscle uptake transporters are useful for delivery of a molecular payload into muscle tissue. Binding to muscle surface recognition elements followed by endocytosis may allow even larger molecules such as antibodies to enter muscle cells. As another example molecular payloads conjugated to transferrin or anti-transferrin receptor antibodies QQPPbn / l 7Π7 / Σ1 / ΥΙΛΙ can be taken up by muscle cells via transferrin receptor binding, which can then be endocytosed, eg, via clathrin-mediated endocytosis. The use of muscle-targeting agents may be useful in concentrating a molecular payload (eg, oligonucleotide) in muscle while reducing toxicity associated with effects in other tissues. In some embodiments, the muscle-targeting agent concentrates a bound molecular payload in muscle cells as compared to another cell type within a subject. In some embodiments, the muscle-targeting agent concentrates a bound molecular payload in muscle cells (eg, skeletal, smooth, or cardiac muscle cells) in an amount that is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times greater than an amount in non-muscle cells (for example, liver, neuronal, blood cells). , or fat). In some embodiments, a molecular payload toxicity in a subject is reduced by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, or 95% when delivered to the subject when the targeting agent binds to the muscles. In some modalities, to achieve muscle selectivity, a muscle recognition element (eg, a muscle cell antigen) may be required. As an example, a muscle-targeting agent can be a small molecule that is a substrate for a muscle-specific uptake transporter. As another example, a muscle-targeting agent may be an antibody that enters a muscle cell via transporter-mediated endocytosis. As another example, a muscle-targeting agent may be a ligand that binds to a cell surface receptor on a muscle cell. It should be appreciated that although transporter-based approaches provide a direct pathway for cell entry, receptor-based targeting may involve stimulated endocytosis to reach the desired site of action. Muscle targeting antibodies In some embodiments, the muscle targeting agent is an antibody. Generally, the high specificity of antibodies for their target antigen provides the potential to target muscle cells (eg, skeletal, smooth, and / or cardiac muscle cells). This specificity can also limit off-target toxicity. Examples of antibodies that are capable of targeting muscle cell surface antigen have been reported and are within the scope of the description. For example, antibodies that are directed to the surface of muscle cells are described in Arahata K., et al. Immunostaining of skeletal and cardiac muscle surface membrane with antibody against Duchenne muscular dystrophy peptide Nature 1988; 333:861-3; Song K.S., et al. Expression of caveolin-3 in skeletal, cardiac, and smooth aarrbn / i 7Π7 / =ι / υιλι muscle cells. Caveolin-3 is a component of the sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins J Bio! Chem 1996; 271: 15160-5; and Weisbart R.H. et al., Cell type specific targeted intracellular delivery into muscle of a monoclonal antibody that binds myosin Ilb Mol Immunol. 2003 Mar, 39(13):78309; the entire contents of each of which are incorporated herein by reference. Anti-transferrin receptor antibodies Some aspects of the disclosure are based on the recognition that transferrin receptor binding agents, eg, anti-transferrin receptor antibodies, are capable of muscle cell targeting. Transferrin receptors are cell surface internalizing receptors that transport transferrin across the cell membrane and are involved in the regulation and homeostasis of intracellular iron levels. Some aspects of the disclosure provide transferrin receptor binding proteins, which are capable of binding to the transferrin receptor. Accordingly, aspects of the disclosure provide binding proteins (eg, antibodies) that bind to the transferrin receptor. In some embodiments, binding proteins that bind to the transferrin receptor are internalized, along with any attached molecular payloads, into a muscle cell. As used herein, an antibody that binds to a transferrin receptor may be referred to as an anti-transferrin receptor antibody. Antibodies that bind, eg specifically bind, to a transferrin receptor can be internalized into the cell, eg via receptor-mediated endocytosis, following binding to a transferrin receptor. It should be appreciated that anti-transferrin receptor antibodies can be produced, synthesized, and / or derivatized using many known methodologies, for example library design using phage display. Exemplary methodologies have been characterized in the art and are incorporated by reference (Diez, P. et al. High-throughput phagedisplay screening in array format, Enzyme and microbial technology, 2015, 79, 34-41.; Christoph M. H. and Stanley, IR. Antibody Phage Display: Technique and Applications J Invest Dermatol. 2014, 134:2.; Engleman, Edgar (Ed.) Human Hybridomas and Monoclonal Antibodies. 1985, Springer.). In other embodiments, an anti-transferrin antibody has been previously characterized or described. Antibodies that specifically bind to the transferrin receptor are known in the art (see, for example, U.S. Patent No. 4,364,934, filed 4 / 12 / 1979, Monoclonal antibody to a human early thymocyte antigen and methods for preparing the same; U.S. Patent No. 8,409,573, filed 6 / 14 / 2006, Anti-CD71 monoclonal antibodies and uses thereof for treating malignant tumor cells; use; US 9,611,323, filed 12 / 19 / 2014, Low aarrbn / i 7Π7 / 3 / ΥΙΛΙ affinity blood brain barrier receptor antibodies and uses therefor; WO 2015 / 098989, filed 12 / 24 / 2014, Novel anti-Transferrin receptor antibody that passes through blood-brain barrier Schneider C. et al. Structural features of the cell surface receptor for transferrin that is recognized by the monoclonal antibody OKT9. J Biol Chem. 1982, 257:14, 8516-8522.; Lee et al. al Targeting 5 Rat Anti-Mouse Transferrin Receptor Monoclonal Antibodies through Blood-Brain Barrier in Mouse 2000, J Pharmacol. Exp. Ther., 292: 1048-1052.). Any appropriate anti-transferrin receptor antibodies can be used in the complexes described herein. Examples of anti-transferrin receptor antibodies, including associated references and binding epitopes are listed in Table 1. In some embodiments, the anti-transferrin receptor antibody comprises the complementarity determining regions (CDR-H1, CDR- H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) of any of the anti-transferrin receptor antibodies provided herein, for example, anti-transferrin receptor antibodies listed in Table 1 . Qorrbn / iznz / q / YiAi TABLE 1 List of anti-transferrin receptor antibody clones, including associated references and binding eoitope information. Antibody Clone Name Reference(s) Epitope / Notes OKT9 U.S. Pat. No. 4,364,934, filed 4 / 12 / 1979, entitled MONOCLONAL ANTIBODY TO A HUMAN EARLY THYMOCYTE ANTIGEN AND METHODS FOR PREPARING SAME Schneider C. et al. Structural features of the cell surface receptor for transferrin that is recognized by the monoclonal antibody OKT9. J Biol Chem. 1982, 257:14, 8516-8522. TfR apical domain (residues 305-366 of human TfR sequence XM_052730.3, available from GenBank) (From JCR) Clone Mil Clone M23 Clone M27 Clone B84 WO 2015 / 098989, filed 12 / 24 / 2014, Novel anti- Transferrin receptor antibody that passes through blood-brain barrier U.S. Pat. No. 9,994,641, Filed 12 / 24 / 2014, Novel anti-Transferrin receptor antibody that passes through blood-brain barrier Apical domain (TfR residues 230-244 and 326-347) and protease-like domain (residues 461473) (From Genentech ) 7A4, 8A2, 15D2, 10D11, 7B10, 15G11, 16G5, 13C3, 16G4, 16F6, 7G7, 4C2, 1B12, and 13D4 WO 2016 / 081643, filed 5 / 26 / 2016, titled ANTI-TRANSFERRIN RE CEPTOR ANTIBODIES AND METHODS OF USE U.S. Patent No. 9,708,406, Filed 5 / 20 / 2014, Anti-transferrin receptor antibodies and methods of use Apical domain and non-apical regions (From Armagen) 8D3 Lee et al. Targeting Rat Anti-Mouse Transferrin Receptor Monoclonal Antibodies through Blood-Brain Barrier in Mouse 2000, J Pharmacol. Exp. Ther., 292: 1048-1052. U.S. Patent Sun 2010 / 077498, filed 11 / 9 / 2008, titled COMPOSITIONS AND METHODS FOR BLOODBRAIN BARRIER DELIVERY IN THE MOUSE 0X26 Haobam, B. et al. 2014. Rabl7-mediated recycling endosomes contribute to autophagosome formation in response to Group A Streptococcus invasion. Cellular microbiology. 16:1806-21. DF1513 Ortiz-Zapater E et al. Trafficking of the human transferrin receptor in plant cells: effects of tyrphostin A23 and brefeldin A. Plant J 48:75770 (2006). 1A1B2, 66IG10, MEM-189, JF0956, 29806, 1A1B2, TFRC / 1818, 1E6, 66IglO, TFRC / 1059, Ql / 71, 23D10, 13E4, TFRC / 1149, ERMP21, YTA74.4, BU54, 2B 6, RI7 217 Commercially available anti-transferrin receptor antibodies. Novus Biologicals 8100 Southpark Way, A8 Littleton CO 80120 (From INSERM) BA120g US Pat. U.S. Pat. No. 7,572,895, filed 7 / 6 / 2004, entitled TRANSFERRIN RECEPTOR ANTIBODIES LUCA31 epitope (Salk Institute) B3 / 25 T58 / 30 Trowbridge, I.S. et al. Anti-transferrin receptor monoclonal antibody and toxinantibody conjugates affect growth of human tumor cells. Nature, 1981, volume 294, pages 171-173 R17 217.1.3, 5E9C11, 0KT9 (BE0023 clone) Commercially available anti-transferrin receptor antibodies. BioXcell 10 Technology Dr., Suite 2B West Lebanon, NH 03784-1671 USA BK19.9, B3 / 25, T56 / 14 and T58 / 1 Gatter, K.C. et al. Transferrin receptors in human tissues: their distribution and possible clinical relevance. J Clin Pathol. 1983 May;36(5):539-45. In some embodiments, the muscle targeting agent is an anti-transferrin receptor antibody. In some embodiments, an anti-transferrin receptor antibody specifically binds to a transferrin protein having an amino acid sequence as described herein. In some embodiments, an anti-transferrin receptor antibody can specifically bind to any extracellular epitope of a transferrin receptor or an epitope that becomes exposed to an antibody, including the apical domain, the transferrin-binding domain, and the transferrin-binding domain. protease type. In some embodiments, an anti-transferrin receptor antibody binds to an amino acid segment of a human or non-human primate transferrin receptor, as provided in SEQ ID Nos. 1-3 in the amino acid range C89 to F760. In some embodiments, an anti-transferrin receptor antibody binds specifically with a binding affinity of at least near ΙΟ'4Μ, ΙΟ'5Μ, ΙΟ'6Μ, ΙΟ'7Μ, ΙΟ'8Μ, ΙΟ'9Μ, 10' 10Μ, ΙΟ'11Μ, ΙΟ'12Μ, ΙΟ'13M, or less. The anti-transferrin receptor antibodies used herein may be capable of competing for binding with other anti-transferrin receptor antibodies, for example OKT9, 8D3, which binds the transferrin receptor with ΙΟ'3Μ, ΙΟ'4Μ, 10' 5Μ, ΙΟ'6Μ, ΙΟ'7M, or less. An example of the amino acid sequence of the human transferrin receptor, corresponding to NCBI sequence NP_003225.2 (transferrin receptor protein 1 isoform 1, homo sapiens) is as follows: MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLAVDEENADNNTKANVTKPKRCSGSICYGTIAVI VFFLIGFMIGYLG YCKGVEPKTECERLGTESPVREEPGEDPAARRLYWDDLKRKLSEKLDSTDFTGTIKLLNEN SYVPREAGSQKDENLALYVENQFREFKLSKVWRDQHFVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKA ATVTGKLVHANFGTKKDFEDLYTPVNGSIVIVRAGKITFAEKV ANAESLNAIGVLIYMDQTKFPIVNAELSFFGHAH LGTGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDSTCRMVTSESKNVKLTV SNVLKEIKILNIFGVIKGFVEPDHYVWGAQRDAWGPGAAKSGVGTALLLKLAQMFSDMVLKDGFQPSRS IIFAS WSAGDFGSVGATEWLEGYLSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQNVKHPVTGQFLYQDSN WASKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELIERIPELNKVARAAAEVAGQFVIKLTH DVELNLDYERYNSQLLSFVRDLNQYRAD IKEMGLSLQWLYSARGDFFRATSRLTTDFGNAEKTDRFVMKKLNDR VMRVEYHFLSPYVSPKESPFRHVFWGSGSHTLPALLENLKLRKQNNGAFNETLFRNQLALATWTIQGAANALSG DVWDIDNEF (SEQ ID NO: 1). An example of the amino acid sequence of the non-human primate transferrin receptor, corresponding to the NCBI sequence NP_001244232.1 (transferrin receptor protein 1, Macaca mulatta) is as follows: MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLGVDEEENTDNNTKPNGTKPKRCGGNICYGTIAVI IFFLIGFMIG YLGYCKGVEPKTECERLGTESPAREEPEEDFPAAPRLYWDDLKRKLSEKLDTTDFTSTIKLLNENL YVPREAGSQKDENLALYIENQFREFKLSKVWRDQHFVKIQVKDSAQNSVIIVDKNGGLVYLVENPGGYVAYSKAA Garran / Lznz / q / YiAi TVTGKLVHANFGTKKDFEDLDSPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVKADLSFFGHAHL GTGDPYTPGFFPSFNHTQFPPSQSSGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDSTCKMVTSENKSVKLTV SNVLKETKILNIFGVIKGFVEPDHYW VGAQRDAWGPGAAKSSVGTALLLKLAQMFSDMVLKDGFQPSRSIIFAS WSAGDFGSVGATEWLEGYLSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQDVKHPVTGRSLYQDSN WASKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELVERIPELNK VARAAAEVAGQFVIKLTH DTELNLDYERYNSQLLLFLRDLNQYRADVKEMGLSLQWLYSARGDFFRATSRLTTDFRNAEKRDKFVMKKLNDR VM RVEYYFLSPYVSPKESPFRH VFWGSGSHTLSALLESLKLRRQN NSAFN ETLFRNQLALATWTIQGAANALSGD VWDIDNEF (SEQ ID NO: 2) An example of the amino acid sequence of the non-human primate transferrin receptor, corresponding to the NCBI sequence XP_005545315.1 (transferrin receptor protein 1, Macaca fascicularis) is as follows: MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLGVDEEENTDNNTKANGTKPKRCGGNICYGTIAVI IFFLIGFMIGYLGYCKGVEPKTECERLGTESPAREEPEEDFPAAPRLYWDDLKRKLSEKLDTTDFTSTIKLLNENL YVPREAGSQKDENLALYIENQFREFKLSKVWRD QHFVKIQVKDSAQNSVIIVDKNGGLVYLVENPGGYVAYSKAA TVTGKLVHANFGTKKDFEDLDSPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVKADLSFFGHAHL GTGDPYTPGFSFNHTQFPPSQSSGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDST CKMVTSENKSVKLTV SNVLKETKILNIFGVIKGFVEPDHYVWGAQRDAWGPGAAKSSVGTALLLKLAQMFSDMVLKDGFQPSRSIIFAS WSAGDFGSVGATEWLEGYLSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQDVKHPVTGRSLYQDSN WASKVEKLTLD NAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELVERIPELNKVARAAAEVAGQFVIKLTH DTELNLDYERYNSQLLLFLRDLNQYRADVKEMGLSLQWLYSARGDFFRATSRLTTDFRNAEKRDKFVMKKLNDR VM RVEYYFLSPYVSPKESPFRH VFWGSGSHTLSALLESLKLRRQN NSAFN ETLFRNQLALATWTIQGAANALSGD VWDIDNEF (SEQ ID NO: 3). An example of the amino acid sequence of the mouse transferrin receptor, corresponding to the NCBI sequence NP_001344227.1 (transferrin receptor protein 1, mus musculus) is as follows: MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLAADEEENADNNMKASVRKPKRFNGRLCFAAIALV IFFLIGFMSGYLGYCKRVEQKEECVKLAETEETDKSETMETEDVPTSSRLYWADLKTLLSEKLNSIEFADTIKQLSQ NTYTPREAGSQKDESLAYYIENQFHEFKFSKV WRDEHYVKIQVKSSIGQNMVTIVQSNGNLDPVESPEGYVAFSK PTEVSGKLVHANFGTKKDFEELSYSVNGSLVIVRAGEITFAEKVANAQSFNAIGVLIYMDKNKFPWEALDLALFGH AHLGTGDPYTPGFSFNHTQFPPSQSSGLPNIPVQTISRAAAEKLFGKMEGSCPARWNI DSSCKLELSQNQNVKL IVKNVLKERRILNIFGVIKGYEEPDRYVWGAQRDALGAGVAAKSSVGTGLLLKLAQVFSDMISKDGFRPSRSIIFA SWTAGDFGAVGATEWLEGYLSSLHLKAFTYINLDKWLGTSNFKVSASPLLYTLMGKIMQDVKHPVDGKSLYRDS NWISKVEK LSFDNAAYPFLAYSGIPAVSFCFCEDADYPYLGTRLDTYEALTQKVPQLNQMVRTAAEVAGQLIIKLT HDVELNLDYEMYNSKLLSFMKDLNQFKTDIRDMGLSLQWLYSARGDYFRATSRLTTDFHNAEKTNRFVMREIND QQPPbn / l 7Π7 / 3 / ΥΙΛΙ RIMKVEYHFLSPYVSPRESPFRHIFWGSGSHTLSALVENLKLRQKNITAFNETLFRNQLALATWTIQGVANALSGD IWNIDNEF (SEQ ID NO: 4) In some embodiments, an anti-transferrin receptor antibody binds to an amino acid segment of the receptor as follows: FVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKLVHANFGTKKDFEDLYTPVNGSIVIVRAGKI TFAEKVANAESLNAIGVLIYMDQTKFPIVNAELSFFGHAHLGTGDPYTPGFPSFNHTQ PSRSSGLPNIPVQTISR AAAEKLFGNMEGDCPSDWKTDSTCRMVTSESKNVKLTVSNVLKE (SEQ ID NO: 5) and does not inhibit binding interactions between transferrin receptors and transferrin protein and / or from human hemochromatosis (also known as HFE). Appropriate methodologies can be used to obtain and / or produce antibodies, antibody fragments, or antigen-binding agents, for example, through the use of recombinant DNA protocols. In some embodiments, an antibody can also be produced through hybridoma generation (see, for example, Kohler, G and Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity, 1975, 256: 495-497). . The antigen of interest can be used as the immunogen in any form or entity, eg, recombinant form or entity or a natural one. Hybridomas are screened using standard methods, eg ELISA assay, to find at least one hybridoma that produces an antibody that is directed to a particular antigen. Antibodies can also be produced through screening protein expression libraries that express antibodies, eg, phage display libraries. The phage display library design may also be used, in some embodiments, (see, for example, U.S. Patent No. 5,223,409, filed 1 / 3 / 1991, Directed evolution of novel binding proteins; WO 1992 / 18619, filed 10 / 4 / 1992, Heterodimeric receptor liberation using phagemids; WO 1991 / 17271, filed 1 / 5 / 1991, Recombinant library screening methods; WO 1992 / 20791, filed 5 / 15 / 1992, Methods for producing members of specific binding pairs; WO 1992 / 15679, filed 2 / 28 / 1992, and Improved epitope displaying phage). In some embodiments, an antigen of interest can be used to immunize a non-human animal, eg, a rodent or goat. In some embodiments, an antibody is then obtained from the non-human animal, and can optionally be modified using a number of methodologies, for example, using recombinant DNA techniques. Additional examples of antibody production and methodologies are known in the art (see, eg, Harlow et al. Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988.). In some embodiments, an antibody is modified, eg, modified via glycosylation, phosphorylation, sumoylation, and / or methylation. In some embodiments, an antibody is Qorrbn / iznz / q / YiAi a glycosylated antibody, which is conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchor binding), and / or phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glucans. In some embodiments, the one or more sugar or carbohydrate molecules is a branched oligosaccharide or a branched glucan. In some embodiments, the one or more sugar or carbohydrate molecules include a mannose unit, a glucose unit, an N-acetylglucosamine unit, a N-acetylgalactosamine unit, a galactose unit, a fucose unit, or a N-acetylgalactosamine unit. phospholipid. In some embodiments, they are about 1-10, about 1-5, about 5-10, about 1-4, about 1-3, or about 2 sugar molecules. In some embodiments, a glycosylated antibody is fully or partially glycosylated. In some embodiments, an antibody is glycated by chemical reactions or by enzymatic means. In some embodiments, an antibody is glycosylated in vitro or within a cell, which may optionally be deficient in an enzyme in the N- or O-glycosylation pathway, for example a glycosyltransferase. In some embodiments, an antibody is functionalized with sugar or carbohydrate molecules as described in International Patent Application Publication WO2014065661, published May 1, 2014, entitled, Modified antibody, antibody-conjugate and process for the preparation thereof. Some aspects of the description provide proteins that bind to the transferrin receptor (eg, an extracellular portion of the transferrin receptor). In some embodiments, the transferrin receptor antibodies provided herein specifically bind to the transferrin receptor (eg, human transferrin receptor). Transferrin receptors are cell surface internalizing receptors that transport transferrin across the cell membrane and are involved in the regulation and homeostasis of intracellular iron levels. In some embodiments, the transferrin receptor antibodies provided herein specifically bind to the transferrin receptor of humans, non-human primates, mouse, rat, etc. In some embodiments, the transferrin receptor antibodies provided herein bind to the human transferrin receptor. In some embodiments, the transferrin receptor antibodies provided herein specifically bind to the human transferrin receptor. In some embodiments, the transferrin receptor antibodies provided herein bind to an apical domain of the human transferrin receptor. In some embodiments, the transferrin receptor antibodies provided herein specifically bind to an apical domain of the human transferrin receptor. QQPPbn / l 7Π7 / Σ1 / ΥΙΛΙ In some embodiments, the transferrin receptor of the present disclosure includes one or more of the CDR-H amino acid sequences (eg, CDR-H1, CDR-H2, and CDR-H3) of any of the anti-receptor antibodies. -transferrin selected from Table 1. In some embodiments, transferrin receptor antibodies include CDR-H1, CDR-H2, and CDR-H3 as provided for any of the selected anti-transferrin receptor antibodies from Table 1. In In some modalities, anti-transferrin receptor antibodies include CDR-L1, CDR-L2, and CDR-L3 as provided for any of the anti-transferrin receptor antibodies selected from Table 1. In some modalities, anti-transferrin antibodies include the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 as provided for any of the anti-transferrin receptor antibodies selected from Table 1. The description also includes any sequences of nucleic acids encoding a molecule comprising a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, or CDR-L3 as provided for any of the anti-transferrin receptor antibodies selected from Table 1 In some embodiments, the heavy and light chain CDR3 domains of the antibody may play a particularly important role in the binding specificity / affinity of an antibody for an antigen. Accordingly, the anti-transferrin receptor antibodies of the disclosure may include at least the CDR3s of the heavy and / or light chain of any of the anti-transferrin receptor antibodies selected from Table 1. In some examples, any of the anti-transferrin receptor antibodies of the disclosure have one or more CDR sequences (eg, CDR-H or CDR-L) substantially similar to any of the CDR-H sequences 1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and / or CDR-L3 of one of the anti-transferrin receptor antibodies selected from Table 1. In some embodiments, the position of one or more CDRs together with the VH region {for example, CDR-H1, CDR-H2, or CDR-H3) and / or VL region (for example, CDR-L1, CDR-L2, or CDR-L3) of an antibody described herein may vary by one, two, three, four, five, or six amino acid positions as long as immunospecific binding to transferrin receptor (eg, human transferrin receptor) is maintained {eg, substantially maintained, eg, by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% binding to the original antibody from which it is derived). For example, in some embodiments, the position defining a CDR of any antibody described herein can be varied by changing the N-terminal and / or C-terminal boundaries of the CDR by one, two, three, four, five, or six amino acids, from the CDR position of any of the antibodies described herein, as long as immunospecific binding to the transferrin receptor (eg, human transferrin receptor) is maintained {eg, that is substantially maintained, eg, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the original antibody from which Garran / Lznz / q / YiAi is derived). In another embodiment, the length of one or more CDRs together with the VH (for example, CDR-H1, CDR-H2, or CDR-H3) and / or VL (for example, CDR-L1, CDR-L2, or CDR-L3) of an antibody described herein can vary (eg, be shorter or longer) by one, two, three, four, five, or more amino acids, as long as immunospecific binding to the antibody receptor is maintained. transferrin (eg, human transferrin receptor) (eg, substantially maintained, eg, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% binding of the original antibody from which it is derived). Accordingly, in some embodiments, a CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or CDR-H3 described herein may be one, two, three, four, five, or more amino acids shorter than one or more of the CDRs described herein (eg, CDRs of any of the anti-transferrin receptor antibodies selected from Table 1) as long as immunospecific binding to the transferrin receptor is maintained (eg , human transferrin receptor) (eg, substantially maintained, eg, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least less than 95% with respect to the binding of the original antibody from which it is derived). In some embodiments, a CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or CDR-H3 described herein may be one, two, three, four, five or more amino acids longer. longer than one or more of the CDRs described herein (eg, CDRs of any of the anti-transferrin receptor antibodies selected from Table 1) as long as immunospecific binding to the transferrin receptor (eg, transferrin receptor) is maintained. human transferrin) (eg, substantially maintained, eg, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95 % with respect to the binding of the original antibody from which it is derived). In some embodiments, the amino portion of a CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or CDR-H3 described herein may be extended by one, two, three, four , five or more amino acids compared to one or more of the CDRs described herein (eg, CDRs of any of the anti-transferrin receptor antibodies selected from Table 1) as long as immunospecific binding to the transferrin receptor is maintained (eg, human transferrin receptor (eg, substantially maintained, eg, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% , at least 95% with respect to the binding of the parent antibody from which it is derived.) In some embodiments, the carboxy portion of a CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or CDR-H3 described herein can be extended by one, two, three, four, five or more amino acids compared to one or more of the CDRs described herein (eg, CDRS of any of the receptor antibodies anti-transferrin QQPPbn / l 7Π7 / Σ1 / ΥΙΛΙ selected from Table 1) as long as immunospecific binding to the transferrin receptor (eg, human transferrin receptor) is maintained (eg, substantially maintained, eg, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% with respect to the binding of the original antibody from which it is derived). In some embodiments, the amino portion of a CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or CDR-H3 described herein may be shortened by one, two, three, four , five or more amino acids compared to one or more of the CDRs described herein (eg, CDRs of any of the anti-transferrin receptor antibodies selected from Table 1) as long as immunospecific binding to transferrin receptor is maintained (eg, human transferrin receptor) (eg, substantially maintained, eg, at least 50%, at least 60%, at least 70%, at least 80%, at least 90 %, at least 95% with respect to the binding of the original antibody from which it is derived). In some embodiments, the carboxy portion of a CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or CDR-H3 described herein may be shortened by one, two, three, four , five or more amino acids compared to one or more of the CDRs described herein (eg, CDRs of any of the anti-transferrin receptor antibodies selected from Table 1) as long as immunospecific binding to the transferrin receptor is maintained (eg, human transferrin receptor) (eg, substantially maintained, eg, at least 50%, at least 60%, at least 70%, at least 80%, at least 90 %, at least 95% with respect to the binding of the original antibody from which it is derived). Any method can be used to ascertain that immunospecific binding to the transferrin receptor (eg, human transferrin receptor) is maintained, eg, using binding assays and conditions described in the art. In some examples, any of the anti-transferrin receptor antibodies of the disclosure have one or more CDR sequences (eg, CDR-H or CDR-L) substantially similar to any of the anti-transferrin receptor antibodies selected from the Table 1. For example, the antibodies can include one or more CDR sequence(s) from any of the anti-transferrin receptor antibodies selected from Table 1 that contain up to 5, 4, 3, 2, or 1 amino acid residue variations. compared to the corresponding CDR region in any of the CDRs provided herein (for example, the CDRs of any of the anti-transferrin receptor antibodies selected from Table 1) as long as immunospecific binding to the receptor is maintained of transferrin (eg, human transferrin receptor) (eg, which is substantially maintained, eg, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% with respect to the binding of the original antibody from which it is derived). In some embodiments, any of the αοΓΓπη / ι 7Π7 / =ι / υιλι amino acid variations in any of the CDRs provided herein may be conservative variations. Conservative variations can be introduced into the CDRs at positions where residues are not likely to be involved in interacting with a transferrin receptor protein (eg, a human transferrin receptor protein), for example, as determined based on in a crystalline structure. Some aspects of the disclosure provide transferrin receptor antibodies comprising one or more heavy chain variable (VH) and / or light chain variable (VL) domains that are provided herein. In some embodiments, any of the VH domains provided herein include one or more of the CDR-H sequences (eg, CDR-H1, CDR-H2, and CDR-H3) provided herein. eg, any of the CDR-H sequences provided in any of the anti-transferrin receptor antibodies selected from Table 1. In some embodiments, any of the VL domains provided herein include one or more of the CDR-L sequences (eg, CDR-L1, CDR-L2, and CDR-L3) provided herein, eg, any of the CDR-L sequences provided in any of the antibodies of the anti-transferrin receptor selected from Table 1. In some embodiments, the anti-transferrin receptor antibodies of the disclosure include any antibody that includes a heavy chain variable domain and / or a light chain variable domain of any anti-transferrin receptor antibody, such as any of the anti-transferrin receptor antibodies. anti-transferrin receptor selected from Table 1. In some embodiments, anti-transferrin receptor antibodies of the description include any antibody that includes the variable heavy chain and variable light chain pairs of any anti-transferrin receptor antibody, such as any of anti-transferrin receptor antibodies selected from Table 1. Aspects of the disclosure provide anti-transferrin receptor antibodies having a heavy chain variable domain (VH) and / or light chain variable domain (VL) amino acid sequence homologous to any of those described herein. In some embodiments, the anti-transferrin receptor antibody comprises a heavy chain variable sequence or a light chain variable sequence that is at least 75% (eg, 80%, 85%, 90%, 95%, 98% , or 99%) identical to the heavy chain variable sequence and / or any light chain variable sequence of any anti-transferrin receptor antibody, such as any of the anti-transferrin receptor antibodies selected from Table 1. In some embodiments , the homologous heavy chain variable and / or light chain variable homologous amino acid sequences do not vary within any of the CDR sequences provided herein. For example, in some embodiments, the degree of sequence variation (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) may occur within a variable sequence. Heavy chain and / or light chain variable QQrrbn / LZnZ / q / YIAI excluding any of the CDR sequences provided herein. In some embodiments, any of the anti-transferrin receptor antibodies provided herein comprise a heavy chain variable sequence and a light chain variable sequence comprising a framework sequence that is at least 75%, 80%, 85% , 90%, 95%, 98%, or 99% identical to the framework sequence of any anti-transferrin receptor antibody, such as any of the anti-transferrin receptor antibodies selected from Table 1. In some embodiments, an anti-transferrin receptor antibody, which specifically binds to the transferrin receptor (eg, human transferrin receptor), comprises a light chain VL domain comprising any of the CDR-L domain variants. (CDR-L1, CDR-L2, and CDR-L3), or the CDR-L domain provided herein, of any of the anti-transferrin receptor antibodies selected from Table 1. In some embodiments, an antibody The anti-transferrin receptor, which specifically binds to the transferrin receptor (eg, human transferrin receptor), comprises a light chain VL domain comprising CDR-L1, CDR-L2, and CDR-L3 of any anti-transferrin receptor antibody, such as any of the anti-transferrin receptor antibodies selected from Table 1. In some embodiments, the anti-transferrin receptor antibody comprises a light chain (VL) variable region sequence comprising a , two, three, or four of the framework regions of the light chain variable region sequence of any anti-transferrin receptor antibody, such as any of the anti-transferrin receptor antibodies selected from Table 1. In some embodiments, the anti-transferrin receptor antibody comprises one, two, three, or four of the framework regions of a light chain variable region sequence that is at least 75%, 80%, 85%, 90%, 95%, or 100% identical to one, two, three, or four of the framework regions of the light chain variable region sequence of any anti-transferrin receptor antibody, such as any of the anti-transferrin receptor antibodies selected from Table 1. In some embodiments, the light chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence but by the presence of up to 10 amino acid substitutions, deletions, and / or insertions, preferably up to 10 amino acid substitutions. . In some embodiments, the light chain variable framework region that is derived from said amino acid sequence consists of said amino acid sequence with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues being substituted for an amino acid found at an analogous position in a corresponding non-human, primate, or human light chain variable framework region. aarrbn / i 7n7 / 3i / υιλι In some embodiments, an anti-transferrin receptor antibody that specifically binds to the transferrin receptor comprises the CDR-L1, CDR-L2, and CDR-L3 of any anti-transferrin receptor antibody, such as any of the antibodies of anti-transferrin receptor selected from Table 1. In some embodiments, the antibody further comprises one, two, three, or all four VL framework regions derived from the VL of a human or primate antibody. The primate or human light chain framework region of the antibody selected for use with the light chain CDR sequences described herein may be, for example, at least 70% {for example, at least 75% , 80%, 85%, 90%, 95%, 98%, or at least 99%) identity with a light chain framework region of a non-human parent antibody. The selected primate or human antibody may have the same or substantially the same number of amino acids in its light chain complementarity determining regions as that of the light chain complementarity determining regions of any of the antibodies provided herein. eg, any of the anti-transferrin receptor antibodies selected from Table 1. In some embodiments, the amino acid residues of the primate or human light chain framework region are from a natural antibody light chain framework region. primate or human that has at least 75% identity, at least 80% identity, at least 85% identity, at least 90% identity, at least 95% identity, at least 98 % identity, at least 99% (or greater) identity to the light chain framework regions of any anti-transferrin receptor antibody, such as any of the anti-transferrin receptor antibodies selected from Table 1. In some In embodiments, an anti-transferrin receptor antibody further comprises one, two, three, or all four VL framework regions derived from a human light chain variable kappa subfamily. In some embodiments, an anti-transferrin receptor antibody further comprises one, two, three, or all four VL framework regions derived from a human light chain variable lambda subfamily. In some embodiments, any of the anti-transferrin receptor antibodies provided herein comprise a light chain variable domain that further comprises a light chain constant region. In some embodiments, the light chain constant region is a kappa light chain constant region, or a lambda. In some embodiments, the kappa or lambda light chain constant region is from a mammal, eg, from a human, monkey, rat, or mouse. In some embodiments, the light chain constant region is a human kappa light chain constant region. In some embodiments, the light chain constant region is a human lambda light chain constant region. It should be appreciated that any of the light chain constant regions provided herein may be variants of any of the light chain constant regions provided herein. Qorrbn / iznz / q / YiAi present. In some embodiments, the light chain constant region comprises an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to any of the light chain constant regions. light of any anti-transferrin receptor antibody, such as any of the anti-transferrin receptor antibodies selected from Table 1. In some embodiments, the anti-transferrin receptor antibody is any anti-transferrin receptor antibody, such as any of the anti-transferrin receptor antibodies selected from Table 1. In some embodiments, an anti-transferrin receptor antibody comprises a VL domain comprising the amino acid sequence of any anti-transferrin receptor antibody, such as any of the anti-transferrin receptor antibodies selected from Table 1, and wherein constant regions comprise the amino acid sequences of the constant regions of an IgG, IgE, IgM, IgD, IgA or IgY immunoglobulin molecule, or an IgG, IgE, IgM, IgD, IgA or IgY human immunoglobulin molecule. In some embodiments, an anti-transferrin receptor antibody comprises any of the VL domains, or VL domain variants, and any of the VH domains, or VH domain variants, wherein the VL and VH domains , or variants thereof, are from the same antibody clone, and wherein the constant regions comprise the amino acid sequences of the constant regions of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, of any class ( eg, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2), or any subclass (eg, IgG2a and IgG2b) of immunoglobulin molecule. Non-limiting examples of human constant regions are described in the art, for example, see Kabat E A et al., (1991) supra. In some embodiments, an antibody of the disclosure can bind to a target antigen (eg, transferrin receptor) with relatively high affinity, eg, with a Kd less than 10'6Μ, 10'7Μ, ΙΟ-8Μ, ΙΟ' 9Μ, 10'10Μ, 10'11M or lower. For example, anti-transferrin receptor antibodies can bind to a transferrin receptor protein (eg, human transferrin receptor) with an affinity between 5 pM and 500 nM, eg, between 50 pM and 100 nM, eg , between 500 pM and 50 nM. The disclosure also includes antibodies that compete with any of the antibodies described herein for binding to a transferrin receptor protein (eg, human transferrin receptor) and that have an affinity of 50 nM or less {eg, 20 nM or less, 10 nM or less, 500 pM or less, 50 pM or less, or 5 pM or less). The affinity and binding kinetics of the anti-transferrin receptor antibody can be tested using any suitable method including without limitation biosensor technology {eg, OCTET or BIACORE). In some embodiments, an antibody of the disclosure can bind to a target aarrbn / i 7Π7 / =ι / υιλι antigen (eg, transferrin receptor) with relatively high affinity, eg, with a Kd less than ΙΟ'6Μ, ΙΟ '7Μ, ΙΟ'8Μ, ΙΟ'9Μ, 1040Μ, 1041M or lower. For example, anti-transferrin receptor antibodies can bind to a transferrin receptor protein (eg, human transferrin receptor) with an affinity between 5 pM and 500 nM, eg, between 50 pM and 100 nM, eg , between 500 pM and 50 nM. The disclosure also includes antibodies that compete with any of the antibodies described herein for binding to a transferrin receptor protein (eg, human transferrin receptor) and that have an affinity of 50 nM or less (eg, 20 nM or less, 10 nM or less, 500 pM or less, 50 pM or less, or 5 pM or less). The affinity and binding kinetics of the anti-transferrin receptor antibody can be tested using any suitable method including without limitation biosensor technology (eg, OCTET or BIACORE). In some embodiments, the muscle-targeting agent is a transferrin receptor antibody (eg, antibody and variants thereof as described in International Application Publication WO 2016 / 081643, incorporated herein by reference). In some embodiments, the heavy chain and light chain CDRs of an exemplary antibody according to the different definition systems are provided in Table 1.1. Different systems of definitions, eg, the Kabat definition, the Chothia definition, and / or the Contact definition have been described. See, for example, (for example, Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242, Chothia et al., (1989) Nature 342:877, Chothia, C. et al (1987) 1 Mol Biol 196:901-917, Al-lazikani et al (1997) 1 Molec Biol 273:927-948, and Almagro, 1 Mol.Recognit.17:132-143 (2004. See also hgmp.mrc.ac.uk and bioinf.org.uk / abs). TABLE 1.1 CDRs from stop-chain v light chain of mouse transferrin receptor antibody CDR Kabat Chothia Contact CDR-H1 SYWMH (SEQ ID NO: 267) GYTFTSY (SEQ ID NO: 273) TSYWMH (SEQ ID NO: 275) CDR-H2 EINPTNGRTNYIEKFKS (SEQ ID NO: 268) NPTNGR (SEQ ID NO: 274) WIGEINPTNGRTN (SEQ ID NO: 276) CDR-H3 GTRAYHY (SEQ ID NO: 269) GTRAYHY (SEQ ID NO: 269) ARGTRA (SEQ ID NO: 277) CDR-L1 RASDNLYSNLA (SEQ ID NO: 270) RASDNLYSNLA (SEQ ID NO: 270) YSNLAWY (SEQ ID NO: 278) CDR-L2 DATNLAD (SEQ ID NO: 271) DATNLAD (SEQ ID NO: 271) LLVYDATNLA (SEQ ID NO: 279) CDR-L3 QHFWGTPLT (SEQ ID NO: 272) QHFWGTPLT (SEQ ID NO: 272) QHFWGTPL (SEQ ID NO: 280) aarrbn / i 7Π7 / 3 / ΥΙΛΙ Examples of the heavy chain variable domain (VH) and light chain variable domain sequences are also provided: VH QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINPTNGRTNYIEKFKSKATLTVD KSSSTAYMQLSSLTSEDSAVYYCARGTRAYHYWGQGTSVTVSS (SEQ ID NO: 283) VL DIQMTQSPASLSVSVGETVTITCRASDNLYSNLAWYQQKQGKSPQLLVYDATNLADGVPSRFSGSGSGTQYSLK INSLQSEDFGTYYCQHFWGTPLTFGAGTKLELK (SEQ ID NO: 284) In some embodiments, the transferrin receptor antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are the same as the CDR-H1, CDR-H2, and CDR-H3 shown in Table 1.1. Alternatively or in addition, the transferrin receptor antibody of the present disclosure comprises a CDR-L1, a CDR-L2, and a CDRL3 which are the same as the CDR-L1, CDR-L2, and CDR-L3 shown in Table 1.1. In some embodiments, the transferrin receptor antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3, which collectively contain no more than 5 amino acid variations (eg, no more than 5, 4, 3, 2, or 1 amino acid variation) compared to CDR-H1, CDR-H2, and CDR-H3 as shown in Table 1.1. Collectively means that the total number of amino acid variations in the three heavy chain CDRs is within the defined range. Alternatively or in addition, the transferrin receptor antibody of the present disclosure may comprise a CDR-L1, a CDR-L2, and a CDR-L3, which collectively contain no more than 5 amino acid variations (eg, no more than 5 , 4, 3, 2, or 1 amino acid variation) compared to CDR-L1, CDR-L2, and CDRL3 as shown in Table 1.1. In some embodiments, the transferrin receptor antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3, at least one of which contains no more than 3 amino acid variations (eg, no more than 3, 2, or 1 amino acid variation) compared to the CDR of the counterpart heavy chain as shown in Table 1.1. Alternatively or in addition, the transferrin receptor antibody of the present disclosure may comprise a CDR-L1, a CDR-L2, and a CDR-L3, at least one of which contains no more than 3 amino acid variations (for example , no more than 3, 2, or 1 amino acid variation) compared to the CDR of the light chain counterpart as shown in Table 1.1. In some embodiments, the transferrin receptor antibody of the present disclosure comprises a CDR-L3, which contains no more than 3 amino acid variations (eg, no more than 3, 2, or 1 amino acid variation) compared to the CDR-L3 as shown in Table 1.1. In some embodiments, the transferrin receptor antibody of the present disclosure comprises a CDR-L3 containing an amino acid variation compared to CDR-L3 as shown in Table 1.1. In some embodiments, the transferrin receptor antibody of the present disclosure comprises a CDR-L3 of QHFAGTPLT (SEQ ID NO: 281 according to the definition system of Kabat and Chothia) or QHFAGTPL (SEQ ID NO: 282 according to the Contact definition system). In some embodiments, the transferrin receptor antibody of the present disclosure comprises a CDR-H1, a CDR-H2, a CDRH3, a CDR-L1 and a CDR-L2 that are the same as the CDR-H1, CDR-H2 , and CDR-H3 shown in Table 1.1, and comprises a CDR-L3 of QHFAGTPLT (SEQ ID NO: 281 according to the Kabat and Chothia definition system) or QHFAGTPL (SEQ ID NO: 282 according to the Contact definition). In some embodiments, the transferrin receptor antibody of the present disclosure comprises heavy chain CDRs that collectively are at least 80% (eg, 80%, 85%, 90%, 95%, or 98%) identical to the heavy chain CDRs as shown in Table 1.1. Alternatively or in addition, the transferrin receptor antibody of the present disclosure comprises light chain CDRs that collectively are at least 80% (eg, 80%, 85%, 90%, 95%, or 98%) identical to the light chain CDRs as shown in Table 1.1. In some embodiments, the transferrin receptor antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 283. Alternatively or in addition, the transferrin receptor antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 284. In some embodiments, the transferrin receptor antibody of the present disclosure comprises a VH containing no more than 20 amino acid variations (eg, no more than 20,19,18,17,16,15,14,13,12 ,11,10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as set forth in SEQ ID NO: 283. Alternatively or in addition, the recipient antibody of the present disclosure comprises a VL containing no more than 15 amino acid variations (for example, no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7 , 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VL as set forth in SEQ ID NO: 284. In some embodiments, the transferrin receptor antibody of the present disclosure comprises a VH comprising an amino acid sequence that is at least 80% (eg, 80%, 85%, 90%, 95%, or 98%). identical to VH as set out in SEQ ID aarrbn / i 7Π7 / 3 / ΥΙΛΙ NO: 283. Alternatively or in addition, the transferrin receptor antibody of the present disclosure comprises a VL comprising an amino acid sequence that is at least 80% (eg, 80%, 85%, 90%, 95%, or 98%) identical to VL as set forth in SEQ ID NO: 284. In some embodiments, the transferrin receptor antibody of the present disclosure is a humanized antibody (eg, a humanized variant). In some embodiments, the transferrin receptor antibody of the present disclosure comprises a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 that are the same as the CDR-H1, CDR-H2, and CDR-H3 shown in Table 1.1, and comprise a humanized heavy chain variable region and / or a humanized light chain variable region. Humanized antibodies are human immunoglobulins (recipient antibody) in which residues of a complementarity determining region (CDR) of the recipient are replaced by residues of a CDR from a non-human species (donor antibody) such as mouse, rat, or rabbit that has the desired specificity, affinity, and capacity. In some embodiments, residues in the Fv framework region (FR) of the human immunoglobulin are replaced by corresponding non-human residues. In addition, the humanized antibody may comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to refine and optimize the performance of the antibody. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody will optimally also comprise at least a portion of an immunoglobulin (Fe) constant region or domain, typically that of a human immunoglobulin. Antibodies can have modified Fc regions as described in WO 99 / 58572. Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, six) that are altered from the parent antibody, which are also referred to as one or more CDRs derived from one or more CDRs of the parent antibody. Humanized antibodies may also involve affinity maturation. In some embodiments, humanization is achieved by grafting CDRs (eg, as shown in Table 1.1) into the human IGKV1-NL1*01 and IGHV1-3*01 variable domains. In some embodiments, the transferrin receptor antibody of the present disclosure is a humanized variant comprising one or more amino acid substitutions at positions 9, 13, 17, 18, 40, 45, and 70 compared to VL as described. set forth in SEQ ID NO: 284, and / or one or more amino acid substitutions at positions 1, 5, 7, 11, 12, 20, 38, 40, aarrbn / i 7Π7 / =ι / υιλι 44, 66, 75, 81, 83, 87, and 108 compared to VH as set forth in SEQ ID NO: 283. In some embodiments, the transferrin receptor antibody of the present disclosure is a humanized variant comprising substitutions amino acid substitutions at all positions 9, 13, 17, 18, 40, 45, and 70 compared to VL as set forth in SEQ ID NO: 284, and / or amino acid substitutions at all positions 1, 5, 7 , 11, 12, 20, 38, 40, 44, 66, 75, 81, 83, 87, and 108 compared to VH as set forth in SEQ ID NO: 283. In some embodiments, the transferrin receptor antibody of the present disclosure is a humanized antibody and contains residues at positions 43 and 48 of the VL as set forth in SEQ ID NO: 284. Alternatively or in addition, the transferrin receptor antibody of the present disclosure is a humanized antibody and contains the residues at positions 48, 67, 69, 71, and 73 of the VH as set forth in SEQ ID NO: 283. The VH and VL amino acid sequences of an exemplary humanized antibody that can be used in accordance with the present disclosure are provided: VH Humanized EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVRQAPGQRLEWIGEINPTNGRTNYIEKFKSRATLTVDK SASTAYMELSSLRSEDTAVYYCARGTRAYHYWGQGTMVTVSS (SEQ ID NO: 285) Humanized VL DIQMTQSPSSLSASVGDRVTrrCRASDNLYSNLAWYQQKPGKSPKLLVYDATNLADGVPSRFSGSGSGTDYSLKI NSLQSEDFGTYYCQHFWGTPLTFGAGTKLELK (SEQ ID NO: 286) In some embodiments, the transferrin receptor antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 285. Alternatively or in addition, the transferrin receptor antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 286. In some embodiments, the transferrin receptor antibody of the present disclosure comprises a VH containing no more than 20 amino acid variations (eg, no more than 20,19,18, 17,16,15,14,13,12 ,11,10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as set forth in SEQ ID NO: 285. Alternatively or in addition, the recipient antibody of the present disclosure comprises a VL containing no more than 15 amino acid variations (for example, no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7 , 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VL as set forth in SEQ ID NO: 286. In some embodiments, the transferrin receptor antibody of the present disclosure comprises a VH comprising an amino acid sequence that is at least 80% (eg, 80%, 85%, 90%, 95%, or 98%). identical to VH as set forth in SEQ ID NO: 285. Alternatively or in addition, the transferrin receptor antibody of the present Qorrbn / iznz / q / YiAi description comprises a VL comprising an amino acid sequence that is at least 80% (eg, 80%, 85%, 90%, 95%, or 98%) identical to the VL as described set to SEQ ID NO: 286. In some embodiments, the transferrin receptor antibody of the present disclosure is a humanized variant comprising amino acid substitutions at one or more of positions 43 and 48 compared to VL as set forth in SEQ ID NO: 284, and / or or amino acid substitutions at one or more of positions 48, 67, 69, 71, and 73 compared to VH as set forth in SEQ ID NO: 283. In some embodiments, the transferrin receptor antibody of the present disclosure is a humanized variant comprising an S43A and / or a V48L mutation as compared to VL as set forth in SEQ ID NO: 284, and / or one or more of A67V, L69I, V71R, and K73T mutations as compared to VL VH as set forth in SEQ ID NO: 283. In some embodiments, the transferrin receptor antibody of the present disclosure is a humanized variant comprising amino acid substitutions at one or more of positions 9, 13, 17, 18, 40, 43, 48, 45, and 70 compared to with the VL as set forth in SEQ ID NO: 284, and / or amino acid substitutions at one or more of positions 1, 5, 7, 11, 12, 20, 38, 40, 44, 48, 66, 67, 69, 71, 73, 75, 81, 83, 87, and 108 compared to VH as set forth in SEQ ID NO: 283. In some embodiments, the transferrin receptor antibody of the present disclosure is a chimeric antibody, which may include a heavy constant region and a light constant region from a human antibody. Chimeric antibodies refer to antibodies having a variable region or part of the variable region from a first species and a constant region from a second species. Typically, in these chimeric antibodies, the variable region of both the heavy and light chains mimics the variable regions of antibodies derived from one mammalian species (for example, a non-human mammal such as mouse, rabbit, and rat), while the constant portions are homologous to sequences in antibodies derived from other mammals such as humans. In some embodiments, amino acid modifications can be made in the variable region and / or the constant region. In some embodiments, the transferrin receptor antibody described herein is a chimeric antibody, which may include a heavy constant region and a light constant region from a human antibody. Chimeric antibodies refer to antibodies having a variable region or part of the variable region from a first species and a constant region from a second species. Typically, in these chimeric antibodies, the variable region of both the heavy and light chains mimics the variable regions of antibodies derived from a mammalian species (for example, a non-human mammal such as a mouse, rabbit, and rat), Qorrbn / iznz / q / YiAi while the constant portions are homologous to sequences in antibodies derived from other mammals such as humans. In some embodiments, amino acid modifications can be made in the variable region and / or the constant region. In some embodiments, the heavy chain of any of the transferrin receptor antibodies as described herein may comprise a heavy chain constant region (CH) or a portion thereof (for example, CH1, CH2, CH3, or a combination thereof). The heavy chain constant region can be of any suitable origin, eg, human, mouse, rat, or rabbit. In a specific example, the heavy chain constant region is from a human IgG (a gamma heavy chain), eg, IgG1, IgG2, or IgG4. An exemplary human IgG1 constant region is given below: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSL GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 287) In some embodiments, the light chain of any of the transferrin receptor antibodies described herein may further comprise a light chain (CL) constant region, which may be any CL known in the art. In some examples, the CL is a kappa light chain. In other examples, the CL is a lambda light chain. In some embodiments, the CL is a kappa light chain, the sequence of which is provided below: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSL GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP (SEQ ID NO: 288) Other antibody heavy and light chain constant regions are well known in the art, for example, those provided in the IMGT database (www.imgt.org) or at www.vbase2.org / vbstat.php. , both of which are incorporated by reference herein. Exemplary heavy chain and light chain amino acid sequences of the described transferrin receptor antibodies are provided below: Heavy Chain (VH + human IgGl constant region) QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINPTNGRTNYIEKFKSKATLTVD KSSSTAYMQLSSLTSEDSAVYYCARGTRAYHYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK aarrbn / iznz / q / YiAi (SEQ ID NO: 289) Light Chain (VL + kappa light chain) QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINPTNGRTNYIEKFKSKATLTVD KSSSTAYMQLSSLTSEDSAVYYCARGTRAYHYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCP (SEQ ID NO: 290) Heavy Chain (humanized VH + human IgGl constant region) EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVRQAPGQRLEWIGEINPTNGRTNYIEKFKSRATLTVDK SASTAYMELSSLRSEDTAVYYCARGTRAYHYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSD ​​IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 291) Light Chain (humanized VL + kappa light chain) DIQMTQSPSSLSASVGDRVTITCRASDNLYSNLAWYQQKPGKSPKLLVYDATNLADGVPSRFSGSGSGTDYSLKI NSLQSEDFGTYYCQHFWGTPLTFGAGTKLELKASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSWTV PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP (SEQ ID NO: 292) In some embodiments, the transferrin receptor antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least 80% (eg, 80%, 85%, 90%, 95%, or 98% ) identical to SEQ ID NO: 289. Alternatively or in addition, the transferrin receptor antibody described herein comprises a light chain comprising an amino acid sequence that is at least 80% (eg, 80%, 85%, 90%, 95%, or 98%) identical to SEQ ID NO: 290. In some embodiments, the transferrin receptor antibody described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 289. Alternatively or further, the transferrin receptor antibody described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 290. In some embodiments, the transferrin receptor antibody of the present disclosure comprises a heavy chain containing no more than 20 amino acid variations (eg, no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the heavy chain as set forth in SEQ ID NO: 289. Alternatively or in addition, the antibody The transferrin receptor of the present disclosure comprises a light chain containing no more than 15 aarrbn / i 7Π7 / 3 / ΥΙΛΙ amino acid variations (for example, no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the light chain as set forth in SEQ ID NO: 290. In some embodiments, the transferrin receptor antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least 80% (eg, 80%, 85%, 90%, 95%, or 98% ) identical to SEQ ID NO: 291. Alternatively or in addition, the transferrin receptor antibody described herein comprises a light chain comprising an amino acid sequence that is at least 80% (eg, 80%, 85%, 90%, 95%, or 98%) identical to SEQ ID NO: 292. In some embodiments, the transferrin receptor antibody described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 291. Alternatively or further, the transferrin receptor antibody described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 292. In some embodiments, the transferrin receptor antibody of the present disclosure comprises a heavy chain containing no more than 20 amino acid variations (eg, no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared to the heavy chain of a humanized antibody set forth in SEQ ID NO: 289. Alternatively or in addition, The transferrin receptor antibody of the present disclosure comprises a light chain containing no more than 15 amino acid variations (for example, no more than 20, 19, 18, 17, 16,15, 14, 13,12,11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the humanized antibody light chain as set forth in SEQ ID NO: 290. In some embodiments, the transferrin receptor antibody is an antigen-binding fragment (FAB) of an intact antibody (full-length antibody). The antigen-binding fragment of an intact antibody (full-length antibody) can be prepared via routine methods. For example, F(ab')2 fragments can be produced by pepsin digestion of an antibody molecule, and Fab fragments can be generated by reducing the disulfide bonds of F(ab')2 fragments. Exemplary FAB amino acid sequences of the transferrin receptor antibodies described herein are provided below: Heavy Chain FAB (VH + a portion of the human IgGl constant region) QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINPTNGRTNYIEKFKSKATLTVD KSSSTAYMQLSSLTSEDSAVYYCARGTRAYHYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAAL GCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCP (SEQ ID NO: 293) Heavy Chain FAB (humanized VH + a portion of the human IgGl constant region) QQPPbn / l 7Π7 / Σ1 / ΥΙΛΙ EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVRQAPGQRLEWIGEINPTNGRTNYIEKFKSRATLTVDK SASTAYMELSSLRSEDTAVYYCARGTRAYHYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CP (SEQ ID NO: 294) The transferrin receptor antibodies described herein can be in any form of antibody, including, without limitation, intact (i.e., full-length) antibodies, antigen-binding fragments thereof (such as Fab, Fab' , F(ab')2, Fv), single chain antibodies, bispecific antibodies, or nanobodies. In some embodiments, the transferrin receptor antibody described herein is an scFv. In some embodiments, the transferrin receptor antibody described herein is a scFvFab (eg, scFv fused to a portion of a constant region). In some embodiments, the transferrin receptor antibody described herein is a scFv fused to a constant region (eg, human IgG1 constant region as set forth in SEQ ID NO:289). Other muscle-targeting antibodies In some embodiments, the muscle-targeting antibody is an antibody that specifically binds to hemojuvelin, caveolin-3, Duchenne muscular dystrophy peptide, myosin lib, or CD63. In some embodiments, the muscle-targeting antibody is an antibody that specifically binds to a myogenic precursor protein. Exemplary myogenic precursor proteins include, without limitation, ABCG2, MCadherin / Cadherin-15, Caveolin-1, CD34, FoxKl, Integrin alpha 7, Integrin alpha 7 beta 1, MYF-5, MyoD, Myogenin, NCAM-1 / CD56, Pax3 , Pax7, and Pax9. In some embodiments, the muscle-targeting antibody is an antibody that specifically binds to a skeletal muscle protein. Exemplary skeletal muscle proteins include, without limitation, alpha-Sarcoglycan, beta-Sarcoglycan, Calpain Inhibitors, Creatine Kinase MM / CKMM, eIF5A, Enolase 2 / Neuron-Specific Enolase, epsilon-Sarcoglycan, FABP3 / H-FABP, GDF-8 / Myostatin, GDF-ll / GDF-8, Integrin alpha 7, Integrin alpha 7 beta 1, Integrin beta 1 / CD29, MCAM / CD146, MyoD, Myogenin, Myosin Light Chain Kinase Inhibitors, NCAM-1 / CD56, and Troponin I. In some embodiments, the muscle-targeting antibody is an antibody that specifically binds to a smooth muscle protein. Exemplary smooth muscle proteins include, without limitation, Alpha Smooth Muscle Actin, VE-Cadherin, Caldesmon / CALD1, Calponin 1, Desmin, Histamine H2 R, Motilin R / GPR38, Transgelin / TAGLN, and Vimentin. However, it should be appreciated that antibodies to additional targets are within the scope of this disclosure and the exemplary lists of targets provided herein are not intended to be limiting. QQPPbn / l 7Π7 / Σ1 / ΥΙΛΙ Characteristics / Alterations of Antibodies In some embodiments, conservative mutations can be introduced into antibody sequences (eg, CDRs or framework sequences) at positions where residues are not likely to be involved in interacting with a target antigen (eg, transferrin receptor), for example, as determined based on a crystal structure. In some embodiments, one, two, or more mutations (eg, amino acid substitutions) are introduced into the Fe region of a muscle-targeting antibody described herein (eg, in a CH2 domain (residues 231-340 of human IgGl) and / or CH3 domain (residues 341-447 of human IgGl) and / or the hinge region, numbered according to the Kabat numbering system (for example, the EU index in Kabat) ) to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fe receptor binding, and / or antigen-dependent cellular cytotoxicity. In some embodiments, one, two, or more mutations (eg, amino acid substitutions) are introduced into the hinge region of the Fe region (CH1 domain) such that the number of cysteine ​​residues in the hinge region is altered ( eg, increases or decreases) as described in, eg, US Pat. from the U.S.A. No. 5,677,425. The number of cysteine ​​residues in the hinge region of the CH1 domain can be altered to, for example, facilitate heavy and light chain assembly, or to alter (for example, increase or decrease) the stability of the antibody, or to facilitate conjugation to the linker. In some embodiments, one, two, or more mutations (eg, amino acid substitutions) are introduced into the F region of a muscle-targeting antibody described herein (eg, in a CH2 domain (residues 231-340 of human IgGl) and / or CH3 domain (residues 341-447 of human IgGl) and / or the hinge region, numbered according to the Kabat numbering system (for example, the EU index in Kabat)) to increase or decrease the affinity of the antibody for an Fe receptor (eg, an activated Fe receptor) on the surface of an effector cell. Mutations in the Fc region of an antibody that decrease or increase the affinity of an antibody for an Fc receptor and techniques for introducing such mutations into the Fc receptor or fragment thereof are known to one of skill in the art. Examples of mutations in the Fe receptor of an antibody that can be made to alter the affinity of the antibody for an Fe receptor are described in, for example, Smith P et al., (2012) PNAS 109: 6181-6186, Pat. . from the U.S.A. No. 6,737,056, and International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631, which are incorporated herein by reference. In some embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into an IgG constant domain, or FcRn-binding αοΓΓπη / ι 7Π7 / =ι / υιλι fragment thereof (preferably a Fe or Fe hinge domain fragment) to alter (eg, decrease or increase) the half-life of the antibody in vivo. See, for example, International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631; and Pat. from the U.S.A. Nos. 5,869,046, 6,121,022, 6,277,375, and 6,165,745 for examples of mutations that will alter (eg, decrease or increase) the half-life of an antibody in vivo. In some embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an IgG Fe or Fe domain fragment). hinge) to decrease the half-life of the anti-transferrin receptor antibody in vivo. In some embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably a Fe or Fe hinge domain fragment). ) to increase the half-life of the antibody in vivo. In some embodiments, antibodies may have one or more amino acid mutations (eg, substitutions) in the second constant domain (CH2) (human IgGl residues 231-340) and / or the third constant domain (CH3) (residues 341). -447 of human IgGl), with numbering according to the EU index in Kabat (Kabat E A et al., (1991) supra). In some embodiments, the IgGl constant region of an antibody described herein comprises a methionine (M) to tyrosine (Y) substitution at position 252, a serine (S) to threonine (T) substitution at position 254 , and a threonine (T) to glutamic acid (E) substitution at position 256, numbered according to the EU index as in Kabat. See Pat. from the U.S.A. No. 7,658,921, which is incorporated herein by reference. This type of IgG mutant, referred to as the YTE mutant, has been shown to have a four-fold increased half-life compared to wild-type versions of the same antibody (see Dall'Acqua W F et al., (2006) J Biol Chem 281: 23514 -24). In some embodiments, an antibody comprises an IgG constant domain comprising one, two, three, or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428- 436, numbered according to the EU index as in Kabat. In some embodiments, one, two, or more amino acid substitutions are introduced into an IgG constant domain F region to alter the effector function(s) of the anti-transferrin receptor antibody. The effector ligand in which the affinity is altered can be, for example, an Fe receptor or the C1 component of complement. This approach is described in greater detail in US Pat. from the U.S.A. Nos. 5,624,821 and 5,648,260. In some embodiments, deletion or inactivation (through point mutations or other means) of a constant region domain can reduce Fe receptor binding of circulating antibody thereby increasing tumor localization. See, for example, US Pats. from the U.S.A. Nos. 5,585,097 and 8,591,886 QQrrbn / LZnZ / q / YIAI for a description of mutations that delete or inactivate the constant domain and thereby increase tumor localization. In some embodiments, one or more amino acid substitutions can be introduced into the Fe region of an antibody described herein to remove potential glycosylation sites in the Fe region, which may reduce Fe receptor binding (see, for example, Shields R L et al., (2001) J Biol Chem 276: 6591-604). In some embodiments, one or more amino in the constant region of a muscle-targeting antibody described herein can be replaced with a different amino acid residue so that the antibody has impaired Clq binding and / or reduced cytotoxicity or complement dependent abolished (CDC). This approach is described in more detail in US Pat. from the U.S.A. No. 6,194,551 (Idusogie et al). In some embodiments, one or more amino acid residues in the N-terminal region of the CH2 domain of an antibody described herein is altered to thereby alter the antibody's ability to fix complement. This approach is further described in International Publication No. WO 94 / 29351. In some embodiments, the F region of an antibody described herein is modified to increase the ability of the antibody to mediate antibody-dependent cellular cytotoxicity (ADCC) and / or to increase the affinity of the antibody for an Fcy receptor. This approach is further described in International Publication No. WO 00 / 42072. In some embodiments, the sequence(s) of the heavy and / or light chain variable domain(s) of the antibodies provided herein can be used to generate, for example, antibodies CDR-grafted, chimeric, humanized, or human antigen-binding compounds or fragments, as described elsewhere herein. As understood by one of ordinary skill in the art, any variant, CDR-grafted, chimeric, humanized antibodies, or compounds derived from any of the antibodies provided herein may be useful in the compositions and methods described in the invention. present and will retain the ability to specifically bind to the transferrin receptor, such that the variant, CDR-grafted, chimeric, humanized, or composite antibody has at least 50%, at least 60%, at least 70%, by at least 80%, at least 90%, at least 95% or more binding to the transferrin receptor relative to the original antibody from which it is derived. In some embodiments, the antibodies provided herein comprise mutations that confer desirable properties to the antibodies. For example, to avoid potential complications due to Fab arm swapping, which are known to occur with native IgG4 mAbs, the antibodies provided herein may comprise a stabilizing 'Adair' mutation (Angal S., et al., A single amino acid substitution abolishes the heterogeneity of chimeric mouse / human (IgG4) antibody, Mol Immunol 30, 105-108, Mol Immunol 30, 105-108; 1993), where serine 228 (ELI numbering; residue 241 in ELI numbering Kabat) becomes Qorrbn / iznz / q / YiAi proline resulting in an IgGl-like hinge sequence. Accordingly, any of the antibodies may include a stabilizing 'Adair' mutation. As provided herein, the antibodies of this disclosure may optionally comprise constant regions or parts thereof. For example, a VL domain may be linked at its C-terminus to a light chain constant domain such as Ck or CÁ. Similarly, a VH domain or portion thereof may be linked to all or part of a heavy chain such as IgA, IgD, IgE, IgG, and IgM, and any isotype subclass. Antibodies can include suitable constant regions (see, for example, Kabat et al., Sequences of Proteins of Immunological Interest, No. 91-3242, National Institutes of Health Publications, Bethesda, Md. (1991)). Thus, antibodies within the scope of this disclosure may include VH and VL domain, or an antigen-binding portion thereof, combined with any suitable constant regions. Muscle targeting peptides Some aspects of the disclosure provide muscle-targeting peptides as muscle-targeting agents. Short peptide sequences (eg, peptide sequences 5-20 amino acids in length) that bind to specific cell types have been described. For example, cell-targeting peptides have been described in Vines e., et al, A. Cell-penetrating and cell-targeting peptides in drug delivery Biochim Biophys Acta 2008, 1786: 126-38; Jarver P., et al, In vivo biodistribution and efficacy of peptide mediated delivery Trends Pharmacol Sci 2010; 31:528-35; Samoylova T.I., et al, Elucidation of muscle-binding peptides by phage display screening Mustie Nerve 1999; 22:460-6; U.S.A. patent No. 6,329,501, issued December 11, 2001, entitled METHODS AND COMPOSITIONS FOR TARGETING COMPOUNDS TO MUSCLE; and Samoylov A.M., et aL, Recognition of cell-specific binding of phage display derived peptides using an acoustic wave sensor. Biomol Eng 2002; 18:269-72; the entire contents of each of which are incorporated herein by reference. By designing peptides to interact with specific cell surface antigens (eg, receptors), selectivity to a desired tissue, eg, muscle, can be achieved. Targeting to skeletal muscle has been investigated and a range of molecular payloads are capable of being delivered. These approaches can have high selectivity for muscle tissue without many of the practical drawbacks of a large antibody or viral particle. Accordingly, in some embodiments, the muscle-targeting agent is a muscle-targeting peptide that is 4 to 50 amino acids in length. In some modalities, the muscle targeting peptide has 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, ααΓΓπη / ι 7n7 / 3i / YiAi 42, 43, 44, 45, 46, 47, 48, 49, or 50 amino acids in length. Muscle targeting peptides can be generated using any of many methods, such as phage display. In some embodiments, a muscle-targeting peptide may bind to a cell surface internalization receptor that is over-expressed or relatively over-expressed in muscle cells, for example a transferrin receptor, compared to certain other cells. . In some embodiments, a muscle targeting peptide can be targeted to, eg, bound to, a transferrin receptor. In some embodiments, a peptide that targets a transferrin receptor may comprise a segment of a natural ligand, eg, transferrin. In some embodiments, a peptide that targets a transferrin receptor is as described in U.S. Pat. No. 6,743,893, filed 11 / 30 / 2000, RECEPTOR-MEDIATED UPTAKE OF PEPTIDES THAT BIND THE HUMAN TRANSFERRIN RECEPTOR. In some embodiments, a peptide that targets the transferrin receptor is as described in Kawamoto, M. et al, A novel transferrin receptor-targeted hybrid peptide disintegrates cancer cell membrane to induce rapid killing of cancer cells. BMC Cancer. 2011 Aug 18;11:359. In some embodiments, a peptide that targets a transferrin receptor is as described in U.S. Pat. No. 8,399,653, filed on 5 / 20 / 2011, TRANSFERRIN / TRANSFERRIN RECEPTOR-MEDIATED SIRNA DELIVERY. As discussed above, examples of muscle targeting peptides have been reported. For example, muscle-specific peptides were identified using phage display libraries displaying surface heptapeptides. As an example a peptide having the amino acid sequence ASSLNIA (SEQ ID NO: 6) binds to murine C2C12 myotubes in vitro, and binds to mouse muscle tissue in vivo. Accordingly, in some embodiments, the muscle targeting agent comprises the amino acid sequence ASSLNIA (SEQ ID NO: 6). This peptide exhibited better specificity for binding to cardiac and skeletal muscle tissue after intravenous injection in mice with decreased binding to liver, kidney, and brain. Additional muscle-specific peptides have been identified using phage display. For example, a 12 amino acid peptide was identified by phage display library for muscle targeting in the context of treatment for DMD. See, Yoshida D., et al., Targeting of salicylate to skin and muscle following topical injections in rats. Int J Pharm 2002; 231: 177-84; the entire contents of which are thus incorporated by reference. Here, a 12 amino acid peptide having the sequence SKTFNTHPQSTP (SEQ ID NO: 7) was identified and this muscle-targeting peptide showed better binding to C2C12 cells relative to the ASSLNIA peptide (SEQ ID NO: 6). An additional method to identify muscle-selective peptides (eg, aarrbn / i 7Π7 / 3 / ΥΙΛΙ skeletal muscle) on other cell types includes in vitro selection, which has been described in Ghosh D., et al., Selection of muscle-binding peptides from context-specific peptide-presenting phage librarles for adenoviral vector targeting J l / / / o / 2005; 79: 13667-72; the entire contents of which are incorporated herein by reference. By pre-incubating a random 12-mer phage display library with a mixture of non-muscle cell types, non-specific cell binders were selected. In subsequent rounds of selection the 12 amino acid peptide TARGEHKEEELI (SEQ ID NO: 8) appeared most frequently. Accordingly, in some embodiments, the muscle targeting agent comprises the amino acid sequence TARGEHKEEELI (SEQ ID NO: 8). A muscle targeting agent can be a molecule or peptide that contains an amino acid. A muscle-targeting peptide may correspond to a sequence of a protein that preferentially binds to a protein receptor found on muscle cells. In some embodiments, a muscle-targeting peptide contains a high propensity for hydrophobic amino acids, eg, valine, such that the peptide preferentially targets muscle cells. In some embodiments, a muscle targeting peptide has not been previously characterized or described. These peptides can be devised from, produced, synthesized, and / or derivatized using any of many methodologies, for example phage-displayed peptide libraries, one-bead one-compound peptide libraries, or combinatorial positional-scanning synthetic peptide libraries. Exemplary methodologies have been characterized in the art and are incorporated by reference (Gray, B.P. and Brown, K.C. Combinatorial! Peptide Librarles: Mining for Cell-Binding Peptides Chem Rev. 2014,114:2, 1020-1081.; Samoylova, T.I. and Smith, B.F. Elucidation of muscle-binding peptides by phage display screening. Muscle Nerve, 1999, 22:4. 460-6.). In some embodiments, a muscle targeting peptide has previously been described (see, for example, Writer M .1 et al. Targeted gene delivery to human airway epithelial cells with synthetic vectors incorporating novel targeting peptides selected by phage display. 1 Drug Targeting. 2004;12:185 Caí, D. BDNFmediated enhancement of inflammation and injury in the aging heart. Physiol Genomics. 2006, 24:3, 191-7.; Zhang, L. Molecular profiling of heart endothelial cells. Circulation, 2005, 112:11, 1601-11.; McGuire, MJ. et al. In vitro selection of a peptide with high selectivity for cardiomyocytes in vivo. J Mol Biol. 2004, 342:1, 171-82.). Exemplary muscle targeting peptides comprise an amino acid sequence from the following group: CQAQGQLVC (SEQ ID NO: 9), CSERSMNFC (SEQ ID NO: 10), CPKTRRVPC (SEQ ID NO: 11), WLSEAGPWTVRALRGTGSW (SEQ ID NO: 12) , ASSLNIA (SEQ ID NO: 6), CMQHSMRVC (SEQ ID NO: 13), and DDTRHWG (SEQ ID NO: 14). In some embodiments, a muscle-targeting peptide may comprise about 225 amino acids, about 2-20 amino acids, about 2-15 amino acids, about 2-10 amino acids, aarrbn / i 7η7 / =ι / γΐΛΐ or about 2-5 amino acids. The muscle-targeting peptides may comprise natural amino acids, eg cysteine, alanine, or unnatural or modified amino acids. Unnatural amino acids include β-amino acids, homo-amino acids, proline derivatives, 3-substituted alanine derivatives, linear core amino acids, N-methyl amino acids, and others known in the art. In some embodiments, a muscle targeting peptide may be linear; in other embodiments, a muscle-targeting peptide may be cyclic, for example bicyclic (see, for example, Silvana, M.G. et al. Mol. Therapy, 2018, 26:1, 132-147.). Muscle Targeting Receptor Ligands A muscle-targeting agent can be a ligand, for example a ligand that binds to a receptor protein. A muscle-targeting ligand can be a protein, eg transferrin, that binds to a cell surface internalizing receptor expressed by a muscle cell. Accordingly, in some embodiments, the muscle targeting agent is transferrin, or a derivative thereof that binds to a transferrin receptor. A muscle-targeting ligand may alternatively be a small molecule, for example a lipophilic small molecule that preferentially targets muscle cells over other cell types. Small lipophilic molecules that can target muscle cells include compounds comprising cholesterol, cholesteryl, stearic acid, palmitic acid, oleic acid, oleyl, linolene, linolenic acid, myristic acid, sterols, dihydrotestosterone, testosterone derivatives, glycerin, alkyl chains , trityl groups, and alkoxy acids. Muscle targeting aptamers A muscle-targeting agent may be an aptamer, for example an RNA aptamer, which preferentially targets muscle cells over other cell types. In some embodiments, a muscle targeting aptamer has not been previously characterized or described. These aptamers can be conceived of, produced, synthesized, and / or derivatized using any of many methodologies, for example Systematic Evolution of Ligands by Exponential Enrichment. Exemplary methodologies have been characterized in the art and are incorporated by reference (Yan, A.C. and Levy, M. Aptamers and aptamer targeted delivery RNA biology, 2009, 6:3, 316-20.; Germer, K. et al. RNA aptamers and their therapeutic and diagnostic applications. Int. J. Biochem. Mol. Biol. 2013; 4: 27-40.). In some embodiments, a muscle-targeted aptamer has been previously described (see, for example, Phillippou, S. et al. Selection and Identification of Skeletal-Muscle-Targeted RNA Aptamers. Mol Ther Nucleic Acids. 2018, 10:199-214 .; Thiel, W. H. et al. Smooth Muscle Cell Qorrbn / iznz / q / YiAi targeted RNA Aptamer Inhibits Neointimal Formation. Mol Ther. 2016, 24:4, 779-87). Exemplary muscle targeting aptamers include the A01B RNA aptamer and RNA Apt 14. In some embodiments, an aptamer is a nucleic acid-based aptamer, an oligonucleotide aptamer, or a peptide aptamer. In some embodiments, an aptamer may be about 5-15 kDa, about 5-10 kDa, about 10-15 kDa, about 1-5 Da, about 1-3 kDa, or smaller. Other muscle targeting agents One strategy for targeting a muscle cell (eg, a skeletal muscle cell) is to use a muscle carrier protein substrate, such as a carrier protein expressed in the sarcolemma. In some embodiments, the muscle-targeting agent is a substrate for an efflux transporter that is specific to muscle tissue. In some embodiments, the efflux transporter is specific to skeletal muscle tissue. Two major classes of transporters are expressed in the sarcolemma of skeletal muscle, (1) the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily, which facilitates efflux from skeletal muscle tissue, and (2) the solute carrier superfamily (SLC), which may facilitate the influx of substrates into skeletal muscle. In some embodiments, the muscle targeting agent is a substrate that binds to an ABC superfamily or SLC superfamily of transporters. In some embodiments, the substrate that binds to the ABC or SLC superfamily of transporters is a natural substrate. In some embodiments, the substrate that binds to the ABC or SLC superfamily of transporters is a non-natural substrate, eg, a synthetic derivative thereof that binds to the ABC or SLC superfamily of transporters. In some embodiments, the muscle targeting agent is a substrate of an SLC superfamily of transporters. SLC transporters are either equilibrating or use proton or sodium ion gradients created across the membrane to drive the transport of substrates. Exemplary SLC transporters that have high expression in skeletal muscle include, without limitation, the SATT transporter (ASCT1; SLC1A4), GLUT4 transporter (SLC2A4), GLUT7 transporter (GLUT7; SLC2A7), ATRC2 transporter (CAT-2; SLC7A2), LAT3 (KIAA0245; SLC7A6), PHT1 transporter (PTR4; SLC15A4), OATP-J transporter (OATP5A1; SLC21A15), OCT3 transporter (EMT; SLC22A3), OCTN2 transporter (FU46769; SLC22A5), ENT transporters (ENT1; SLC29A1 and ENT2; SLC29A2), PAT2 transporter (SLC36A2), and SAT2 transporter (KIAA1382; SLC38A2). These transporters may facilitate the influx of substrates into skeletal muscle, providing opportunities for muscle targeting. aarrbn / i 7Π7 / =ι / υιλι In some embodiments, the muscle-targeting agent is a substrate of an equilibrating nucleoside transporter 2 (ENT2) transporter. Relative to other transporters, ENT2 has one of the highest mRNA expressions in skeletal muscle. Although human ENT2 (hENT2) is expressed in most organs of the body such as the brain, heart, placenta, thymus, pancreas, prostate, and kidney, it is especially abundant in skeletal muscle. Human ENT2 facilitates the uptake of its substrates depending on its concentration gradient. ENT2 plays a role in maintaining nucleoside homeostasis by transporting a wide variety of purine and pyrimidine nucleobases. The hENT2 transporter has a low affinity for all nucleosides (adenosine, guanosine, uridine, thymidine, and cytidine) except for inosine. Accordingly, in some modalities, the muscle targeting agent is an ENT2 substrate. Exemplary ENT2 substrates include, without limitation, inosine, 2',3'-dideoxynosine, and calofarabine. In some embodiments, any of the muscle-targeting agents provided herein is associated with a molecular payload (eg, oligonucleotide molecular payload). In some embodiments, the muscle targeting agent is covalently linked to the molecular payload. In some embodiments, the muscle targeting agent is not covalently linked to the molecular payload. In some embodiments, the muscle-targeting agent is a substrate of an organic cation transporter / carnitine (OCTN2), which is a high affinity, sodium-dependent transporter to carnitine. In some embodiments, the muscle targeting agent is carnitine, mildronate, acetylcarnitine, or any derivative thereof that binds to OCTN2. In some embodiments, carnitine, mildronate, acetylcarnitine, or derivative thereof is covalently linked to the molecular payload (eg, oligonucleotide payload). A muscle-targeting agent may be a protein that is protein existing in at least one soluble form that targets muscle cells. In some modalities, a muscle targeting protein may be hemojuvelin (also known as repulsive guidance molecule C or type 2 hemochromatosis protein), a protein involved in iron overload and homeostasis. In some embodiments, the hemojuvelin can be full length or a fragment, or a mutant with at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, for at least 98% or at least 99% sequence identity to a functional hemojuvelin protein. In some embodiments, a hemojuvelin mutant may be a soluble fragment, may lack N-terminal signaling, and / or lack a C-terminal anchor domain. In some modalities, hemojuvelin can be annotated under GenBank RefSeq Accession Numbers NM_001316767.1, NM_145277.4, NM_202004.3, NM_213652.3, or NM_213653.3. It should be appreciated that an αοΓΓπη / ι 7η7 / =ι / γΐΛΐ hemojuvelin may be of human, non-human primate, or rodent origin. Molecular payloads Some aspects of the description provide molecular payloads, for example, for the modulation of a biological outcome, eg, the transcription of a DNA sequence, the splicing and processing of an RNA sequence, the expression of a protein, or the activity of a protein. In some embodiments, a molecular payload is linked to, or otherwise associated with, a muscle-targeting agent. In some embodiments, such molecular payloads are capable of targeting a muscle cell, eg, via specifically binding to a nucleic acid or protein in the muscle cell after delivery to the muscle cell by an associated muscle-targeting agent. It should be appreciated that various types of muscle targeting agents may be used in accordance with the disclosure. For example, the molecular payload can comprise, or consist of, an oligonucleotide (eg, antisense oligonucleotide), a peptide (eg, a peptide that binds to a nucleic acid or protein associated with disease in a muscle cell) , a protein (for example, a protein that binds to a nucleic acid or disease-associated protein in a muscle cell), or a small molecule (for example, a small molecule that modulates the function of a nucleic acid or protein associated with disease in a muscle cell). In some embodiments, the molecular payload is an oligonucleotide comprising a strand having a region of complementarity to a mutated DMD allele. Exemplary molecular payloads are described in greater detail herein, however, it should be appreciated that the molecular payloads provided herein are not intended to be limiting. Oligonucleotides Any suitable oligonucleotide can be used as a molecular payload, as described herein. In some embodiments, the oligonucleotide can be designed to induce exon skipping, eg, EXONDYS 51 oligonucleotide (Sarepta Therapeutics, Inc.), comprising SEQ ID NO: 195 (CUCCAACAUCAAGGAAGAUGGCAUUUCUAG); WVE-210201 (Wave Life Sciences), comprising SEQ ID NO: 186 (UCAAGGAAGAUGGCAUUUCU); Casimersen (Sarepta Therapeutics, Inc.), comprising SEQ ID NO: 159 (CAAUGCCAUCCUGGAGUUCCUG); or Golodirsen (Sarepta Therapeutics, Inc.), comprising SEQ ID NO: 231 (GUUGCCUCCGGUUCUGAAGGUGUUC). In some embodiments, the oligonucleotide can be designed to cause degradation of an mRNA (for example, the oligonucleotide can be a gapmer, siRNA, QQPPbn / l 7Π7 / Σ1 / ΥΙΛΙ ribozyme or an aptamer that causes degradation). In some embodiments, the oligonucleotide can be designed to block translation of an mRNA (eg, the oligonucleotide can be a mixmer, siRNA, or translation-blocking aptamer). In some embodiments, an oligonucleotide can be designed to cause degradation and block translation of an mRNA. In some embodiments, the oligonucleotide can be designed to promote stability of an mRNA. In some embodiments, the oligonucleotide can be designed to promote translation of an mRNA. In some embodiments, an oligonucleotide can be designed to promote stability and promote translation of an mRNA. In some embodiments, an oligonucleotide can be a guide nucleic acid (eg, guide RNA) to direct the activity of an enzyme (eg, a gene editing enzyme). In some embodiments, a guide nucleic acid can direct an enzyme to remove all or part of a mutated DMD allele (eg, to facilitate in-frame exon skipping). In some embodiments, the oligonucleotide can be designed to target repressive regulators of DMD expression, eg, miR-31. Other examples of oligonucleotides are provided herein. It should be appreciated that, in some embodiments, oligonucleotides in one format (eg, antisense oligonucleotides) can be conveniently adapted to another format (eg, siRNA oligonucleotides) by incorporating functional sequences (eg, antisense strand sequences). ) from one format to the other format. Examples of oligonucleotides useful for targeting DMD are provided in U.S. Patent Application Publication US20100130591A1, published May 27, 2010, entitled MULTIPLE EXON SKIPPING COMPOSITIONS FOR DMD; U.S.A. patent No. 8,361,979, issued January 29, 2013, entitled MEANS AND METHOD FOR INDUCING EXON-SKIPPING; U.S. Patent Application Publication 20120059042, published March 8, 2012, entitled METHOD FOR EFFICIENT EXON (44) SKIPPING IN DUCHENNE MUSCULAR DYSTROPHY AND ASSOCIATED MEANS; U.S. Patent Application Publication 20140329881, published November 6, 2014, entitled EXON SKIPPING COMPOSITIONS FOR TREATING MUSCULAR DYSTROPHY; U.S.A. patent No. 8,232,384, issued July 31, 2012, entitled ANTISENSE OLIGONUCLEOTIDES FOR INDUCING EXON SKIPPING AND METHODS OF USE THEREOF; U.S. Patent Application Publication 20120022134A1, published January 26, 2012, entitled METHODS AND MEANS FOR EFFICIENT SKIPPING OF EXON 45 IN DUCHENNE MUSCULAR DYSTROPHY PRE-MRNA; U.S. Patent Application Publication 20120077860, published March 29, 2012, entitled ADENO-ASSOCIATED VIRAL VECTOR FOR EXON SKIPPING IN A GENE ENCODING A DISPENSARLE DOMAN PROTEIN; U.S.A. patent No. 8,324,371, issued December 4, 2012, entitled OLIGOMERS; U.S.A. patent No. 9,078,911, issued July 14, 2015, entitled ANTISENSE OLIGONUCLEOTIDES; U.S.A. patent No. 9,079,934, issued on Qorrbn / iznz / q / YiAi of July 2015, titled ANTISENSE NUCLEIC ACIDS; U.S.A. patent No. 9,034,838, issued May 19, 2015, entitled MIR-31 IN DUCHENNE MUSCULAR DYSTROPHY THERAPY; and International Patent Publication WO2017062862A3, published April 13, 2017, entitled OLIGONUCLEOTIDE COMPOSTTIONS AND METHODS THEREOF; the contents of each 5 of which are incorporated herein in their entirety. Table 2 provides non-limiting examples of oligonucleotide sequences that are useful for DMD targeting, eg, for exon skipping. In some embodiments, an oligonucleotide can comprise any sequence that is provided in Table 2. TABLE 2 Oligonucleotide sequences for DMD targeting. EXON SEQ ID NO: SEQUENCE 8 15 CUUCCUGGAUGGCUUCAAU 8 16 GUACAUUAAGAUGGACUUC 8 17 UAUCUGGAUAGGUGGUAUCAAGAUCUGUAA 8 18 AUGUAACUGAAAAUGUUCUUCUUUA 8 19 UGGAUAGGUGGUAUCAACAUCUGUAAGCAC 8 20 GAUAGGUGGUAUCAACAUCU GU 8 21 UAUCUGGAUAGGUGGUAUCAAGAUCUGUAA 8 22 AAACUUGGAAGAGUGAUGUGAUGUA 8 23 GCUCACUUGUUGAGGGCAAAACUUGGAA 8 24 GCCUUGGCAACAUUUCCACUUCCUG 8 25 UACACACUUUACCUGUGAGAAUAG 8 26 GAUAGGUGGUAUCAACAUCUGUAA 8 27 GAUAGGUGGUAUCAACAUCUG 8 28 GAUAGGUGGUAUCAACAUCUGUAAG 8 29 GGUGGUAUCAACAUCUGUAA 8 30 GUAUCAACAUCUGUAAGCAC 23 31 CGGCUAAUUUCAGAGGGCGCUUUCUUNGAC 23 32 ACAGUGGUGCUGAGAUAGUAUAGGCC 23 33 UAGGCCACUUUGUUGCUCUUGC 23 34 UUCAGAGGGCGCUUUCUUC 23 253 GGCCAA ACCUCGGCUUACCUGAAAU 23 254 GGCCAAACCUCGGCUUACCU 35 35 UCUUCAGGUGCACCUUCUGUUUCUCAAUCU 35 36 UCUGUGAUACUCUUCAGGUGCACCUUCUGU 35 37 UCUUCUGCUCGGGAGGUGACA 35 38 CCAGU UACUAU UCAGAAGAC 35 39 UCUUCAGGUGCACCUUCUGU 43 40 UGCUGCUGUCUUCUUUGCU 43 41 UUGUUUAACUUUUUUCCCAUU 43 42 UGUUAACUUUUUUCCCAUUGG 43 43 CAUUUUGUUAACUUUUUUCCC 43 44 CUGUAGCUUCACCCUUUCC 43 45 GAGAGCUUCCUGUAGCUUCACCCUUU 43 46 UCCUGUAGCUUCACCCUUUCCACAGGCG 43 47 UGUGUUACCUACCCUUUGCG 43 48 UAGACUAUCUUUUAUAUUCUGUAAUAU 43 49 GAGAGCUUCCUGUAGCUUCACCCUUUCCA 43 50 UUCCUGUAGCUUCACCCUUUCCACAGGCGUU 4 3 51 AGCUUCCUGUAGCUUCACCCUUU 43 52 GGAGAGAGCUUCCUGUAGCUUCACCCUUU 43 53 GAGAGCUUCCUGUAGCUUCACCC 43 54 UAUGUGUUACCUACCCUUGUCGGUC 43 55 GGAGAGAGCUUCCUGUAGCU 43 56 UCACCCUUUCCACAGGCGUUGCA 43 57 GCUGGGAGAGAGCUUCCUGUAGCUUCAC 43 58 UGUUACCUACCCUUGUCGGUCCUUGUAC 43 59 CUGCUGUCUUCUUGCUAUGAAUAAUGUC 43 60 GGCGUUGCACUUUGCAAUGCUGCUGUCU 43 61 UUGGAAAUCAAGCUGGGAGAGAGCUUCC 43 62 CUACCCUUGUCGGUCCUUGUACAUUUUG 43 63 GUCAAUCCGACCUGAGCUUUGUUGUAGA 43 64 CUUGCUAUGAAUAAUGUCAAUCCGACC 43 65 UAUAUGUGUUACCUACCC UUGUCGGUCC 43 255 AAUCAGCUGGGAGAGAGCUUCCUGUAGCU 43 256 UCGUUUCUUCUGUCGUCGUAACGUUUC 44 66 UUUGUGUCUUUCUGAGAAAC 44 67 AAAGACUUUACCUUAAGAUAC 44 68 AUCGUCAAAUCGCCUGCAG 44 69 CGCCGCCAUUUCUCAACAG 44 70 UUUGUAUUUAGCAUGUUCCC 44 71 CCGCCAUUUCUCAACAG 44 72 UUCUCAGGAAUUUGUGUCUUU 44 73 GACAACUCUUU 44 74 UCAGCUUCUGUUUAGCCACUG 44 75 UGUUCAGCUU CUGUUAGCCACUGA 44 76 CUGUUCAGCUUCUGUUUAGCCACUGAUU 44 77 UUCUCAACAGAUCUGUCAAAUCGCCUGCAG 44 78 GCCACUGAUUAAAUAUCUUUAUAUAUC 44 79 UCUGUUAGCCACUGAUUAAAUAUCUUUAUA 44 80 GAGAAACUGUUCAGCUUCUGUUUAGCCACUGA 44 81 UCUUUCUGAGAAACUGUUCAGCUUCUGUUAG 44 82 CAGAU CUGUCAAAUCGCCUGCAGGUA 44 83 CAACAGAUCUGUCAAAUCGCCUGCAG 44 84 AAACUGUUCAGCUUCUGUUUAGCCACUGAUUAAA 44 85 GAAACUGUUCAGCUUCUGUUAGCCACUGAUU 44 86 AAACUGUUCAGCUUCUGUUAGCCACUGA 44 87 UGAGAAACUGUUCAGCUUCUGUU AGCCA 44 88 UUCUGAAACUGUUCAGCUUCUGUUUAGCCAC 44 89 UUCUGAGAAACUGUUCAGCUUCUGUU 44 90 GAUCUGUCAAAUCGCCUGCAGGUAA 44 91 AUAAUGAAAACGCCGCCAUUUCUCA 44 92 AAACUGUUCAGCUUCUGUUAGCCAC 44 93 UUGUGUCUUUCUGAGAAACUGUUCA 44 94 CCAAUUCUCAGGAAUUUGUGUCUUU 44 95 AUCGCCUGCAGGUAAAAAGCAUAUGG 44 96 UGAAAACGCCGCCAUUUCUCAACAGAUCUG 44 97 CAUAAUGAAAACGCCGCCAUUUCUCAACAG 44 98 UGUUCAGCUUCUGUUUAGCCACUGAUUAA AU 44 99 CAGAUCUGUCAAAUCGCCUGCAGG 44 100 CAACAGAUCUGUCAAAUCGCCUGCAGG 44 101 CUCAACAGAUCUGUCAAAUCGCCUGCAGG 44 102 GAUCUGUCAAAUCGCCUGCAGGU 44 103 GAUCUGUCAAAUCGCCUGCAGG 44 104 GAUCUGUCA AAUCGCCUGCAG 44 105 CAGAUCUGUCAAAUCGCCUGCAGGU 44 106 CAGAUCUGUCAAAUCGCCUGCAG 44 107 GUGUCUUUCUGAGAAACUGUUCAGC 44 108 GAGAAACUGUUCAGCUUCUGUUAGCCAC 44 109 GAAACUGUUCAGCUUCUGUUAGCCACUG 44 110 CUGUUCAGCUUCUGUUUAGCCACUG 44 111 AUCUGUCAAUCGCCUGCAGGUAAAAAG 44 112 GAUCUGUCAAAUCGCCUGCAGGUAAAAAGC 44 257 CACCGAUUGUCUUCGA 44 258 CCCUUGUACGAUUUAUG 44 259 UCUGUGUUUAAGGACUCU 45 113 GCU GAAUUAUUUCUUCCCCC 45 114 UUUUUCUGUCUGACAGCUG QQPPbn / l 7Π7 / 3 / ΥΙΛΙ 45 115 UCUGUUUUUGAGGAUUGC 45 116 CCACCGCAGAUUCAGGC 45 117 GCCCAAUGCCAUCCUGG 45 118 UUUGCAGACCUCCUGCC 45 119 CAGUUUGCCGCUGCCCA 45 120 GUUGCAUUCAAUGUUCUGAC 45 121 AUUUUUCCUGUAGAAUA CUGG 45 122 GCUGCCCAAUGCGAUCCUGGAGUUCCUGUAAGAU 45 123 GCUGCCCAAUGCCAUCCUGGAGUUCCUG 45 124 GCUGCCCAAUGCCAUCCUGGAGUUCCUGUAA 45 125 CAAUGCCAUCCUGGAGUUCCUGUAAGAUACC 45 126 GCUGCCCAAUGCCAUCCUGGAGU UCCUGUAAG 45 127 CCAAUGCCAUCCUGGAGUUCCUGUAAGAUA 45 128 UUGCCGCUGCCCAAUGCCAUCCUGGAGUUCCUGUAAGAU 45 129 GCUGCCCAAUGCCAUCCUGGAGUUCCUGUAAGAU 45 130 CAAUGCCAUCCUGGAGUUCCUGUAGA 45 131 CAGUUUGCCGCUGCCCAAUGCCAUCC 45 132 CUUCCCCAGUUGCAUUCAAUGUUC 45 133 CUGGCAUCUGUUUUUUGAGGAUUG 45 134 UUAGAUCUGUGUCGCCCUACCU 45 135 GCUGCCCAAUGCCAUCCUGGAGUUCCUGUAAGAUACCAA 45 136 GCCCAAUGCCAUCCUGGAGUUC CUGUAAGAUACC 45 137 CAUCCUGGAGUUCCUGUAAGAUACC 45 138 UGCCAUCCUGGAGUUCCUGUAAGAUACC 45 139 UGCCAUCCUGGAGUUCCUGUAAGAU 45 140 CAAUGCCAUCCUGGAGUUCCUGUAAGAU 45 141 GCCCAAUGCCAUCCUGGAGUUCCUGUAAGAU 45 142 GCCCAAUGCCAUCCUGGAGUUCCUGUAA 45 143 GCCGCUGCCCAAUGACAUCCUGGAGUUCCUGUAA 45 144 GCCAUCCUGGAGUUCCUGUAAGAUA 45 145 CCAAUGCCAUCCUGGAGUUCCUGUA 45 146 CUGACAACAGUUUUGCCGCUGCCCAA 45 147 UUUGAGGAUUGCUGAA 45 148 CAGUUUGCCGCUGCCCAAUGCCAUCCUGGA 45 149 UUGCCGCUGCCCAAUGCCAUCCUGGAGUUC 45 150 UUUGCCGCUGCCCAAUGCCAUCCUG 45 151 CCAAUGCCAUCCUGGAGUUCCU 45 152 CCCAAUGCCAUCCUGGAGUUCCUGUAGA 45 153 CCG CUGCCCAAUGCCAUCCUGGAGUUCC 45 154 CCCAAUGCCAUCCUGGAGUUCCUGUAAGAU 45 155 CCGCUGCCCAAUGCCAUCCUGGAGUUCCUG Garran / Lznz / q / γΐΛΐ 45 156 UGCCCAAUGCCAUCCUGGAGUUCCUGUAAG 45 157 CCCAAUGCCAUCCUGGAGUUCCUGUAAG 45 158 UGCCCAAUGCCAUCCUGGAGUUCCUGUA 45 159 CAAUGCCAUCCUGGAGUUCCUG 45 260 GCCGCUGCCCAAUGCCAUCCUGGAGUUCCUG 45 261 AUUAGAUCUGUCGCCCUACCUCUUUUUUC 45 262 UGUCGCCCUACCUUUUUUUUCUGUCUG 45 263 GCCCAAUGCCAUCCUGGAGUUCCUG 55 160 AGCCUCUCGCUCACUCACCCUGCAAAGGA 50 161 CCACUCAGAGCUCAGAUCUUCUAACUUCC 50 162 CUUCCACUCAGAGCUCAGAUC UUCUAA 50 163 GGGAUCCAGUAUACUUACAGGCUCC 50 164 CUCAGAGCUCAGAUCUU 50 165 GGCUGCUUUUGCCCUC 50 166 CUCAGAUCUUCUAACUUCCUCUUUAAC 50 167 CUCAGAGCUCAGAUCUUCUAACUUCCUCU 50 168 CGCCUUCCACUCAGAGCUCAGAUCUUC 50 169 UCAGCUCUUGAAGUAACGGUUUACG 50 170 UUUGCCCUCAGCUCUUGAAGUAAACGG 50 171 GGCUGCUUUGCCCUCAGCUCUUGAAGU 50 172 CAGGAGCUAGGUCAGGCUGCUUUGCC 50 173 UCCAAUAGUGGU CAGUCCAGGAGCU 50 174 AAAGAGAAUGGGAUCCAGUAUACUUAC 50 175 AAAUAGCUAGAGCCAAAGAGAAUGGGA 50 176 GGCUGCUUUGCCCUCAGCUCUUGAAGUAAACGG 50 177 AGGCUGCUUUGCCCUCAGCUCUUGAGUAA 50 178 GUCAGGCUGCUUUGCCCU CAGCUCUUGAAG 50 179 AGGUCAGGCUGCUUUGCCCUCAGCUCUUGA 50 180 CAGAGCUCAGAUCUUCUAACUUCCU 50 181 CUUACAGGCUCCAAUAGUGGUCAGU 50 182 AUGGGAUCCAGUAUACUUACAGGCU 50 183 AGAGAAUGGGAUCCAGUAUACUUAC 50 1 84 AACUUCCUCUUUAACAGAAAAGCAUAC 50 264 GAGCCUCUCGCUCACUCACCCUGCAAAGGA 51 185 CUCAUACCUUCUGCUUGAUGAUC 51 186 UCAAGGAAGAUGGCAUUUCU 51 187 GAAAGCCAGUCGGUAAGUUC 51 188 CACCCACCAUCACCC 51 189 CCUCUGUGAUUUUAUAACUUGAU 51 190 U GAUAUCCUCAAGGUCACCC 51 191 GGUACCUCCAACAUCAAGGAAGAUGGCAUU 51 192 AUUUCUAGUUUUGGAGAUGGCAGUUUC 51 193 CAUCAAGGAAGAUGGCAUUUCUAGUU 51 194 GAGCAGGUACCUCCAACAUCAAGGAA 51 195 CUCCAACAUCAAGGAAUGGCAUUUCUAG 51 196 ACCAGAGUAACAGUCUGAGUAGGAG 51 197 CACCAGA GUAACAGUCUGAGUAGGA 51 198 UCACCAGAGUAACAGUCUGAGUAGG 51 199 GUCACCAGAGUAACAGUCUGAGUAG 51 200 ACCAGAGUAACAGUCUGAGUAGGAGC 51 201 UUCUGUCCAAGCCCGGUUGAAAUC 51 202 ACAUCAAGGAAGAUGGCAUUUCUAGUUUGG 51 203 ACAUCAAGGAAGAUGGCAUUUCUAG 51 204 AUCAUUUUUUCUCAUACCUUCUGCU 51 205 CACCCACCAUCACCCUCUGUG 51 206 AUCAUCUCGU UGAUAUCCUCAA 51 207 CUCCAACAUCAAGGAAGAUGGCAUUUCU 51 208 CAUCAAGGAAGAUGGCAUUUCUAGU 51 265 AUCAUUUUUU UCUCAUACCU UCUGCUAGGAGCUAAAA 52 209 UUGCUGGUCUUGUUUUUUUC 52 210 CCGUAAUGAUUGUUCU 52 211 GCUGGUCUUGUUUUUUCAA 52 212 UGGUCUUGUUUUUUCAAUUU 52 2 13 GUCUUUUUUUCAAAUUUUG 52 214 CUUGUUUUUUCAAAUUUUGGG 52 215 UGUUUUUCAAAUUUUGGGC 52 216 UCCAACUGGGGACGCCUCUGUUCCAAAUCCUGC 52 217 UCCUGCAUUGUUGCCUGUAAG 52 218 UCCAACUGGGGACGCCUCUGUUCCAAAUCC 52 219 ACUGGGGACGCCUCUGUUCCA 52 220 CCGUAAUGAUUGUGUUCUAGCC 52 221 UGUUAAAAAAACUUACUUCGA 53 222 CUGUUGCCUCCGGUUCUG 53 223 UUGGCUCUGGCCUGUCCU 53 224 UUCAACUGUUGCCUCCGGUUCUGAAGGUGUUCU 53 225 UACUUCAUCCACUGAUUCUCUGAAUU 53 226 CUGAAGGUGUUCUUGUACUUCAUCC 53 227 CUGUUGCCUCCGGUUCUGAAGGUGU 53 228 CUGUUGCCCUCCGGUUCUGAAG GUGUUCUUG 53 229 CAACUGUUGCCUCCGGUUCUGAAGGUGUUC 53 230 UUGCCUCCGGUUCUGAAGGUGUUUUGUAC 53 231 GUUGCCCUCGGUUCUGAAGGUGUUC 53 232 CUCCGGUUCUGAAGGUGUUCUUUG 53 233 CUCCGGUUCUGAAGGUGUUCUU 53 234 CUCCGGUUCUGAAGGUGUUCU 53 235 CUCCGGUUCUGAAGGUGUUC 53 236 CUCCGGUUCUGAAGGUGUU 53 237 CAUUCAACUGUUGCCCUCCGGUUCUG 53 23 8 CUGUUGCCUCCGGUUCUGAAGGUG 53 239 CAUUCAACUGUUGCCUCCGGUUCUGAAGGUG 53 240 UACUAACCUUGGUUUCUGUGA 53 241 UGUAUAGGGACCCUCCUUCCAUGACUC 53 242 CUAACCUUGGUUUCUGUGAUUUUCU 53 243 GGUAUCUUUGAUACUAACCUUGGUUU C 53 244 AUUCUUUCAACUAGAAUAAAAG 53 245 GAUUCUGAAUUCUUUCAACUAGAAU 53 246 AUCCCACUGAUUCUGAAUUC 53 247 AACCGAGACCGGACAGGAUUCU 53 266 GGAAGCUAAGGAAGAAGCUGAGCAGG 55 248 CUGUUGCAGUAAUCUAUGAG 55 249 UGCCAUUGUUUCAUCAGCUCUUU 55 250 UGCAGUAAUCUAUGAGUUUC 55 251 UCCUGUAGGACAUUGGCAGU 55 252 GAGUCUUUCUAGGAGCCUU aarrbn / i 7Π7 / 3 / ΥΙΛΙ Examples of oligonucleotides to promote DMD gene editing include International Patent Publication WO2018053632A1, published March 29, 2018, entitled METHODS OF MODIFYING THE DYSTROPHIN GENE AND RESTORING DYSTROPHIN EXPRESSION AND USES THEREOF; International Application Publication WO2017049407A1, published March 30, 2017, entitled MODIFICATION OF THE DYSTROPHIN GENE AND USES THEREOF; International Application Publication WO2016161380A1, published October 6, 2016, entitled CRISPR / CAS-RELATED METHODS AND COMPOSITIONS FOR TREATING DUCHENNE MUSCULAR DYSTROPHY AND BECKER MUSCULAR DYSTROPHY; International Application Publication WO2017095967, published June 8, 2017, titled THERAPEUTIC TARGETS FOR THE CORRECTION OF THE HUMAN DYSTROPHIN GENE BY GENE EDITING AND METHODS OF USE; International Application Publication WO2017072590A1, published May 4, 2017, entitled MATERIALS AND METHODS FORTREATMENT OF DUCHENNE MUSCULAR DYSTROPHY; International Application Publication WO2018098480A1, published on May 31, 2018, entitled PREVENTION OF MUSCULAR DYSTROPHY BY CRISPR / CPF1-MEDIATED GENE EDITING; U.S. Patent Application Publication US20170266320A1, published September 21, 2017, entitled RNA-Guided Systems for In Vivo Gene Editing; Request Publication International WO2016025469A1, published on February 18, 2016, titled PREVENTION OF MUSCULAR DYSTROPHY BY CRISPR / CAS9-MEDIATED GENE EDITING; U.S. Patent Application Publication 2016 / 0201089, published July 14, 2016, entitled RNA-GUIDED GENE EDITING AND GENE REGULATION; and U.S. Patent Application Publication 2013 / 0145487, published June 6, 2013, entitled MEGANUCLEASE VARIANTS CLEAVING A DNA TARGET SEQUENCE FROM THE DYSTROPHN GENE AND USES THEREOF, the contents of each of which are incorporated herein by reference in their entirety. In some embodiments, an oligonucleotide may have a region of complementarity to DMD gene sequences from multiple species, eg, selected human, mouse, and non-human species. In some embodiments, the oligonucleotide may have the region of complementarity to a mutant DMD allele, for example, a DMD allele with at least one mutation in any of human DMD exons 1-79 that leads to a change of framework and improper RNA splicing / processing. In some embodiments, the oligonucleotide can be targeted to cRNA or mRNA, eg, for degradation. In some embodiments, the oligonucleotide can be targeted, eg, for degradation, to a nucleic acid encoding a protein involved in a mismatch repair pathway, eg, MSH2, MutLalpha, MutSbeta, MutLalpha. Non-militant examples of proteins involved in mismatch repair pathways, for which mRNAs encoding such proteins can be targeted by the oligonucleotides described herein, are described in lyer, R.R. et al., DNA tryp / et repeat expansion and mismatch repaii1' Annu Rev Biochem. 2015;84:199-226.; and Schmidt M.H. and Pearson C.E., Diseases associated repeat instability and mismatch repair DNA Repair (Amst). 2016 Feb;38:117-26. Oligonucleotide size / sequence Oligonucleotides can have a variety of different lengths, eg, depending on the format. In some embodiments, an oligonucleotide is 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, 75, or more nucleotides in length. In some embodiments, the oligonucleotide is 8 to 50 nucleotides in length, 8 to 40 nucleotides in length, 8 to 30 nucleotides in length, 10 to 15 nucleotides in length, 10 to 20 nucleotides in length, 15 to 25 nucleotides in length, 21 to 23 nucleotides in length, etc. In some embodiments, a nucleic acid sequence complementary to an oligonucleotide for purposes of this disclosure is specifically hybridizable or specific for the target nucleic acid when binding of the sequence to the target molecule (for example, aarrbn / i 7Π7 / 3 / ΥΙΛΙ mRNA) interferes with the function of the target (eg, mRNA) to cause a change in activity (eg, inhibit translation, disrupt splicing, exon skipping) or expression (eg, degrade a target mRNA) and exists a sufficient degree of complementarity to prevent non-specific binding of the sequence to non-target sequences under conditions where evasion of non-specific binding is desired, for example, under physiological conditions in the case of in vivo assays or therapeutic treatment, and in the case of in vitro tests, under conditions in which the tests are carried out under conditions of adequate stringency. Thus, in some embodiments, an oligonucleotide may be at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%. %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary to consecutive nucleotides of a target nucleic acid. In some embodiments a complementary nucleotide sequence is not required to be 100% complementary to that of its target to be specifically hybridizable or specific for a target nucleic acid. In some embodiments, an oligonucleotide comprises the region of complementarity to a target nucleic acid that is in the range of 8 to 15, 8 to 30, 8 to 40, or 10 to 50, or 5 to 50, or 5 to 40 nucleotides in length. length. In some embodiments, a region of complementarity of an oligonucleotide to a target nucleic acid has 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, or 50 nucleotides in length. In some embodiments, the region of complementarity is complementary to at least 8 consecutive nucleotides of a target nucleic acid. In some embodiments, an oligonucleotide may contain 1, 2, or 3 base mismatches compared to the portion of the target nucleic acid consecutive nucleotides. In some embodiments the oligonucleotide may have up to 3 mismatches over 15 bases, or up to 2 mismatches over 10 bases. b. Oligonucleotide Modifications: The oligonucleotides described herein can be modified, for example, comprise a modified sugar moiety, a modified internucleoside linkage, a modified nucleotide, and / or combinations thereof. Furthermore, in some embodiments, the oligonucleotides may exhibit one or more of the following properties: they do not mediate alternative splicing; they are not immune stimulants; they are resistant to nuclease; have better cellular uptake compared to unmodified oligonucleotides; they are not toxic to cells or mammals; they have better endosomal output internally in a cell; minimizes TLR stimulation; o Avoid pattern recognition receptors. Any of the oligonucleotide chemistries or modified formats described herein can be combined with each other. By Qorrbn / iznz / q / YiAi example, one, two, three, four, five, or more different types of modifications can be included within the same oligonucleotide. In some embodiments, certain nucleotide modifications can be used that make up an oligonucleotide into which they are incorporated that are more resistant to nuclease digestion than native oligodeoxynucleotide or oligoribonucleotide molecules; these modified oligonucleotides survive intact for a longer time than unmodified oligonucleotides. As examples of modified oligonucleotides include those comprising modified backbones, for example, modified internucleoside linkages such as phosphorothioates, phosphotriesters, methyl phosphonates, short chain alkyl or cycloalkyl intersugar linkages or short chain heteroatomic or heterocyclic intersugar linkages. Accordingly, the oligonucleotides of the disclosure can be stabilized against nucleolytic degradation such as by the incorporation of a modification, eg, a nucleotide modification. In some embodiments, an oligonucleotide can be up to 50 or up to 100 nucleotides in length where 2 to 10, 2 to 15J2 to 16, 2 to 17, 2 to 18, 2 to 19, 2 to 20, 2 to 25, 2 to 30, 2 to 40, 2 to 45, or more nucleotides of the oligonucleotide are modified nucleotides. The oligonucleotide can be from 8 to 30 nucleotides in length where 2 to 10, 2 to 15„ 2 to 16, 2 to 17, 2 to 18, 2 to 19, 2 to 20, 2 to 25, 2 to 30 nucleotides of the oligonucleotide are modified nucleotides. The oligonucleotide can be 8 to 15 nucleotides in length where 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 2 to 13, 2 to 14 nucleotides of the oligonucleotide are modified nucleotides. Optionally, the oligonucleotides can have every nucleotide except 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides modified. Oligonucleotide modifications are described hereinafter. c. modified nucleotides In some embodiments, an oligonucleotide includes a modified 2'-nucleotide, for example, a 2'-deoxy, 2'-deoxy-2'-fluoro, 2'-O-methyl, 2'-O-methoxyethyl (2' -O-MOE), 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2'-O-dimethylaminopropyl (2'-O-DMAP), 2'-Odimethylaminoethyloxyethyl (2'-O-DMAEOE), or 2'-O-N-methylacetamido (2'-O-NMA). In some embodiments, an oligonucleotide can include at least one modified 2'-O-methyl nucleotide, and in some embodiments, all nucleotides include a 2'-O-methyl modification. In some embodiments, an oligonucleotide comprises modified nucleotides in which the ribose ring comprises a bridging portion connecting two atoms in the ring, eg, connecting the 2'-0 atom to the 4'-C atom. In some embodiments, the oligonucleotides are blocked, eg, they comprise modified nucleotides in which the ribose ring is blocked by a methylene bridge connecting the 2'-0 atom and the 4'-C atom. aarrbn / i 7n7 / 3i / υιλι Examples of LNAs are described in International Patent Application Publication WO / 2008 / 043753, published April 17, 2008, and entitled RNA Antagonist Compounds For The Modulation Of PCSK9', the content of which is hereby incorporated by reference in its whole. Other modifications that can be used in the oligonucleotides described herein include ethylene-bridged nucleic acids (ENAs). ENAs include, but are not limited to, 2'-O,4'-C-ethylene bridged nucleic acids. Examples of ENAs are provided in International Patent Publication No. WO 2005 / 042777, published May 12, 2005, and entitled APP / ENA Antisensdj Morita et al., Nucleic Acid Res., Suppl 1:241-242, 2001. ; Surono et al., Hum. GeneTher., 15:749-757, 2004; Koizumi, Curr. Opinion. Mol. Ther., 8:144-149, 2006 and Horie et al., Nucleic Acids Symp. Being (Oxf), 49:171-172, 2005; the disclosures of which are incorporated herein by reference in their entireties. In some embodiments, the oligonucleotide may comprise a bridged nucleotide, such as a locked nucleic acid (LNA) nucleotide, a restricted ethyl nucleotide (cEt), or an ethylene bridged nucleic acid (ENA) nucleotide. In some embodiments, the oligonucleotide comprises a modified nucleotide described in one of the following United States Patents or Patent Application Publications: U.S. Pat. 7,399,845, issued July 15, 2008, and entitled Έ-Modified Bicydic Nucleic Acid Anaiogd', U.S. Pat. 7,741,457, issued June 22, 2010, and entitled 6-Modified Bicyciic Nucleic Acid Anaiogdj U.S. Pat. 8,022,193, issued September 20, 2011, and entitled 6Modified Bicyciic Nucleic Acid Analogd', U.S. Pat. 7,569,686, issued August 4, 2009, and entitled Compounds And Methods For Synthesis Of Bicyciic Nucleic Acid Anaiogd', U.S. Pat. 7,335,765, issued on February 26, 2008, and entitled Nove! Nucieoside And Oligonucleotide Anaiogued', U.S. Pat. 7,314,923, issued January 1, 2008, and entitled Nove! Nudeoside And Oligonucleotide Analogue', U.S. Pat. 7,816,333, issued Oct. 19, 2010, and entitled Oligonucleotide Anaiogues And Methods UtUizing The Samé' and U.S. Publication Number 2011 / 0009471 now U.S. Patent. 8,957,201, issued February 17, 2015, and entitled Oligonucleotide Anaiogues And Methods UtUizing The Samé', the contents of each of which are incorporated herein by reference for all purposes. In some embodiments, the oligonucleotide comprises at least one modified nucleotide at the 2' position of the sugar, preferably a 2'-O-alkyl, 2'O-alkyl-O-alkyl or 2'-fluoro-nucleotide modified nucleotide. In other preferred embodiments, RNA modifications include 2'-fluoro, 2'-amino, and 2' O-methyl modifications to the pyrimidine ribose, basic a residues, or an inverted base at the 3' end of the RNA. In some embodiments, the oligonucleotide may have at least one modified nucleotide that results in an increase in the Tm of the oligonucleotide over a range of 1°C, 2°C, Garran / Lznz / q / YiAi 3°C, 4°C, or 5°C compared to an oligonucleotide that does not have the at least one modified nucleotide. The oligonucleotide may have a plurality of modified nucleotides that results in an overall increase in the Tm of the oligonucleotide over a range of 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C C, 9 °C, 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C or more compared to an oligonucleotide that does not have the modified nucleotide . The oligonucleotide may comprise alternating nucleotides of different types. For example, an oligonucleotide can comprise deoxyribonucleotides or alternating ribonucleotides and 2'-fluoro-deoxyribonucleotides. An oligonucleotide can comprise deoxyribonucleotides or alternating ribonucleotides and 2'-O-methyl nucleotides. An oligonucleotide may comprise alternating 2'-fluoro nucleotides and 2'-O-methyl nucleotides. An oligonucleotide can comprise alternating bridged nucleotides and 2'-fluoro or 2'-O-methyl nucleotides. Internucleotide Linkages / Major Structures In some embodiments, the oligonucleotide may contain a phosphorothioate linkage or other modified internucleotide. In some embodiments, the oligonucleotide comprises phosphorothioate internucleoside linkages. In some embodiments, the oligonucleotide comprises phosphorothioate internucleoside linkages between at least two nucleotides. In some embodiments, the oligonucleotide comprises phosphorothioate internucleoside linkages between all of the nucleotides. For example, in some embodiments, oligonucleotides comprise modified internucleotide linkages at the first, second, and / or third internucleoside linkage at the 5' or 3' end of the nucleotide sequence. Phosphorus-containing linkages that can be used include, but are not limited to, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates comprising 3'alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates comprising 3' '-aminophosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates that have normal 3'-5' bonds, analogs of those 2'-5' bonds, and those that have reversed polarity where adjacent pairs of nucleoside are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'; see U.S. Pat. us. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563, 253; 5,571,799; 5,587,361; and 5,625,050. In some embodiments, the oligonucleotides may have heteroatom backbones, such as methylene(methylene) or MMI backbones; amide backbones (see De Mesmaeker et al. Ace. Chem. Res. 1995, 28:366-374); structures QQPPbn / ΙΖΠΖ / ^ / ΥΙΛΙ morpholino principals (see Summerton and Weller, U.S. Pat. No. 5,034,506); or peptide nucleic acid (PNA) backbones (where the phosphodiester backbone of the oligonucleotide is replaced with a polyamide backbone, the nucleotides are attached directly or indirectly to the aza nitrogen atoms of the polyamide backbone, see Nielsen et al., Science 1991, 254,1497). Stereospecific oligonucleotides In some embodiments, the internucleotide phosphorus atoms of the oligonucleotides are chiral, and the properties of the oligonucleotides are tuned based on the configuration of the chiral phosphorus atoms. In some embodiments, appropriate methods can be used to synthesize P-chiral oligonucleotide analogs in a stereocontrolled fashion (for example, as described in Oka N, Wada T, Stereocontrolled synthesis of oligonucleotide analogs containing chiral internucleotidic phosphorus atoms. Chem Soc Rev. 2011 Dec;40(12):5829-43.) In some embodiments, phosphorothioate-containing oligonucleotides are provided that comprise nucleoside units that are linked together by either substantially all Sp or substantially all Rp phosphorothioate intersugar bonds. In some embodiments, such substantially chirally pure intersugar phosphorothioate oligonucleotides are prepared by enzymatic or chemical synthesis, as described, for example, in U.S. Pat. 5,587,261, issued December 12, 1996, the contents of which are incorporated herein by reference in their entirety. In some embodiments, chirally controlled oligonucleotides provide selective cleavage patterns for a target nucleic acid. For example, in some embodiments, a chirally controlled oligonucleotide provides a unique cleavage site within a complementary sequence of a nucleic acid, as described, for example, in U.S. Patent Application Publication Ser. 20170037399 Al, published February 2, 2017, titled CHIRAL DESIGN, the contents of which are incorporated herein by reference in their entirety. Morpholinos In some embodiments, the oligonucleotide can be a morpholino-based compound. Oligomeric morpholino-based compounds are described in Dwaine A. Braasch and David R. Corey, Biochemistry, 2002, 41(14), 4503-4510); Genesis, volume 30, issue 3, 2001; Heasman, ]., Dev. Biol., 2002, 243, 209-214; Nasevicius et al., Nat. Genet., 2000, 26, 216-220; Lacerra et al., Proc. nati. Acad. Sci., 2000, 97, 9591-9596; and Pat. from the U.S.A. No. 5,034,506, issued Jul. 23, 1991. In some embodiments, the morpholino-based oligomeric compound is a morpholino phosphorodiamidate (PMO) oligomer (for example, as described in Iverson, Curr. aarrbn / i 7Π7 / =ι / υιλι Opinion. Mol. Ther., 3:235-238, 2001; and Wang et al., 1 gene Med., 12:354-364, 2010; the disclosures of which are incorporated herein by reference in their entireties). G. Peptide Nucleic Acids (PNAs) In some embodiments, both a sugar bond and an internucleoside (backbone) nucleotide unit of an oligonucleotide are replaced with novel groups. In some embodiments, the base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an oligonucleotide mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of an oligonucleotide is replaced with an amide-containing backbone, eg, an aminoethylglycine backbone. The nucleobases are retained and are attached directly or indirectly to the aza nitrogen atoms of the amide portion of the backbone. Representative publications reporting the preparation of PNA compounds include, but are not limited to, U.S. Pat. us. 5,539,082; 5,714,331; and 5,719,262, each of which is incorporated herein by reference. Additional teaching of PNA compounds can be found in Nielsen et al., Science, 1991, 254, 1497-1500. gapmers In some embodiments, the oligonucleotide is a gapmer. A gapmer oligonucleotide generally has the formula 5'-X-Y-Z-3', with X and Z as flanking regions around a gap region Y. In some embodiments, the Y region is a contiguous stretch of nucleotides, for example, a gap region. at least 6 nucleotides of DNA, which are capable of recruiting a seRNA, such as seRNA H. In some embodiments, the gapmer binds to the target nucleic acid, at which point a seRNA is recruited and can then cleave the target nucleic acid. In some embodiments, the Y region is flanked at both 5' and 3' by X and Z regions comprising high affinity modified nucleotides, eg, one to six modified nucleotides. Examples of modified nucleotides include, but are not limited to, 2' MOE or 2'OMe or Locked Nucleic Acid (LNA) bases. The X and Z framing sequences can be one to twenty nucleotides, one to eight nucleotides, or one to five nucleotides in length, in some embodiments. The flanking sequences X and Z may be similar in length or different in length. The gap segment Y may be a nucleotide sequence of five to twenty nucleotides, twelve nucleotides in size, or six to ten nucleotides in length, in some embodiments. In some embodiments, the gap region of gapmer oligonucleotides may contain modified nucleotides known to be acceptable for the efficient action of seRNAH. Qorrbn / iznz / q / γΐΛΐ as well as DNA nucleotides, such as C4'-substituted nucleotides, acyclic nucleotides, and arabin-configured nucleotides. In some embodiments, the gap region comprises one or more unmodified internucleosides. In some embodiments, each of the one or both flanking regions comprises one or more phosphorothioate internucleoside linkages (eg, phosphorothioate internucleoside linkages or other linkages) between at least two, at least three, at least four, at least five or more nucleotides. In some embodiments, the gap region and two flanking regions each independently comprise modified internucleoside linkages (eg, phosphorothioate internucleoside linkages or other linkages) between at least two, at least three, at least four, at least five or more nucleotides. A gapmer can be produced using appropriate methods. U.S. Patents, U.S. Patent Publications, and PCT Publications teaching gapmer preparation include, but are not limited to, Pat. from the U.S.A. Nos. 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; 5,700,922; 5,898,031; 7,432,250; and 7,683,036; U.S. Patent Publications Nos. US20090286969, US20100197762, and US20110112170; and PCT Publication Nos. WO2008049085 and WO2009090182, each of which is incorporated herein by reference in its entirety. mixmers In some embodiments, an oligonucleotide described herein may be a mixmer or comprise a mixmer sequence pattern. In general, mixmers are oligonucleotides that comprise both natural and non-natural nucleotides or comprise two different types of non-natural nucleotides typically in an alternating pattern. Mixmers generally have high binding affinity compared to unmodified oligonucleotides and can be used to specifically bind to a target molecule, for example, to block a binding site on the target molecule. Generally, mixmers do not recruit an seRNA to the target molecule and thus do not promote cleavage of the target molecule. Such oligonucleotides that are unable to recruit seRNA H have been described, for example, see WO2007 / 112754 or WO2007 / 112753. In some embodiments, the mixmer comprises or consists of a repeating pattern of nucleotide analogs and natural nucleotides, or one type of nucleotide analog and a second type of nucleotide analog. However, a mixmer need not comprise a repeating pattern and may instead comprise any arrangement of modified nucleotides and natural nucleotides or any arrangement of one type of modified nucleotide and a second type of modified nucleotide. The repeating pattern can, for example, be every second or every third nucleotide is a modified nucleotide, such as LNA, and the remaining nucleotides are natural aarrbn / i 7η7 / =ι / γΐΛΐ nucleotides, such as DNA, or are an analogue of 2' substituted nucleotide such as 2'MOE or 2'fluoro analogs, or any other modified nucleotides described herein. It is recognized that the repeating pattern of modified nucleotides, such as LNA units, may combine with the modified nucleotide at fixed positions—for example, at the 5' or 3' end. In some embodiments, a mixmer does not comprise a region of more than 5, more than 4, more than 3, or more than 2 consecutive natural nucleotides, such as DNA nucleotides. In some embodiments, the mixmer comprises at least one region consisting of at least two consecutive modified nucleotides, such as at least two consecutive LNAs. In some embodiments, the mixmer comprises at least one region consisting of at least three consecutive modified nucleotide units, such as at least three consecutive LNAs. In some embodiments, the mixmer does not comprise a region of more than 7, more than 6, more than 5, more than 4, more than 3, or more than 2 consecutive nucleotide analogs, such as LNAs. In some embodiments, the LNA units can be replaced with other nucleotide analogs, such as those referred to herein. Mixmers can be designed to comprise a mixture of affinity-enhancing modified nucleotides, such as in the non-limiting example of LNA nucleotides and 2'-O-methyl nucleotides. In some embodiments, a mixmer comprises modified internucleoside linkages (eg, phosphorothioate internucleoside linkages or other linkages) between at least two, at least three, at least four, at least five, or more nucleotides. A mixmer can be produced using any suitable method. Representative U.S. patents, U.S. Patent publications, and PCT publications teaching the preparation of mixmers include U.S. Patent publications. Nos. US20060128646, US20090209748, US20090298916, US20110077288, and US20120322851, and U.S. Pat. No. 7687617. In some embodiments, a mixmer comprises one or more morpholino nucleotides. For example, in some embodiments, a mixmer may comprise morpholino nucleotides mixed (for example, in an alternating fashion) with one or more other nucleotides (for example, DNA, RNA nucleotides) or modified nucleotides (for example, nucleotides of LNA, 2'O-Methyl). In some embodiments, mixmers are useful for splicing correction or exon skipping, for example, as reported in Touznik A., et al., LNA / DNA mixmer-based antisense oligonucleotides corred alternative spiicing of the SMN2 gene and restore SMN protein expression in type 1SMA fibroblasts Scientific Reports, volume 7, Article number: 3672 (2017), Chen S. et al., Synthesis of a Morphoiino Nudeic Acid (MNA)-Uridine Phosphoramidite, and Exon αοΓΓπη / ι 7η7 / =ι / γΐΛΐ Skipping Using MNA / 2 -O-Methy / Mixmer Antisense Oligonucleotide, Molecules 2016, 21, 1582, the contents of each of which are incorporated herein by reference. RNA Interference (RNAi) In some embodiments, the oligonucleotides provided herein may be in the form of small interfering RNAs (siRNAs), also known as short interfering RNAs or silencing RNAs. siRNA is a class of double-stranded RNA molecules, typically about 20-25 base pairs in length, that target nucleic acids (e.g., mRNA) for degradation via RNA interference (RNAi) pathways in cells. cells. The specificity of siRNA molecules can be determined by the binding of the antisense strand of the molecule to its target RNA. Effective siRNA molecules are generally less than 30 to 35 base pairs in length to prevent activation of non-specific RNA interference pathways in the cell via the interferon response, although longer siRNA may also be effective. After selection of an appropriate target RNA sequence, siRNA molecules comprising a nucleotide sequence complementary to all or a portion of the target sequence, ie an antisense sequence, can be designed and prepared using appropriate methods (see, for example, PCT Publication number WO 2004 / 016735, and U.S. Patent Publication Nos. 2004 / 0077574 and 2008 / 0081791). The siRNA molecule can be double-stranded (ie a dsRNA molecule comprising an antisense strand and a complementary sense strand) or single-stranded (ie a ssRNA molecule comprising only one antisense strand). The siRNA molecules may comprise a duplex, asymmetric duplex, hairpin, or asymmetric hairpin secondary structure, having self-complementary sense and antisense strands. Double-stranded siRNA can comprise RNA strands that are of the same or different lengths. Double-stranded siRNA molecules can also be assembled from a single oligonucleotide in a stem-loop structure, where the sense and antisense self-complementary regions of the siRNA molecule are linked via nucleic acid-based linker(s). or non-nucleic acid-based, as well as circular single-stranded RNA having two or more loop structures and a stem comprising sense and antisense self-complementary strands, wherein the circular RNA can be processed either in vivo or in vitro to generate a molecule of active siRNA capable of mediating RNAi. Small hairpin RNA (shRNA) molecules are thus also contemplated herein. These molecules comprise a specific antisense sequence in addition to the reverse complement (sense) sequence, typically separated by a spacer or loop sequence. The separator split Qorrbn / iznz / q / YiAi or loop provides a single-stranded RNA molecule and its reverse complement, so that they can be annealed to form a dsRNA molecule (optionally with additional processing steps that may result in the addition or deletion of one, two, three or more nucleotides from the 3' end and / or the 5' end of either or both strands). A spacer may be of a sufficient length to allow antisense and sense sequences to anneal and form a double-stranded structure (or stem) prior to cleavage of the spacer (and, optionally, subsequent processing steps that may result in the addition or removal of spacers). one, two, three, four, or more nucleotides from the 3' end and / or the 5' end of either or both strands). A spacer sequence can be an unrelated nucleotide sequence that is located between two regions of complementary nucleotide sequences that, when annealed into a double-stranded nucleic acid, comprise shRNA. The total length of siRNA molecules can vary from about 14 to about 100 nucleotides depending on the type of siRNA molecule being designed. Generally between about 14 and about 50 of these nucleotides are complementary to the RNA target sequence, that is, they constitute the specific antisense sequence of the siRNA molecule. For example, when the siRNA is a b¡- or single-stranded siRNA, the length can range from about 14 to about 50 nucleotides, whereas when the siRNA is a shRNA or circular molecule, the length can range from about 40 nucleotides. to about 100 nucleotides. A siRNA molecule may comprise a 3' pendant at one end of the molecule. The other end can be blunt end or also have a pendant (5' or 3'). When the siRNA molecule comprises a pendant at both ends of the molecule, the length of the pendants may be the same or different. In one embodiment, the siRNA molecule of the present disclosure comprises 3' overhangs of about 1 to about 3 nucleotides at both ends of the molecule. QQrrbn / LZnZ / q / YIAI microRNA (miRNAs) In some embodiments, an oligonucleotide may be a microRNA (miRNA). MicroRNAs (referred to as miRNAs) are small non-coding RNAs, which belong to a class of regulatory molecules that control gene expression by binding to complementary sites on a target RNA transcript. Typically, miRNAs are generated from large RNA precursors (termed pri-miRNAs) that are processed in the nucleus into approximately 70 nucleotide pre-miRNAs, which fold into imperfect stem-loop structures. These pre-miRNAs typically undergo a further processing step within the cytoplasm where mature miRNAs of 18-25 nucleotides in length are excised from one side of the pre-miRNA hairpin by an RNAse III enzyme, Dicer. As used herein, miRNAs including pri-miRNA, pre-mRNA, mature miRNA, or fragments of variants thereof that retain the biological activity of mature miRNA. In one embodiment, the miRNA size range can be from 21 nucleotides to 170 nucleotides. In one embodiment the miRNA size range is 70 to 170 nucleotides in length. In another embodiment, mature miRNAs from 21 to 25 nucleotides in length can be used. aptamers In some embodiments, the oligonucleotides provided herein may be in the form of aptamers. Generally, in the context of molecular payloads, an aptamer is any nucleic acid that specifically binds to a target, such as a small molecule, protein, nucleic acid in a cell. In some embodiments, the aptamer is a DNA aptamer or an RNA aptamer. In some embodiments, an aptamer nucleic acid is a single-stranded DNA or RNA (ssDNA or ssRNA). It should be understood that a single stranded nucleic acid aptamer can form helices and / or loop structures. The nucleic acid forming the nucleic acid aptamer may comprise natural nucleotides, modified nucleotides, natural nucleotides with hydrocarbon (eg, an alkylene) linkers or a polyether linker (eg, a PEG linker) inserted between one or more nucleotides, nucleotides modified with hydrocarbon or PEG linkers inserted between one or more nucleotides, or a combination thereof. Exemplary publications and patents describing aptamers and methods of producing the aptamers include, for example, Lorsch and Szostak, 1996; Jayasena, 1999; Pat. from the U.S.A. Nos. 5,270,163; 5,567,588; 5,650,275; 5,670,637; 5,683,867; 5,696,249; 5,789,157; 5,843,653; 5,864,026; 5,989,823; 6,569,630; 8,318,438 and PCT application WO 99 / 31275, each of which is incorporated herein by reference. ribozymes In some embodiments, the oligonucleotides provided herein may be in the form of a ribozyme. A ribozyme (ribonucleic acid enzyme) is a molecule, typically an RNA molecule, that is capable of carrying out specific biochemical reactions, similar to the action of protein enzymes. Ribozymes are molecules with catalytic activities including the ability to cleave specific phosphodiester bonds in RNA molecules to which they hybridize, such as mRNA substrates, RNA-containing substrates, jRNAs, and ribozymes, themselves. Ribozymes can assume one of many physical structures, one of which is called a hammerhead. A hammerhead ribozyme is composed of a nucleus Catalytic Garran / Lznz / q / YiAi containing nine conserved bases, a double-stranded stem-and-loop structure (stemloop II), and two regions complementary to the target RNA flanking regions of the catalytic core. The flanking regions enable the ribozyme to bind to the target RNA specifically through the formation of double-stranded stems I and III. Cleavage occurs in cis (ie, cleavage of the same RNA molecule containing the hammerhead motif) or trans (cleavage of a different RNA substrate containing the ribozyme) next to a specific ribonucleotide triplet by a transesterification reaction of a 3',5'-phosphate diester to a 2',3'-cyclic phosphate diether. Without wishing to be bound by theory, it is believed that this catalytic activity requires the presence of specific, highly conserved sequences in the catalytic region of the ribozyme. Modifications in ribozyme structure have also included substitution or replacement of various non-core portions of the molecule with non-nucleoside molecules. For example, Benseler et al. (1 Am. Chem. Soc. (1993) 115:8483-8484) describe hammerhead-like molecules in which two of the stem II base pairs, and all four of the loop II nucleotides were replaced with non-nucleoside linkers based on hexaethylene glycol, propanediol, bis(triethylene glycol) phosphate, tris(propanediol) bisphosphate, or bis(propanediol) phosphate. Ma et al. (Biochem. (1993) 32:1751-1758; Nucleic Acids Res. (1993) 21:2585-2589) replaced the six nucleotide loops of the TAR ribozyme hairpin with ethylene glycol-related, non-nucleotide linkers. Thomson et al. (Nucleic Acids Res. (1993) 21:5600-5603) replaced loop II with linear, non-nucleotide linkers of 13, 17, and 19 atoms in length. Ribozyme oligonucleotides can be prepared using well-known methods (see, for example, PCT Publications WO9118624; WO9413688; WO9201806; and WO 92 / 07065; and U.S. Patents 5436143 and 5650502) or can be purchased from commercial sources (by example, US Biochemicals) and, if desired, can incorporate nucleotide analogs to increase the resistance of the oligonucleotide to degradation by nudeases in a cell. The ribozyme can be synthesized in any known manner, eg, using a commercially available synthesizer produced, eg, by Applied Biosystems, Inc. or Milligen. The ribozyme can also be produced in recombinant vectors by conventional means. See, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory (Current edition). Ribozyme RNA sequences can be conventionally synthesized, for example, through the use of RNA polymerases such as T7 or SP6. N. Guide Nucleic Acids In some embodiments, the oligonucleotides are guide nucleic acids, eg, guide RNA (gRNA) molecules. Generally, a guide RNA is a synthetic RNA short QQrrbn / LZOZ / q / YIAI composed of (1) a scaffold sequence that binds to a programmable nucleic acid DNA-binding protein (napDNAbp), such as Cas9, and (2) a nucleotide spacer portion that defines the target DNA sequence (eg, target genomic DNA) to which the gRNA binds to bring the programmable nucleic acid DNA-binding protein into proximity to the target DNA sequence. In some embodiments, the napDNAbp is a programmable nucleic acid protein that complexes with (eg, binds or associates with) one or more RNAs that direct the programmable nucleic acid protein to a target DNA sequence (eg , a target genomic DNA sequence). In some embodiments, a programmable nucleic acid nuclease, when in complex with an RNA, may be referred to as a nuclease:RNA complex. Guide RNA can exist as a complex of two or more RNAs, or as a single RNA molecule. Guide RNAs (gRNAs) that exist as a single RNA molecule can be referred to as simple guide RNAs (sgRNAs), although gRNA is also used to refer to guide RNAs that exist either as single molecules or as a group. complex of two or more molecules. Typically, gRNAs that exist as a single RNA species comprise two domains: (1) a domain that shares homology with a target nucleic acid (ie, directs binding of a Cas9 complex to the target); and (2) a domain that binds to a Cas9 protein. In some embodiments, domain (2) corresponds to a sequence known as a tracrRNA and comprises a stem-loop structure. In some embodiments, domain (2) is identical or homologous to a tracrRNA as provided in Jinek et al, Science 337:816-821 (2012), the entire contents of which are incorporated herein by reference. In some embodiments, a gRNA comprises two or more of domains (1) and (2), and may be referred to as an extended gRNA. For example, an extended gRNA will bind to two or more Cas9 proteins and bind to a target nucleic acid in two or more distinct regions, as described herein. The gRNA comprises a nucleotide sequence that complements a target site, which mediates the binding of the nuclease / RNA complex to said target site, providing the sequence specificity of the nuclease:RNA complex. In some embodiments, the programmable RNA nuclease is endonuclease Cas9 (CRISPR-associated system), eg, Cas9 (Csnl) from Streptococcus pyogenes (see, eg, Complete genome sequence of an MI strain of Streptococcus pyogenes. Ferretti 11, McShan W.M., Ajdic D.l, Savic D.J., Savic G., Lyon K., Primeaux C., Sezate S., Suvorov A.N., Kenton S., Lai H.S., Lin S.P., Qian Y., lia H.G., Najar F.Z., Ren Q ., Zhu H., Song L., White 1, Yuan X., Clifton S.W., Roe B.A., McLaughlin R.E., Proc. Nati. Acad. Sci. U.S.A. 98:4658-4663 (2001); encoded small RNA and host factor RNase III Deltcheva E., Chylinski K., Sharma C.M., Gonzales K., Chao Y., Pirzada Z.A., Eckert M.R., Vogel 1, Charpentier E., Nature 471:602-607 aarrbn / i 7Π7 / 3 / ΥΙΛΙ (2011) and A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity Jinek M., Chylinski K., Fonfara I., Hauer M., Doudna J.A., Charpentier E. Science 337:816 -821 (2012), the full contents of each of which are incorporated herein by reference. multimers In some embodiments, the molecular payloads may comprise multimers (eg, concatemers) of 2 or more oligonucleotides connected by a linker. Thus, in some embodiments, the oligonucleotide charge of a complex can be increased beyond the available binding sites on a targeting agent (for example, the available thiol sites on an antibody) or otherwise adjusted to achieve a particular payload payload content. The oligonucleotides in a multimer can be the same or different (eg, they target different genes or different sites on the same gene or products thereof). In some embodiments, multimers comprise 2 or more oligonucleotides linked together by a cleavable linker. However, in some embodiments, the multimers comprise 2 or more oligonucleotides linked together by a non-cleavable linker. In some embodiments, a multimer comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, or more oligonucleotides linked together. In some embodiments, a multimer comprises 2 to 5, 2 to 10, or 4 to 20 oligonucleotides linked together. In some embodiments, a multimer comprises 2 or more oligonucleotides linked end-to-end (in a linear arrangement). In some embodiments, a multimer comprises 2 or more oligonucleotides linked end-to-end via an oligonucleotide-based linker (eg, poly-dT linker, abasic linker). In some embodiments, a multimer comprises a 5' end of one oligonucleotide linked to a 3' end of another oligonucleotide. In some embodiments, a multimer comprises a 3' end of one oligonucleotide linked to a 3' end of another oligonucleotide. In some embodiments, a multimer comprises a 5' end of one oligonucleotide linked to a 5' end of another oligonucleotide. In some embodiments, the multimers can even comprise a branched structure comprising multiple oligonucleotides linked together by a branching linker. Additional examples of multimers that can be used in the complexes provided herein are described, for example, in U.S. Patent Application Ser. Number 2015 / 0315588 Al, titled Methods of delivering multiple targeting oligonucleotides to a cell using available linkers, which was published on November 5, 2015; U.S. Patent Application Number 2015 / 0247141 Al, titled Multimeric OHgonudeotide Compounds, which was published on September 3 aarrbn / i 7η7 / =ι / γΐΛΐ, 2015, U.S. Patent Application Number US 2011 / 0158937 Al, titled Immunostimulatory O / igonuc / eotide Multimers, which was published on June 3, 2011; and U.S. Pat. Number 5,693,773, entitled Triplex-Forming Antisense OHgonudeotides Having Abasic Linkers Targeting Nudeic Adds Comprising Mixed Sequences Of Purines And Pyrimidines, which was issued on December 2, 1997, the contents of each of which are incorporated herein by reference in their whole. small molecules: Any suitable small molecule can be used as a molecular payload, as described herein. In some embodiments, the small molecule increases exon skipping of DMD mutant sequences. In some embodiments, the small molecule is as described in US Patent Application Publication Ser. US20140080896A1, published March 20, 2014, entitled IDENTIFICATION OF SMALL MOLECULES THAT FACILITATE THERAPEUTIC EXON SKIPPING. Additional examples of small molecule payloads are provided in U.S. Pat. No. 9,982,260, issued May 29, 2018, entitled Identification of structurally similar small molecules that enhance therapeutic exon skipping. For example, in some embodiments, the small molecule is an exon skipping enhancer such as perphenazine, flupentixol, zuclopenthixol, or corynanthine. In some embodiments, a small molecule exon skipping enhancer inhibits the ryanodine or calmodulin receptor. In some embodiments, the small molecule is an inhibitor of the Η-Ras pathway such as manumicin A. In some embodiments, the small molecule is a stop codon suppressor and desensitizes ribosomes to premature stop codons. In some embodiments, the small molecule is ataluren, as described in McEIroy S.P. et al. A Lack of Premature Termination Codon Read Through Efficacy of PTC124 (Ataluren) in a Diverse Array of Reporter Assays. PLOS Biology, published June 25, 2013. In some embodiments, the small molecule is a corticosteroid, for example, as described in Manzur, A.Y. et al. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2004;(2):CD003725. In some embodiments, the small molecule upregulates the expression and / or activity of genes that can replace dystrophin function, such as utrophin. In some embodiments, a utrophin modulator is as described in International Publication No. WO2007091106, published August 16, 2007, entitled TREATMENT OF DUCHENNE MUSCULAR DYSTROPHY and / or International Publication No. WO / 2017 / 168151, published on October 5, 2017, titled COMPOSITION FOR THE TREATMENT OF DUCHENNE MUSCULAR DYSTROPHY. ααΓΓπη / ι 7Π7 / 3 / ΥΙΛΙ Peptides / Proteins Any suitable peptide or protein can be used as a molecular payload, as described herein. In some embodiments, a protein is an enzyme. In some embodiments, peptides or proteins can be produced, synthesized, and / or derivatized using many methodologies, for example phage display peptide libraries, one-bead one-compound peptide libraries, or combinatorial position-scanning synthetic peptide libraries. . Exemplary methodologies have been characterized in the art and are incorporated by reference (Gray, B.P. and Brown, K.C. Combinatorial Peptide Librarles: Mining for Cell-Binding Peptides Chem Rev. 2014, 114:2, 1020-1081.; Samoylova, T.I. and Smith, B.F. Elucidation of muscle-binding peptides by phage display screening. Muscle Nerve, 1999, 22:4. 4606.). In some embodiments, a peptide can facilitate exon skipping in an expressed mRNA of a mutated allele of DMD. In some embodiments, a peptide can promote the expression of functional dystrophin and / or the expression of a protein capable of functioning in place of dystrophin. In some embodiments, the payload is a protein that is a functional fragment of dystrophin, for example an amino acid segment of a functional dystrophin protein. In some embodiments, the peptide or protein comprises at least one zinc finger. In some embodiments, the peptide or protein may comprise about 2-25 amino acids, about 2-20 amino acids, about 2-15 amino acids, about 2-10 amino acids, or about 2-5 amino acids. The peptide or protein may comprise natural amino acids, for example cysteine, alanine, or unnatural or modified amino acids. Unnatural amino acids include β-amino acids, homo-amino acids, proline derivatives, 3-substituted alanine derivatives, linear core amino acids, N-methyl amino acids, and others known in the art. In some embodiments, the peptide may be linear; in other embodiments, the peptide may be cyclic, eg bicyclic. Nucleic Acid Constructs Any suitable gene expression construct can be used as a molecular payload, as described herein. In some embodiments, a gene expression construct can be a vector or a cDNA fragment. In some embodiments, a gene expression construct can be messenger RNA (mRNA). In some embodiments, an mRNA used herein can be a modified mRNA, for example, as described in U.S. Pat. 8,710,200, issued April 24, 2014, entitled Engineered nudeic acids encoding a modified erythropoietin and their expressiorf'. In some embodiments, an mRNA can QOCCbn / LZnZ / q / YIAI comprise a 5' methyl cap. In some embodiments, an mRNA may comprise a polyA tail, optionally up to 160 nucleotides in length. A gene expression construct can encode a dystrophin protein sequence, a dystrophin fragment, a minidystrophin, a utrophin protein, or any protein that shares a common function with dystrophin. In some embodiments, the gene expression construct can be expressed, eg, over-expressed, within the nucleus of a muscle cell. In some embodiments, the gene expression constructs encode a protein that comprises at least one zinc finger. In some embodiments, the gene expression construct encodes a protein that promotes dystrophin expression or a protein that shares function with dystrophin, eg, utrophin. In some embodiments, the gene expression construct encodes a gene editing enzyme. In some embodiments, the gene expression construct is as described in U.S. Patent Application Publication No. US20170368198A1, published December 28, 2017, titled Optimized mini-dystrophin genes and expression cassettes and their use; Duan D. Myodys, a full-length dystrophin plasmid vector for Duchenne and Becker muscular dystrophy gene therapy. Curr Opin Mol Ther 2008;10:86-94; and the expression cassettes described in Tang, Y. et al., AAV-directed muscular dystrophy gene therapy Expert Opin Biol Ther. 2010 Mar;10(3):395-408; the contents of each of which are incorporated herein by reference in their entirety. linkers The complexes described herein generally comprise a linker that connects a muscle-targeting agent to a molecular payload. A linker comprises at least one covalent bond. In some embodiments, a linker may be a single bond, eg, a disulfide bond or disulfide bridge, that connects a muscle-targeting agent to a molecular payload. However, in some embodiments, a linker can connect a muscle targeting agent to a molecule through multiple covalent bonds. In some embodiments, a linker may be a cleavable linker. However, in some embodiments, a linker may be a non-cleavable linker. A linker is generally stable in vitro and in vivo, and may be stable in certain cellular environments. Additionally, generally a linker does not negatively impact the functional properties of either the muscle-targeting agent or the molecular payload. Examples and methods of linker synthesis are known in the art (see, for example, Kline, T. et al. Methods to Make Homogenous Antibody Drug Conjugates. Pharmaceutical Research, 2015, 32:11, 3480-3493.; Jain, N. et al Current ADC Linker Chemistry Pharm Res. Selection of Linker, Payload and Conjugation Chemistry AAPS 1 2015, 17:2, 339-351.). A precursor to a linker will typically contain two different reactive species that allow binding of both the muscle targeting agent and a molecular payload. In some embodiments, the two different reactive species may be a nucleophile and / or an electrophile. In some embodiments, a linker is linked to a muscle-targeting agent via conjugation to a lysine residue or a cysteine ​​residue of the muscle-targeting agent. In some embodiments, a linker is connected to a cysteine ​​residue of a muscle-targeting agent via a maleimide-containing linker, where optionally the maleimide-containing linker comprises a maleimidocaproyl or maleimidomethyl cyclohexane-1-carboxylate group. In some embodiments, a linker is linked to a cysteine ​​residue of a muscle-targeting agent or thiol-functionalized molecular payload via a 3-arylpropionitrile functional group. In some embodiments, a linker is connected to a muscle-targeting agent and / or a molecular payload via an amide bond, a hydrazide, a trizaol, a thioether, or a disulfide bond. Cleavable linkers A cleavable linker can be a protease sensitive linker, a pH sensitive linker, or a glutathione sensitive linker. These linkers are generally cleavable only intracellularly and are preferably stable in extracellular environments, eg extracellular to a muscle cell. Protease sensitive linkers are cleavable by protease enzymatic activity. These linkers typically comprise peptide sequences and may be 2-10 amino acids, about 2-5 amino acids, about 5-10 amino acids, about 10 amino acids, about 5 amino acids, about 3 amino acids, or about 2 amino acids in length. . In some embodiments, a peptide sequence may comprise natural amino acids, eg, cysteine, alanine, or unnatural or modified amino acids. Unnatural amino acids include β-amino acids, homo-amino acids, proline derivatives, 3-substituted alanine derivatives, linear core amino acids, N-methyl amino acids, and others known in the art. In some embodiments, a protease-responsive linker comprises a valine-citrulline or alanine-citrulline dipeptide sequence. In some embodiments, a protease-sensitive linker can be cleaved by a lysosomal protease, eg, cathepsin B, and / or an endosomal protease. A pH sensitive linker is a covalent bond that is easily degraded in high or low pH environments. In some embodiments, a pH sensitive linker can be cleaved at a pH in the range of 4 to 6. In some embodiments, a pH sensitive linker comprises a hydrazone or cyclic acetal. In some embodiments, a pH sensitive linker is Garran / Lznz / q / YiAi cleaved within an endosome or a lysosome. In some embodiments, a glutathione sensitive linker comprises a disulfide moiety. In some embodiments, a glutathione-responsive linker is cleaved by a disulfide exchange reaction with a glutathione species within a cell. In some embodiments, the disulfide moiety further comprises at least one amino acid, eg, a cysteine ​​residue. In some embodiments, the linker is a Val-cit linker (for example, as described in U.S. Patent 6,214,345, incorporated herein by reference). In some embodiments, prior to conjugation, the val-cit linker has a structure of: Qorrbn / iznz / q / YiAi In some embodiments, after conjugation, the val-cit linker has a structure of: HNΛcr'nh2 non-cleavable linkers In some embodiments, non-cleavable linkers may be used. Generally, a non-cleavable linker cannot be readily degraded in a cellular or physiological environment. In some embodiments, a non-cleavable linker comprises an optionally substituted alkyl group, where substitutions can include halogens, hydroxyl groups, oxygen species, and other common substitutions. In some embodiments, a linker may comprise an optionally substituted alkyl, an optionally substituted alkylene, an optionally substituted arylene, a heteroarylene, a peptide sequence comprising at least one unnatural amino acid, a truncated glucan, a sugar or sugars that cannot be enzymatically degraded, an azide, an alkyne azide, a peptide sequence comprising an LPXT sequence, a thioether, a biotin, a biphenyl, polyethylene glycol repeating units or equivalent compounds, acid esters, acid amides, sulfonamides, and / or or an alkoxyamine linker. In some embodiments, sortase-mediated ligation will be used to covalently link a muscle-targeting agent comprising an LPXT sequence to a molecular payload comprising a (G)n sequence (see for example Proft T. Sortasemediated protein ligation : an emerging biotechnology tool for protein modification and immobilization. Biotechnol Lett. 2010, 32(1):1-10.). In some embodiments, a linker may comprise a substituted alkylene, an optionally substituted alkenylene, an optionally substituted alkynylene, an optionally substituted cycloalkylene, an optionally substituted cycloalkenylene, an optionally substituted arylene, an optionally substituted heteroarylene further comprising at least one selected heteroatom of N, 0, and S,; an optionally substituted heterocyclylene comprising at least one heteroatom selected from N, O, and S,; an imino, an optionally substituted nitrogen species, an optionally substituted oxygen species O, an optionally substituted sulfur species, or a poly(alkylene oxide), for example polyethylene oxide or polypropylene oxide. linker conjugation In some embodiments, a linker is connected to a muscle-targeting agent and / or molecular payload via a phosphate, thioether, ether, carboncarbon, or amide bond. In some embodiments, a linker is connected to an oligonucleotide through a phosphate or phosphorothioate group, for example a phosphate terminus of an oligonucleotide backbone. In some embodiments, a linker is linked to a muscle-targeting agent, for example an antibody, through a lysine or cysteine ​​residue present in the muscle-targeting agent. In some embodiments, a linker is linked to a muscle-targeting agent and / or molecular payload by a cycloaddition reaction between an azide and an alkylene to form a triazole, where the azide and alkylene can be located on the agent. muscle targeting, molecular payload, or the linker. In some embodiments, an alkyne can be a cyclic alkyne, for example, a cydooctin. In some embodiments, an alkyne can be bicyclononine (also known as bicyclo[6.1.0]nonine or BCN) or substituted bicyclononine. In some embodiments, a cyclooctane is as described in International Patent Application Publication WO2011136645, published November 3, 2011, entitled, "Fused Cydooctyne Compounds And Their Use In Metal-free CHck Reaction." In Garran / Lznz / q / YiAi In some embodiments, an azide can be a sugar or carbohydrate molecule comprising an azide. In some embodiments, an azide may be 6-azido-6-deoxygalactose or 6-azido-N-acetylgalactosamine. In some embodiments, a sugar or carbohydrate molecule comprising an azide is as described in International Patent Application Publication WO2016170186, published October 27, 2016, entitled, Process For The Modifier! Of A Giycoprotein Using A Giycosyitransferase That Is Or Is Derived From A β(1,4)-ΝAcetylgalactosaminyltransferase'. In some embodiments, an acid addition reaction between an azide and an alkyne to form a triazole, where the azide and alkyne can be located in the muscle targeting agent, molecular payload, or linker is as described in the Publication of the International Patent Application WO2014065661, published on May 1, 2014, entitled, Modified antibody, antibody-conjugate andprocess for the preparer) thereof'·, or the Publication of the International Patent Application WO2016170186, published on October 27, 2016, entitled, Process For The Modification Of A Giycoprotein Using A Giycosyitransferase That Is Or Is Derived From A P(l,4)-N-Acetyigaiactosaminyitransferasd'. In some embodiments, a linker further comprises a spacer, eg, a polyethylene glycol spacer or an acyl / carbomoyl sulfamide spacer, eg, a HydraSpace™ spacer. In some embodiments, a separator is as described in Verkade, 1M.M. et al., / 1 Polar Sulfamide Spacer Significantly Enhances the Manufacturability, StabiHty, and Therapeutic Index of Antibody-Drug Conjugate^', Antibodies, 2018, 7,12. In some embodiments, a linker is linked to a muscle targeting agent and / or molecular payload by the Diels-Alder reaction between a dienophile and a diene / hetero-diene, wherein the dienophile and the diene / hetero-diene it may be located in the muscle targeting agent, molecular payload, or the linker. In some embodiments a linker is linked to a muscle targeting agent and / or molecular payload by other pericyclic reactions, eg ene reaction. In some embodiments, a linker is linked to a muscle targeting agent and / or molecular payload by an amide, thioamide, or sulfonamide linkage reaction. In some embodiments, a linker is linked to a muscle-targeting agent and / or molecular payload by a condensation reaction to form an oxime, hydrazone, or semicarbazide group that exists between the linker and the muscle-targeting agent and / or or the molecular payload. In some embodiments, a linker is linked to a muscle-targeting agent and / or molecular payload by conjugate addition reactions between a nucleophile, for example an amine or hydroxyl group, and an electrophile, for example a carboxylic acid or an aldehyde. In some embodiments, a nucleophile may exist in a linker and an electrophile may exist in a muscle-targeting agent or molecular payload prior to Qorrbn / iznz / q / YiAi a reaction between a linker and a muscle-targeting agent or molecular payload. In some embodiments, an electrophile may exist in a linker and a nucleophile may exist in a muscle-targeting agent or molecular payload prior to a reaction between a linker and a muscle-targeting agent or molecular payload. In some embodiments, an electrophile can be an azide, silicon centers, a carbonyl, a carboxylic acid, an anhydride, an isocyanate, a thioisocyanate, a succinimidyl ester, a sulfosuccinimidyl ester, a maleimide, an alkyl halide, a pseudohalide alkyl, an epoxide, an episulfide, an aziridine, an aryl, an activated phosphorous center, and / or an activated sulfur center. In some embodiments, a nucleophile can be an optionally substituted alkene, optionally substituted alkyne, optionally substituted aryl, optionally substituted heterocyclyl, hydroxyl group, amino group, alkylamino group, anilide group, or thiol group. QQPPbn / l 7Π7 / 3 / ΥΙΛΙ Examples of antibody molecular complexes Other aspects of the present disclosure provide complexes comprising any of the muscle-targeting agent (eg, a transferrin receptor antibody) described herein covalently linked to any of the molecular payloads (eg, an oligonucleotide) described in the present. In some embodiments, the muscle-targeting agent (eg, a transferrin receptor antibody) is covalently linked to a molecular payload (eg, an oligonucleotide) via a linker. Any of the linkers described herein can be used. In some embodiments, the linker is linked to the 5' end, the 3' end, or internally of the oligonucleotide. In some embodiments, the linker is linked to the antibody via a thiol-reactive bond (eg, via a cysteine ​​on the antibody). An exemplary structure of a complex comprising a transferrin receptor antibody covalently linked to an oligonucleotide via a Val-cit linker is provided below: wherein the linker is linked to the 5' end, the 3' end, or internally of the oligonucleotide, and wherein the linker is linked to the antibody via a thiol-reactive bond (eg, via a cysteine ​​on the antibody). It should be appreciated that antibodies can be linked to oligonucleotides with different stoichiometries, a property that can be referred to as a drug-to-antibody ratio (DAR) with the drug being the oligonucleotide. In some embodiments, an oligonucleotide is linked to an antibody (DAR = 1). In some embodiments, two oligonucleotides are linked to one antibody (DAR = 2). In some embodiments, three oligonucleotides are linked to an antibody (DAR = 3). In some embodiments, four oligonucleotides are linked to one antibody (DAR = 4). In some modalities, a mixture of different complexes is provided, each of which has a different DAR. In some embodiments, an average DAR of complexes in such a mixture may range from 1 to 3, 1 to 4, 1 to 5, or more. The DAR can be increased by conjugating oligonucleotides to different sites on an antibody and / or by conjugating multimers to one or more sites on the antibody. For example, a DAR of 2 can be obtained by conjugating a single oligonucleotide to two different sites on an antibody or by conjugating a dimeric oligonucleotide to a single site on an antibody. In some embodiments, the complex described herein comprises a transferrin receptor antibody (eg, an antibody or any variant thereof as described herein) covalently linked to an oligonucleotide (eg, an oligonucleotide that is capable of induce DMD exon skipping). In some embodiments, the complex described herein comprises a transferrin receptor antibody (eg, an antibody or any variant thereof as described herein) covalently linked to an oligonucleotide (eg, an oligonucleotide that is capable of induce DMD exon skipping) via a linker (eg, a Val-cit linker). In some embodiments, the linker (eg, a Val-cit linker) is linked to the 5' end, the 3' end, or internally of the nucleotide (eg, an oligonucleotide that is capable of inducing DMD exon skipping ). In some embodiments, the linker (eg, a Valcit linker) is linked to the antibody (eg, an antibody or any variant thereof as described herein) via a thiol-reactive bond (eg, via a cysteine on the antibody). In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to a DMD targeting oligonucleotide, wherein the transferrin receptor antibody comprises a CDRH1, a CDR-H2, and a CDR-H3 that they are the same as CDR-H1, CDR-H2, and CDR-H3 shown in Table 1.1; and a CDR-L1, a CDR-L2, and a CDR-L3 that are the same as the CDR-L1, CDR-L2, and CDR-L3 shown in Table 1.1. In some embodiments, the complex described herein comprises a Qorrbn / iznz / q / YiAi transferrin receptor antibody covalently linked to a DMD targeting oligonucleotide, wherein the transferrin receptor antibody comprises a VH having the amino acid sequence of SEQ ID NO: 283 and a VL having the amino acid sequence of SEQ ID NO: 284. In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to a DMD-targeting oligonucleotide, wherein the transferrin receptor antibody comprises a VH that has the amino acid sequence of SEQ ID NO: 285 and a VL having the amino acid sequence of SEQ ID NO: 286. In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to a DMD targeting oligonucleotide, wherein the transferrin receptor antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 289 and a light chain having the amino acid sequence of SEQ ID NO: 290. In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to a DMD targeting oligonucleotide, wherein the antibody to the transferrin receptor transferrin receptor comprises a heavy chain having the amino acid sequence of SEQ ID NO: 291 and a light chain having the amino acid sequence of SEQ ID NO: 292. In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to a DMD targeting oligonucleotide via a linker (eg, a Val-cit linker), wherein the transferrin receptor antibody comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are the same as the CDR-H1, CDR-H2, and CDR-H3 shown in Table 1.1; and a CDR-L1, a CDR-L2, and a CDR-L3 that are the same as the CDR-L1, CDR-L2, and CDR-L3 shown in Table 1.1. In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to a DMD targeting oligonucleotide via a linker (eg, a Val-cit linker), wherein the transferrin receptor antibody comprises a VH having the amino acid sequence of SEQ ID NO: 283 and a VL having the amino acid sequence of SEQ ID NO: 284. In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to an oligonucleotide targeting DMD via a linker (eg, a Val-cit linker), wherein the transferrin receptor antibody comprises a VH having the amino acid sequence of SEQ ID NO: 285 and a VL having the amino acid sequence of SEQ ID NO: 286. In some embodiments, the complex described herein comprises a QQPPbn / l 7Π7 / Σ1 / ΥΙΛΙ transferrin receptor antibody covalently linked to a DMD-targeting oligonucleotide via a linker (eg, a Val-cit linker), wherein the transferrin receptor antibody comprises a heavy chain that has the amino acid sequence of SEQ ID NO: 289 and a light chain having the amino acid sequence of SEQ ID NO: 290. In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to an oligonucleotide targeting DMD via a linker (eg, a Val-cit linker), wherein the transferrin receptor antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 291 and a light chain having the amino acid sequence of SEQ ID NO: 292. In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to a DMD targeting oligonucleotide via a Val-cit linker, wherein the transferrin receptor antibody comprises a CDR-H1, a CDR -H2, and a CDR-H3 that are the same as the CDR-H1, CDR-H2, and CDR-H3 shown in Table 1.1; and a CDR-L1, a CDR-L2, and a CDR-L3 that are the same as the CDR-L1, CDR-L2, and CDR-L3 shown in Table 1.1, and wherein the complex comprises the structure of: aarrbn / i 7Π7 / =ι / υιλι antibody —g wherein the Val-cit linker is linked to the 5' end, 3' end, or internally of the DMD targeting oligonucleotide, and wherein the Val-cit linker is linked to the antibody (eg, an antibody or any variant thereof as described herein) via a thiol-reactive bond (eg, via a cysteine ​​in the antibody). In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to a DMD targeting oligonucleotide via a Val-cit linker, wherein the transferrin receptor antibody comprises a VH having the sequence of amino acids of SEQ ID NO: 283 and a VL having the amino acid sequence of SEQ ID NO: 284, and wherein the complex comprises the structure of: antibody -$ DMPK oligonucleotide QQPPbn / LZnZ / q / YIAI Λ 0' nh2 where the linker of the Val-cit linker is linked to the 5' end, the 3' end, or internally of the DMD targeting oligonucleotide, and where the Val-cit linker is linked to the antibody (by eg, an antibody or any variant thereof as described herein) via a thiol-reactive bond (eg, via a cysteine ​​in the antibody). In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to a DMD targeting oligonucleotide via a Val-cit linker, wherein the transferrin receptor antibody comprises a VH having the sequence of amino acids of SEQ ID NO: 285 and a VL having the amino acid sequence of SEQ ID NO: 286, and wherein the complex comprises the structure of: antibody -3 DMPK oligonucleotide wherein the Val-cit linker is linked to the 5' end, 3' end, or internally of the DMD targeting oligonucleotide, and wherein the Val-cit linker is linked to the antibody (eg, a antibody or any variant thereof as described herein) via a thiol-reactive bond (eg, via a cysteine ​​in the antibody). In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to a DMD targeting oligonucleotide via a Val-cit linker, wherein the antibody receptor antibody comprises a heavy chain having the sequence of amino acids of SEQ ID NO: 289 and a light chain having the amino acid sequence of SEQ ID NO: 290, and wherein the complex comprises the structure of: hn 0^'NHz EITHER ΌN' h DMPK aorcbn / i 7Π7 / =ι / υιλι oligonucleotide wherein the Val-cit linker linker is linked to the 5' end, 3' end, or internally of the DMD targeting oligonucleotide, and wherein the Val-cit linker cit is linked to the antibody (eg, an antibody or any variant thereof as described herein) via a thiol-reactive bond (eg, via a cysteine ​​on the antibody). In some embodiments, the complex described herein comprises a transferrin receptor antibody covalently linked to a DMD targeting oligonucleotide via a Val-cit linker, wherein the transferrin receptor antibody comprises a heavy chain having the sequence of amino acids of SEQ ID NO: 291 and a light chain having the amino acid sequence of SEQ ID NO: 292, and wherein the complex comprises the structure of: DMPK oligonucleotide wherein the linker of the Val-cit linker is linked to the 5' end, the 3' end, or internally of the DMD targeting oligonucleotide, and wherein the Val-cit linker is linked to the antibody (eg, an antibody or any variant thereof as described herein) via a thiol-reactive bond (eg, via a cysteine ​​on the antibody). formulations The complexes provided herein may be formulated in any suitable manner. Generally, the complexes provided herein are formulated in a manner suitable for pharmaceutical use. For example, the complexes can be delivered to a subject using a formulation that minimizes degradation, facilitates delivery and / or uptake, or provides another beneficial property to the complexes in the formulation. In some embodiments, compositions comprising pharmaceutically acceptable carriers and complexes are provided herein. Such compositions can conveniently be formulated so that when administered to a subject, either in the immediate vicinity of a target cell or systemically, a sufficient amount of the complexes enters the target muscle cells. In some embodiments, the complexes are formulated in buffers such as phosphate buffered saline, liposomes, micellar scaffolds, and capsids. It should be appreciated that, in some embodiments, the compositions may separately include one or more complex components provided herein (for example, muscle targeting agents, linkers, molecular payloads, or precursor molecules for any of these). ). In some embodiments, the complexes are formulated in water or an aqueous solution (eg, water with pH adjustments). In some embodiments, the complexes are formulated in basic buffered aqueous solutions (eg, PBS). In some embodiments, the formulations as described herein comprise an excipient. In some embodiments, an excipient confers to a composition improved stability, improved absorption, improved solubility, and / or therapeutic potentiation of the active ingredient. In some embodiments, an excipient is a buffer (eg, sodium citrate, sodium phosphate, tris base, or sodium hydroxide) or a vehicle (eg, buffer, petrolatum, dimethyl sulfoxide, or mineral oil). In some embodiments, a complex or component thereof (eg, oligonucleotide or antibody) is lyophilized to extend its shelf life and then formed as a solution prior to use (eg, administration to a subject). Accordingly, an excipient in a composition comprising a complex, or component thereof, described herein may be a lyoprotectant {for example, mannitol, lactose, polyethylene glycol, or polyvinyl pyrolidone), or a collapse temperature modifier {for example, dextran, ficoll, or gelatin). In some embodiments, a pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of administration routes include parenteral administration, eg, intravenous, intradermal, subcutaneous. Typically, the route of administration is intravenous or subcutaneous. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (when soluble in water) or dispersions, and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions. The vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, aarrbn / iznz / q / YiAi propylene glycol and liquid polyethylene glycol and the like), and suitable mixtures thereof. In some embodiments, the formulations include isotonic agents, eg, sugars, polyols such as mannitol, sorbitol, and sodium chloride in the composition. Sterile injectable solutions can be prepared by incorporating the complexes in a required amount in a selected solvent with one or a combination of the ingredients listed above, as required, followed by filtered sterilization. In some embodiments, a composition may contain at least about 0.1% of the complex, or component thereof, or more, although the percentage of active ingredient(s) may be between about 1% and about 80%. or more than the weight or volume of the total composition. One of skill in the art of preparing such pharmaceutical formulations will contemplate factors such as solubility, bioavailability, biological half-life, route of administration, shelf-life of the product, and other pharmacological considerations, and as such, a variety of dosages and treatment regimens may be desirable. Methods of Use / Treatment Complexes comprising a muscle-targeting agent covalently to a molecular payload as described herein are effective in treating a subject having a dystrophinopathy, eg, Duchenne muscular dystrophy. In some embodiments, the complexes comprise a molecular payload that is an oligonucleotide, eg, an antisense oligonucleotide that facilitates exon skipping of an mRNA expressed from a mutated allele of DMD. In some embodiments, a subject may be a human subject, a non-human primate subject, a rodent subject, or any suitable mammalian subject. In some modalities, a subject may have Duchenne muscular dystrophy or another dystrophinopathy. In some embodiments, a subject has a mutated DMD allele, which may optionally comprise at least one mutation in a DMD exon that causes a frameshift mutation and leads to improper RNA splicing / processing. In some embodiments, a subject is suffering from symptoms of a severe dystrophinopathy, eg, muscle atrophy or muscle wasting. In some embodiments, a subject has an asymptomatic increase in serum creatine phosphokinase (CK) concentration and / or muscle cramps with myoglobinuria. In some embodiments, a subject has a progressive muscular disease, such as Duchenne or Becker muscular dystrophy or DMD-associated dilated cardiomyopathy (DCM). In some embodiments, a subject is not suffering from symptoms of a dystrophinopathy. One aspect of the disclosure includes a method that involves administering to a subject an effective amount of a complex as described herein. In some aarrbn / i 7Π7 / =ι / υιλι embodiments, an effective amount of a pharmaceutical composition comprising a complex comprising a muscle-targeting agent covalently to a molecular payload may be administered to a subject in need of treatment. In some embodiments, a pharmaceutical composition comprising a complex as described herein may be administered by a suitable route, which may include intravenous administration, for example, as a bolus or by continuous infusion over a period of time. In some modalities, intravenous administration can be accomplished by intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intra-articular, intrasynovial, or intrathecal routes. In some embodiments, a pharmaceutical composition may be in a solid form, an aqueous form, or a liquid form. In some embodiments, an aqueous or liquid form may be nebulized or lyophilized. In some embodiments, a nebulized or lyophilized form can be reconstituted with an aqueous or liquid solution. Compositions for intravenous administration may contain various carriers such as vegetable oils, dimethylactamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristrate, ethanol, and polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like). For intravenous injection, water-soluble antibodies can be administered by the drip method, whereby a pharmaceutical formulation containing the antibody and a physiologically acceptable carrier is infused. Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution, or other suitable excipients. Intramuscular preparations, eg, a sterile formulation of a suitable soluble salt form of the antibody, can be dissolved and administered in a pharmaceutical carrier such as water for injection, 0.9% saline, or 5% glucose solution. In some embodiments, a pharmaceutical composition comprising a complex comprising a muscle-targeting agent covalently to a molecular payload is administered via local or site-specific delivery techniques. Examples of these techniques include implantable reservoir sources of the complex, local delivery catheters, site-specific carriers, direct injection, or direct application. In some embodiments, a pharmaceutical composition comprising a complex comprising a muscle-targeting agent covalently to a molecular payload is administered at an effective concentration that confers therapeutic effects on a subject. Effective amounts vary, as recognized by those skilled in the art, depending on the severity of the disease, the unique characteristics of the subject being treated, for example age, physical conditions, health, or weight, the duration of treatment, the nature of any concurrent therapies, the route of administration, and related factors. These related factors QQPPbn / l 7Π7 / 3 / ΥΙΛΙ are known to those in the art and can be solved with no more than routine experimentation. In some modalities, an effective concentration is the maximum dose that is considered safe for the patient. In some embodiments, an effective concentration will be the lowest possible concentration that provides maximum efficacy. Empirical considerations, for example the half-life of the complex in a subject, will generally contribute to the determination of the concentration of the pharmaceutical composition that is used for treatment. The frequency of administration can be determined empirically and adjusted to maximize the efficacy of the treatment. Generally, for administration of any of the complexes described herein, a candidate initial dosage may be from about 1 to 100 mg / kg, or more, depending on factors described above, eg safety or efficacy. In some modalities, a treatment will be administered once. In some modalities, a treatment will be administered daily, biweekly, weekly, bimonthly, monthly, or at any time interval that provides maximum efficacy while minimizing safety risks to the subject. Generally, efficacy and treatment and safety risks can be monitored throughout the entire course of treatment. The efficacy of the treatment can be evaluated using any suitable methods. In some modalities, treatment efficacy can be assessed by observational assessment of symptoms associated with a dystrophinopathy, eg, muscle atrophy or muscle weakness, through measures of a subject's self-reported outcome, eg, mobility, self-reported -care, normal activities, pain / discomfort, and anxiety / depression, or by quality of life indicators, for example life expectancy. In some embodiments, a pharmaceutical composition comprising a complex comprising a muscle-targeting agent covalently at a molecular payload described herein is administered to a subject at an effective concentration sufficient to modulate the activity or expression of a target gene by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least less than 90% or at least 95% relative to a control, eg baseline level of gene expression before treatment. In some embodiments, a single dose or administration of a pharmaceutical composition comprising a complex comprising a muscle-targeting agent covalently to a molecular payload described herein to a subject is sufficient to inhibit the activity or expression of a target gene. at least for 1-5, 1-10, 5-15,10-20,1530, 20-40, 25-50, or more days. In some embodiments, a single dose or administration of a pharmaceutical composition comprising a complex comprising an aarrbn / i 7Π7 / 3 / ΥΙΛΙ agent covalently targeting a molecular payload described herein to a subject is sufficient to inhibit the activity or expression of a target gene for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In some embodiments, a single dose or administration of a pharmaceutical composition comprising a complex comprising a muscle-targeting agent covalently to a molecular payload described herein to a subject is sufficient to inhibit the activity or expression of a target gene. at least for 1, 2, 3, 4, 5, or 6 months. In some embodiments, a pharmaceutical composition may comprise more than one complex comprising a muscle-targeting agent covalently to a molecular payload. In some embodiments, a pharmaceutical composition may further comprise any other therapeutic agent suitable for the treatment of a subject, for example a human subject having a dystrophinopathy. In some embodiments, the other therapeutic agents may augment or complement the efficacy of the complexes described herein. In some embodiments, the other therapeutic agents may function to treat a different symptom or disease than the complexes described herein. EXAMPLES EXAMPLE 1 Targeting of HPRT with Transfected Antisense Oligonucleotides A siRNA that targets hypoxanthine phosphoribosyltransferase (HPRT) was tested in vitro for its ability to reduce HPRT expression levels in an immortalized cell line. Briefly, Hepa 1-6 cells were transfected with either control siRNA (siCTRL; 100 nM) or the siRNA that targets HPRT (siHPRT; 100 nM), formulated with lipofectamine 2000. HPRT expression levels were assessed 48 hours after transfection. A control experiment was also performed in which vehicle (phosphate buffered saline) was delivered to cultured Hepa 1-6 cells and the cells were maintained for 48 hours. As shown in Figure 1, HPRT siRNA was found to reduce HPRT expression levels by ~90% compared to controls. aarrbn / i 7n7 / 3i / υιλι TABLE 3 HPRTsi v CTRLsi Sequences QQPPbn / l 7Π7 / Σ1 / ΥΙΛΙ Sequence HPRTsi sense chain 5'-UcCuAuGaCuGuAgAuUuUaU-(CH2)6NH2-3' HPRTsi antisense chain 5'-paUaAaAuCuAcAgUcAuAgGasAsu-3' CTRLsi sense chain 5'-UgUaAuAaCcAuAuCuAcCuU-(CH2)6NH2-3' Antisen chain CTRLsi 5' -aAgGuAgAuAuGgUuAuUaHouseHandle-3' *Lowercase letter - 2'0me ribose; Capital letter - 2'Fluoro ribose; p - phosphate bond; s - phosphorothioate bond EXAMPLE 2 HPRT targeting with a muscle targeting complex A muscle-targeting complex was generated comprising the HPRT siRNA used in Example 1 (HPRTsi) covalently linked, via a non-cleavable Ngamma-maleimidobutyryl-oxysuccinimide ester (GMBS) linker, to DTX-A-002, a anti-transferrin receptor antibody. Briefly, the GMBS linker was dissolved in dry DMSO and coupled to the 3' end of the HPRTsi sense strand via amide bond formation under aqueous conditions. The completion of the reaction was verified by the Kaiser test. Excess linker and organic solvents were removed by gel permeation chromatography. The purified, maleimide functionalized sense chain of HPRTsi was then coupled to the DTX-A-002 antibody using a Michael addition reaction. The product of the antibody coupling reaction was then subjected to hydrophobic interaction chromatography (HIC-HPLC). Anti-TfR-HPRTsi complexes comprising one or two HPRTsi molecules covalently linked to a DTX-A-002 antibody were purified. Densitometry confirmed that the sample purified from the complexes had an average HPRTsi to antibody ratio of 1.46. SDS-PAGE analysis demonstrated that >90% of the purified sample of the complexes comprised DTX-A-002 bound to either one or two HPRTsi molecules. Using the same methods as described above, a control IgG2a-HPRTsi complex was generated comprising the HPRT siRNA used in Example 1 (HPRTsi) covalently linked via the GMBS linker to an IgG2a (Fab) antibody (DTX -A-003). Densitometry confirmed that DTX-C-001 had an average HPRTsi to antibody ratio of 1.46 and SDS-PAGE demonstrated that >90% of the purified sample of control complexes comprised DTX-A-003 bound to either one or two HPRTsi molecules. The antiTfR-HPRTsi complex was then tested for cell internalization and HPRT inhibition in ceiiuio. Hepa 1-6 cells, which have relatively high expression levels of the transferrin receptor, were incubated in the presence of vehicle (phosphate buffered saline), IgG2a-HPRTsi (100 nM), anti-TfR-CTRLsi (100 nM), or antiTfR-HPRTsi (100 nM), for 72 hours. After 72 hours of incubation, cells were isolated and tested for HPRT expression levels (Figure 2). Cells treated with the antiTfR-HPRTsi demonstrated a reduction in HPRT expression by ~50% relative to cells treated with the vehicle control. Meanwhile, cells treated with either IgG2a-HPRTsi or anti-TfR-CTRLsi had HPRT expression levels comparable to vehicle control (no reduction in HPRT expression). These data indicate that the anti-transferrin receptor antibody of anti-TfRHPRTsi enabled cellular internalization of the complex, thereby allowing HPRTsi to inhibit HPRT expression. EXAMPLE 3 Targeting of HPRT in Mouse Muscle Tissues with a Muscle Targeting Complex The muscle targeting complex described in Example 2, antiTfRHPRTsi, was tested for inhibition of HPRT in mouse tissues. Wild type C57BL / 6 mice were injected intravenously with a single dose of a vehicle control (phosphate buffered saline); HPRTsi (2 mg / kg RNA); IgG2a-HPRTsi (2 mg / kg RNA, corresponding to 9 mg / kg antibody complex); or anti-TfR-HPRTsi (2 mg / kg RNA, corresponding to 9 mg / kg antibody complex. Each experimental condition was replicated in four individual C57BL / 6 wild-type mice. After a three-day post-injection period , mice were euthanized and segmented into isolated tissue types.Individual tissue samples were subsequently tested for HPRT expression levels (Figures 3A to 3B and 4A to 4E). Mice treated with the antiTfR-HPRTsi complex demonstrated a reduction in HPRT expression in the gastrocnemius (31% reduction; p<0.05) and heart (30% reduction; p<0.05), with respect to mice treated with the HPRTsi control (Figures 3A to 3B). Meanwhile, mice treated with the IgG2a-HPRTs¡ complex had HPRT expression levels comparable to the HPRTsi control (little or no reduction in HPRT expression) for all muscle tissue types tested. aarrbn / i 7Π7 / =ι / υιλι Mice treated with the antiTfR-HPRTsi complex demonstrated no change in HPRT expression in non-muscle tissues such as brain, liver, lung, kidney, and spleen tissues (Figures 4A to 4E). These data indicate that the anti-transferrin receptor antibody of the anti-TfR-HPRTsi complex enabled cellular internalization of the complex into specific muscle tissues in an in vivo mouse model, thereby allowing HPRTsi to inhibit HPRT expression. These data further demonstrate that antiTfR-oligonucleotide complexes of the current disclosure are capable of specifically targeting muscle tissues. EXAMPLE 4 DMD targeting with a muscle targeting complex A muscle targeting complex is generated comprising an antisense oligonucleotide that targets a DMD mutant allele (DMD ASO), for exon skipping, for example, an oligonucleotide having a sequence as described in Table 2, linked covalently, via a cathepsin cleavable linker, to DTX-A-002 (RI7 217 (Fab)), an anti-transferrin receptor antibody. Briefly, a maleimidocaproyl-L-valine-L-citrullinealcohol p-aminobenzyl p-nitrophenyl carbonate (MC-Val-Cit-PABC-PNP) linker molecule is coupled to NH2-C6-DMD ASO using an amide coupling reaction . Excess linker and organic solvents are removed by gel permeation chromatography. The purified Val-Cit-DMD ASO linker is then coupled to a thiol-reactive anti-transferrin receptor antibody (DTX-A002). The product of the antibody coupling reaction is then subjected to hydrophobic interaction chromatography (HIC-HPLC) to purify the muscle targeting complex. Densitometry and SDS-PAGE analysis of the purified complex allowed determination of the average ASO-to-antibody ratio and total purity, respectively. Using the same methods as described above, a control complex is generated comprising DMD ASO covalently linked via a Val-cit linker to an IgG2a (Fab) antibody. The purified muscle targeting complex comprising DTX-A-002 covalently linked to DMD ASO is then tested for cellular internalization and modulation of DMD exon skipping. Disease-relevant muscle cells that have relatively high expression levels of the transferrin receptor are incubated in the presence of vehicle control (saline), muscle targeting complex (100 nM), or control complex (100 nM). for 72 hours. After 72 hours of incubation, cells are isolated and tested for Garran / Lznz / q / YiAi DMD expression levels. EQUIVALENTS and TERMINOLOGY The disclosure illustratively described herein may be practiced in the absence of any element(s), limitation(s), or limitations, not specifically disclosed herein. Thus, for example, in each example herein any of the terms comprising, consisting essentially of and consisting of may be replaced with either term. The terms and expressions that have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions to exclude any equivalent of the features shown and described or portions thereof, and are acknowledges that various modifications are possible within the scope of the description. Thus, it is to be understood that although this description has been specifically described by preferred embodiments, optional features, modification and variation of the concepts described herein may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this description. Furthermore, when features or aspects of the invention are described in terms of Markush groups or other groupings of alternatives, those skilled in the art will recognize that the description is also described in terms of any individual member or subgroup of members of the Markush group or another group. It should be appreciated that, in some embodiments, the sequences presented in the sequence listing may refer to the description of the structure of an oligonucleotide or other nucleic acid. In such embodiments, the actual oligonucleotide or other nucleic acid may have one or more alternative nucleotides (for example, an RNA counterpart to a DNA nucleotide or a DNA counterpart to an RNA nucleotide) and / or one or more modified nucleotides. and / or one or more modified internucleotide linkages and / or one or more additional modifications compared to the specified sequence while retaining essentially the same or similar complementary properties to the specified sequence. The use of the terms a, an, the and the and similar references in the context to describe the invention (especially in the context of the following claims) should be considered as covering both the singular and the plural form, unless otherwise indicated. otherwise herein or clearly contradicted by the context. The terms comprising, must include, and contain are to be interpreted as open terms (ie, meaning including but not limited to) unless otherwise stated. Mention of ranges of values ​​herein is intended solely to serve as a shortcut for individually acknowledging each separate value that falls within the range, unless aarrbn / i 7Π7 / =ι / υιλι 100 is indicated otherwise herein, and each separate value is incorporated into the specification as if individually mentioned herein. All of the methods described herein may be performed in any suitable order unless otherwise stated herein or otherwise clearly contradicted by the context. The use of any and all examples, or illustrative language (for example, such as) provided herein, is intended merely to further elucidate the invention and does not pose a limitation on the scope of the invention unless otherwise indicated. . No language in the specification should be construed as indicating that any unclaimed element is essential to the practice of the invention. Embodiments of this invention are described herein. Variations of those embodiments may be made visible to those of average skill in the art upon reading the above description. The inventors expect such variations to be used by skilled persons as appropriate, and the inventors intend that the invention be carried out other than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, any combination of the elements described above in all possible variations thereof is encompassed by the invention unless otherwise stated herein or otherwise clearly contradicted by the context. Those skilled in the art will recognize, or be able to determine using no more than routine experimentation, numerous equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A complex comprising a muscle-targeting agent covalently linked to a molecular payload configured to promote the expression or activity of a DMD, wherein the muscle-targeting agent specifically binds to a cell-surface internalization receptor on muscle cells.

2. The complex according to claim 1, further characterized in that the muscle-targeting agent is a muscle-targeting antibody.

3. The complex according to claim 2, further characterized in that the muscle-targeting antibody binds specifically to an extracellular epitope of a transferrin receptor.

4. The complex according to claim 3, further characterized in that the extracellular epitope of the transferrin receptor comprises an epitope of the apical domain of the transferrin receptor.

5. The complex according to claim 3 or 4, further characterized in that the muscle-targeting antibody binds specifically to an epitope of a sequence in the range C89 to F760 of SEQ ID NO: 1-3.

6. The complex according to any of claims 3 to 5, further characterized in that the equilibrium dissociation constant (Kd) of the muscle-targeting antibody binding to the transferrin receptor is in the range of 10'11 M to 10'6 M.

7. The complex according to any of claims 3 to 6, further characterized in that the muscle-targeting antibody competes for specific binding to a transferrin receptor epitope with an antibody listed in Table 1.

8. The complex according to claim 7, further characterized in that the muscle-targeting antibody competes for specific binding to a transferrin receptor epitope with a Kd of less than or equal to 10'6 M.

9. The complex according to claim 8, further characterized in that the Kd is in a range of 10'11 M to 10'6 M.

10. The complex according to any of claims 3 to 9, further characterized in that the muscle-targeting antibody does not specifically bind to the transferrin-binding site of the transferrin receptor and / or wherein the muscle-targeting antibody does not inhibit the binding of transferrin to the transferrin receptor.

11. The complex according to any of claims 3 to 10, further characterized in that the muscle-targeting antibody cross-reacts with extracellular epitopes of two or more of a human, non-human primate, and rodent transferrin receptor.

12. The complex according to any of claims 3 to 11, further characterized in that the complex is configured to promote transferrin receptor-mediated internalization of the molecular payload in a muscle cell.

13. The complex according to any of claims 2 to 12, further characterized in that the muscle-targeting antibody is a chimeric antibody, optionally wherein the chimeric antibody is a humanized monoclonal antibody.

14. The complex according to any of claims 2 to 13, further characterized in that the muscle-targeting antibody is in the form of an ScFv, Fab fragment, Fab' fragment, F(ab')2 fragment, or Fv fragment.

15. The complex according to any of claims 1 to 14, further characterized in that the molecular payload is an oligonucleotide.

16. The complex according to claim 15, further characterized in that the oligonucleotide comprises a sequence listed in Table 2.

17. The complex according to claim 16, further characterized in that the oligonucleotide comprises a region of complementarity to a mutated allele of DMD.

18. The complex according to any of claims 1 to 14, further characterized in that the molecular payload is a polypeptide.

19. The complex according to claim 18, further characterized in that the polypeptide is a functional fragment of the dystrophin protein.

20. The complex according to any of claims 15 to 17, further characterized in that the oligonucleotide is configured to suppress a truncating mutation in a DMD allele by single- or multi-exon skipping.

21. The complex according to any of claims 15 to 17, further characterized in that the oligonucleotide promotes antisense strand-mediated exon skipping to produce in-frame dystrophin mRNA.

22. The complex according to claim 21, further characterized in that the oligonucleotide promotes the skipping of an exon of DMD in the interval from exon 8 to exon 55, optionally from exon 23 to exon 53.

23. The complex according to claim 22, further characterized in that the oligonucleotide promotes skipping of exon 8, exon 23, exon 44, exon 45, exon 50, exon QQrrbn / LZnZ / q / YIAI 103 51, exon 52, exon 53, and / or exon 55.

24. The complex according to claim 21, further characterized in that the oligonucleotide promotes the skipping of exon 51.

25. The complex according to claim 24, further characterized in that the oligonucleotide promotes the skipping of multiple exons in the interval from exon 44 to exon 53.

26. The complex according to any of claims 15 to 17 or 20 to 25, further characterized in that the oligonucleotide comprises at least one modified internucleotide linkage.

27. The complex according to claim 26, further characterized in that the at least one modified internucleotide bond is a phosphorothioate bond.

28. The complex according to claim 27, further characterized in that the oligonucleotide comprises phosphorothioate linkages in the Rp stereochemical conformation and / or in the Sp stereochemical conformation.

29. The complex according to claim 28, further characterized in that the oligonucleotide comprises phosphorothioate linkages all in the Rp stereochemical conformation or all in the Sp stereochemical conformation.

30. The complex according to any of claims 15 to 17 or 20 to 29, further characterized in that the oligonucleotide comprises one or more modified nucleotides.

31. The complex according to claim 30, further characterized in that one or more modified nucleotides are 2' modified nucleotides.

32. The complex according to any of claims 15 to 17 or 20 to 31, further characterized in that the oligonucleotide is a gapmer oligonucleotide that directs RNase H-mediated cleavage of a miRNA that negatively regulates DMD expression in a cell, optionally wherein the miRNA is mIR-31.

33. The complex according to claim 32, further characterized in that the gapmer oligonucleotide comprises a central portion of 5 to 15 deoxyribonucleotides flanked by wings of 2 to 8 modified nucleotides.

34. The complex according to claim 33, further characterized in that the modified nucleotides of the wings are 2' modified nucleotides.

35. The complex according to any of claims 15 to 17 or 20 to 31, further characterized in that the oligonucleotide is a mixomer oligonucleotide.

36. The complex according to claim 35, further characterized in that the mixomer oligonucleotide promotes exon skipping. Garran / Lznz / q / YiAi 104 37. The complex according to claim 35 or 36, further characterized in that the mixomer oligonucleotide comprises two or more different 2' modified nucleotides.

38. The complex according to any of claims 15 to 17 or 20 to 31, further characterized in that the oligonucleotide is an RNAi oligonucleotide that promotes RNAi-mediated cleavage of a miRNA that negatively regulates DMD expression in a cell, optionally wherein the miRNA is mIR-31.

39. The complex according to claim 38, further characterized in that the RNAi oligonucleotide is a double-stranded oligonucleotide of 19 to 25 nucleotides in length.

40. The complex according to claim 38 or 39, further characterized in that the RNAi oligonucleotide comprises at least one 2' modified nucleotide.

41. The complex according to any of claims 31, 34, 37, or 40, further characterized in that each 2' modified nucleotide is selected from the group consisting of: 2'-O-methyl, 2'-fluoro (2'-F), 2'-O-methoxyethyl (2'-MOE), and 2',4' bridged nucleotides.

42. The complex according to claim 30, further characterized in that the one or more modified nucleotides are bridged nucleotides.

43. The complex according to any of claims 31, 34, 37, or 40, further characterized in that at least one 2' modified nucleotide is a 2',4'-bridged nucleotide selected from: 2'-O-ethyl restricted at 2',4' (cEt) and locked nucleic acid nucleotides (LNA).

44. The complex according to any of claims 15 to 17 or 20 to 31, further characterized in that the oligonucleotide comprises a guide sequence for a genome editing nuclease.

45. The complex according to any of claims 15 to 17 or 20 to 31, further characterized in that the oligonucleotide is a morpholino phosphorodiamidate oligomer.

46. ​​The complex according to any of claims 1 to 45, further characterized in that the muscle-targeting agent is covalently linked to the molecular payload via a scinti-coated linker.

47. The complex according to claim 46, further characterized in that the scintisole linker is selected from: a protease-sensitive linker, a pH-sensitive linker, and a glutathione-sensitive linker.

48. The complex according to claim 47, further characterized in that the cleavage linker is a protease-sensitive linker. QQPPbn / l 7P7 / 3 / YILI 105 49. The complex according to claim 48, further characterized in that the protease-sensitive linker comprises a sequence cleaveable by an α-sosomal protease and / or an endosomal protease.

50. The complex according to claim 48, further characterized in that the protease-sensitive linker comprises a valine-citrulline dipeptide sequence.

51. The complex according to claim 47, further characterized in that the linker is a pH-sensitive linker that is cleavable at a pH in the range of 4 to 6.

52. The complex according to any of claims 1 to 45, further characterized in that the muscle-targeting agent is covalently linked to the molecular payload via a non-clearable linker.

53. The complex according to claim 52, further characterized in that the non-scissible linker is an alkane linker.

54. The complex according to any of claims 2 to 53, further characterized in that the muscle-targeting antibody comprises a non-natural amino acid to which the oligonucleotide is covalently linked.

55. The complex according to any of claims 2 to 53, further characterized in that the muscle-targeting antibody is covalently linked to the oligonucleotide via conjugation to a lysine or cysteine ​​residue of the antibody.

56. The complex according to claim 55, further characterized in that the oligonucleotide is conjugated to the cysteine ​​of the antibody via a linker containing maleimide, optionally wherein the linker containing maleimide comprises a maleimidocaproyl group or maleimidomethyl cyclohexane-1-carboxylate.

57. The complex according to any of claims 2 to 56, further characterized in that the muscle-targeting antibody is a glycosylated antibody comprising at least one sugar portion to which the oligonucleotide is covalently linked.

58. The complex according to claim 57, further characterized in that the sugar portion is a branched stalk.

59. The complex according to claim 57 or 58, further characterized in that the muscle-targeting antibody is a glycosylated antibody comprising one to four sugar portions, each of which is covalently linked to a separate oligonucleotide.

60. The complex according to claim 57, further characterized in that the muscle-targeting antibody is a fully glycosylated antibody.

61. The complex according to claim 57, further characterized in that the muscle-targeting antibody is a partially glycosylated antibody.

62. The complex according to claim 61, further characterized in that the partially glycosylated antibody is produced via chemical or enzymatic means.

63. The complex according to claim 61, further characterized in that the partially glycosylated antibody is produced in a cell that is deficient in an enzyme in the N- or O- glycosylation pathway.

64. A method for delivering a molecular payload to a cell expressing the transferrin receptor, the method comprising contacting the cell with the complex of any of claims 1 to 63.

65. A method for promoting the expression or activity of a DMD protein in a cell, the method comprising contacting the cell with the complex of any one of claims 1 to 63 in an amount effective to promote internalization of the molecular payload into the cell.

66. The method according to claim 65, further characterized in that the cell is in vitro.

67. The method according to claim 65, further characterized in that the cell is in vitro.

68. The subject. The method according to claim 67, further characterized in that the subject is a human.

69. A method of treating a subject having a mutated allele of DMD that is associated with dystrophinopathy, the method comprising administering to the subject an effective amount of the complex of any of claims 1 to 63.

70. A method of promoting an exon skip of a DMD mRNA transcript in a cell, the method comprising administering to the cell an effective amount of the complex of any of claims 1 to 63.

71. The method according to claim 70, further characterized in that the method promotes skipping of exon 8, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, and / or exon 55 of the DMD mRNA transcript.

72. The complex according to claim 70 or 71, further characterized in that the method promotes skipping of exon 51 of the DMD mRNA transcript.