Targeted delivery to retinal pigment epithelium in treatment of ocular diseases

Abstract

A method of administering, by a route other than intravitreal injection, a therapeutic agent to the retinal pigment epithelium (RPE) in a subject in need of a therapeutic agent effective for the treatment of the RPE or adjacent cells comprising administering to the subject a conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α (FRα), L is a linker, and A is the therapeutic agent effective for treatment of the RPE; a conjugate of formula F-L-A; and a pharmaceutical composition comprising a conjugate of formula F-L-A and a pharmaceutically acceptable carrier.

Description

70628-02 3220-422529 TARGETED DELIVERY OF THERAPEUTIC AGENT TO RETINAL PIGMENT EPITHELIUM IN TREATMENT OF OCULAR DISEASES RELATED APPLICATIONS 5 This application claims the benefit of U.S. Provisional Application No. 63 / 639,195, filed April 26, 2024, the entire disclosure of which is incorporated herein by reference. TECHNICAL FIELD The present disclosure relates to the targeted delivery of therapeutic agents, such as 10 oligonucleotides and small molecule drugs, to the retinal pigment epithelium by a route of administration other than intravitreal injection in the treatment of ocular diseases, such as neurodegenerative ocular diseases, including age-related macular degeneration and proliferative diabetic retinopathy. 15 BACKGROUND Age-related macular degeneration (AMD) is a leading cause of irrevocable vision loss in an aging population. In the United States approximately 20 million individuals over the age of 40 are suffering from some form of AMD. AMD is divided into two stages – dry and wet. In the early dry stage, the macula 20 gradually thins out. In the wet stage, the condition worsens. The choroid is a highly vascularized structure that supplies oxygen and nutrients to the outer retina. In the wet stage of AMD, neovascularization of the choroid occurs. Abnormal blood vessels in the choroid traverse the retina and hamper vision. The retinal pigment epithelium (RPE) is a single cell layer located between the choroid capillaries and the retinal 25 photoreceptors and functions as a protective blood retinal barrier (BRB). In wet AMD, the RPE secretes elevated levels of vascular endothelial growth factor (VEGF), which binds VEGF receptors on the endothelial cells and facilitates neovascularization. With elevated levels of VEGF as a hallmark of wet AMD and proliferative diabetic retinopathy, the standard treatment option is the injection of VEGF-neutralizing antibodies 30 (e.g., Bevacizumab (Genentech), Lucentis (Genentech), and aflibercept (Regeneron Pharmaceuticals)) into the vitreous humor of the eye in an effort to slow down disease progression. Intravitreal injection, however, can lead to scarring, blood leakage, inflammation in the retinal vessels, and retinal detachment. And it is difficult to deliver an active agent to 170628-02 3220-422529 the posterior of the eye because the active agent would have to diffuse from the vitreous humor across several retinal cell layers. In view of the above, it is an object of the present disclosure to provide platform technology that overcomes the disadvantages of intravitreal injection. This and other objects 5 and advantages, as well as inventive features, will be apparent from the detailed description provided herein. SUMMARY Provided is a method of administering a therapeutic agent to the retinal pigment 10 epithelium (RPE) in a subject in need of a therapeutic agent effective for the treatment of the RPE or adjacent cells. The method comprises administering, by a route other than intravitreal injection, to the subject a conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α (FRα), L is a linker, and A is the therapeutic agent effective for treatment of the RPE. In some embodiments of the method, the therapeutic agent comprises nucleotides and / or 15 modified nucleotides. In some embodiments of the therapeutic agent, the therapeutic agent is an oligonucleotide, an interfering RNA (iRNA), a small interfering RNA (siRNA), an RNA aptamer, a microRNA, a ribozyme, a short hairpin RNA, an antisense oligonucleotide (i.e., a single-stranded or double-stranded oligodeoxynucleotide), or an analog or derivative of any of the foregoing. In some embodiments of the therapeutic agent, the therapeutic agent is an 20 oligonucleotide, such as an siRNA or an antisense oligonucleotide (ASO). In some embodiments of the therapeutic agent, the therapeutic agent is modified with a 2’-F sugar, a 2’- O-methyl sugar, a 5-alkylamino base, a 5-allylamino base, a phosphorothioate modification of a nucleotide, a P-alkyl modification of a nucleotide, a phosphonate modification of a nucleotide, a phosphoroselenate modification of a nucleotide, a phosphoroamidate 25 modification of a nucleotide, a modification of a terminal phosphate, or any combination thereof. In some embodiments of the therapeutic agent, the therapeutic agent silences the gene that expresses vascular endothelial growth factor (VEGF). In some embodiments of the siRNA, the siRNA is Bevasiranib. In some embodiments of the RNA aptamer, the RNA 30 aptamer binds VEGF. In some embodiments of the RNA aptamer, the RNA aptamer is Pegaptanib. In some embodiments of the method, the therapeutic agent is a VEGF decoy receptor. In some embodiments of the VEGF decoy receptor, the VEGF decoy receptor is Aflibercept or Conbercept. In some embodiments of the method, the therapeutic agent is an ankyrin repeat protein (DARPin). In some embodiments of the DARPin, the DARPin is 270628-02 3220-422529 Abicipar pegol. In some embodiments of the therapeutic agent, the therapeutic agent is a stress resilience-enhancing drug (SRED). In some embodiments of the SRED, the SRED inhibits a cyclic nucleotide phosphodiesterase (PDE). In some embodiments of the SRED that inhibits a PDE, the SRED is BAY 60-7550, rolipram, or BC 11-38. In an embodiment of the method, the 5 therapeutic agent is a corticosteroid. In some embodiments of the corticosteroid, the corticosteroid is triamcinolone acetonide, dexamethasone, or fluocinolone acetonide. In some embodiments of the method, the subject has age-related macular degeneration (AMD) (e.g., wet AMD or dry AMD), diabetic retinopathy (DR), or retinitis pigmentosa (RP). In some embodiments of AMD, the AMD is wet. 10 In some embodiments of F, F is a folate or a derivative or analog thereof. In embodiments of F, F is 5-methyltetrahydrofolate (5-MTHF) or an N5,N10-dimethylated derivative of tetrahydrofolic acid (DMTHF). In an embodiment of F, F has or comprises the structure (or a radical thereof): 1). 15ure (or a radical thereof): O COOH OH 2).re (or a radical thereof): 3)., e (or a radical thereof): 370628-02 3220-422529 4). ructure (or a radical thereof):5). dibenzocyclooctane. In some5 embodiments of L, L is or comprises a portion formed from a strain-promoted alkyne-azide cycloaddition (SPAAC) reaction (e.g., a fused dibenzocyclooctane-triazole). Further provided are conjugates of formula F-L-A. In some embodiments of F-L-A, F is a ligand that targets FRα, L is a linker, and A is an siRNA. In some embodiments of F-L-A, F is a ligand that targets FRα, L is a linker, and A is Bevasiranib; in embodiments thereof, L is 10 or comprises dibenzocyclooctane. In some embodiments of F-L-A, F is a ligand that targets FRα, L is a linker, and A is an ASO. In some embodiments of F-L-A, F is a ligand that targets FRα, L is a linker, and A is Pegaptanib. In some embodiments of F-L-A, F is a ligand that targets FRα, L is a linker, and A is Aflibercept or Conbercept. In some embodiments of F-L- A, F is a ligand that targets FRα, L is a linker, and A is Abicipar pegol. In some embodiments 15 of F-L-A, F is a ligand that targets FRα, L is a linker, and A is BAY 60-7550, rolipram, or BC 11-38. In some embodiments of F-L-A, F is a ligand that targets FRα, L is a linker, and A is triamcinolone acetonide or fluocinolone acetonide. Still further provided is a pharmaceutical composition. The pharmaceutical composition comprises a conjugate of formula F-L-A and a pharmaceutically acceptable 20 carrier. In the conjugate of formula F-L-A, F is a ligand that targets FRα, L is a linker, and A is Bevasiranib, Pegaptanib, Aflibercept, Conbercept, Abicipar pegol, BAY 60-7550, rolipram, BC 11-38, triamcinolone acetonide, or fluocinolone acetonide. BRIEF DESCRIPTION OF THE FIGURES 25 Figs.1A-1C show images of 25-μm sections of eyes from mice treated with folate-Cy5 (cyanine-5). Images were taken at 20x magnification with a Nikon A1rsi microscope. Fig.1A: 470628-02 3220-422529 non-injected. Fig. 1B: seven days post-injection. Fig. 1C: 14 days post-injection. GCL: ganglion cell layer; RPE: retinal pigment epithelium; ONL: outer nuclear layer; INL: inner nuclear layer. Fig. 2A shows the reaction of Bevasiranib (SEQ. ID No. 60 (sense strand) and SEQ. 5 ID No.61(anti-sense strand)) with folate-DBCO. Fig.2B shows the reaction of Bevasiranib (SEQ. ID No.60 (sense strand) and SEQ. ID No.61 (anti-sense strand)) with folate-Cy5-DBCO. Fig.3A shows the structures of folate-Bevasiranib and folate-Cy5-Bevasiranib. Nucleotides indicated as “rN” are ribonucleotides. In Bevasiranib (SEQ. ID No.60 (sense 10 strand) and SEQ. ID No.61 (anti-sense strand)), all the nucleobases have a phosphodiester backbone. Fig.3B shows the structures of folate-ASO and folate-ASO-Cy5. Nucleotides indicated as N (upper case) are 2'-O-methoxyethyl modified, and n (lower case) are 2'-deoxy modified (deoxyribonucleotides). In the ASO (SEQ ID NO.10), all the nucleobases have 15 phosphorothioate backbone modifications. Fig.4 shows the structures of azide-ASO (N3-10), ASO-Cy5, and folate-glucosamine. Figs. 5A-5E show images of folate-Bevasiranib targeting at arising retinal pigment epithelium 19 (ARPE-19) cells in vitro. Fig. 5A: no dye or DAPI. Fig. 5B: folate-Cy5 or DAPI. Fig. 5C: folate-Bevasiranib or DAPI. Fig. 5D: merged image of folate-Bevasiranib- 20 treated cells. Fig.5E: enlargement of boxed area in Fig.5D. DAPI: nucleus stain. DAPI, Cy5 and Atto647 dye have laser excitation of 647 nm. Figs. 6A-6C show images of folate-Bevasiranib targeting the RPE in mice. Fig. 6A: no dye. Fig. 6B: folate-Cy5. Fig. 6C: folate-Bevasiranib. GCL: ganglion cell layer; INL: inner nuclear layer; ONL: outer nuclear layer; RPE retinal pigment epithelium. 25 Fig.7 show images of competition between folate-Bevasiranib and folate glucosamine in vitro. DAPI: nucleus stain. ZO-1: tight junction protein. Fig.8 shows images of folate-Cy5 uptake by receptor-mediated endocytosis. In the top panels, cells were treated with only 50 nM folate-Cy5. In the bottom panels, cells were treated with 50 nM folate-Cy5 + 5,000 nM folate-glucosamine. DAPI: nucleus stain. ZO-1: tight 30 junction protein. Fig.9 shows images of folate-bevasiranib uptake by ARPE-19 cells by folate receptor- mediated endocytosis. In the top panels, cells were treated with only 50 nM folate-Cy5. In the bottom panels, cells were treated with 50 nM folate-Cy5 + 5,000 nM folate-glucosamine. DAPI: nucleus stain. ZO-1: tight junction protein. 570628-02 3220-422529 Fig. 10 shows ELISA results of VEGF concentration (pg / ml) versus sample. The results represent means + standard deviation. Each sample condition was done in triplicate. Fig. 11 shows the relative remain of mVegf mRNA (%) in the screening of ASOs in AMPL12 cells. Cells were treated with 33 nM ASO. The x-axis shows from left to right, the 5 ASO of SEQ. ID No.56 (mVEGF_3A), followed by the in-silico-designed ASOs of SEQ. ID No. 1-52. SEQ. ID Nos 3, 6, 7, 10, 34, 38, 47, and 51 are indicated by solid bars. The cutoff was set at ddCt =1, which equals a 50% reduction. mGapdh was used as an internal control gene. Fig. 12 shows the cell viability of AML12 cells treated with 33 nM ASO. The x-axis10 shows from left to right, the ASO of SEQ. ID No.56 (mVEGF_3A), followed by the in silico- designed ASOs of SEQ. ID No.1-52. SEQ. ID Nos 3, 6, 7, 10, 34, 38, 47, and 51 are indicated by solid bars. The cutoff was set at 90% for cytotoxicity evaluation in CCK8 assay. Fig. 13 shows the relative remainder of mVegf mRNA (%) in the liver of in vivo screening of wild-type mice (C57BL / 6) treated with ASO SEQ. ID Nos.38 and 10. Mice were 15 treated with 60 mg / kg of ASO subcutaneously (SC) on day 1 (D1) and day 3 (D3). The cutoff was set at ddCt =1, which equals a50% reduction. mGapdh was used as an internal control gene. Fig. 14 shows the relative remainder of mVegf mRNA (%) in the liver of in vivo screening of wild-type mice (C57BL / 6) treated with ASO SEQ. ID No. 56 (mVEGF_3A) and 20 ASO SEQ. ID No.10 with (N3-10) and without (10) conjugation to an azide tether. Mice were treated with 60 mg / kg of ASO subcutaneously (SC) on day 1 (D1). The cutoff was set at ddCt =1, which equals a 50% reduction. mGapdh was used as an internal control gene. Fig. 15A shows the percent VEGF mRNA knockdown in liver (left), kidney (middle), and retina (right) in VLDLR mice. Folate-ASO suppresses VEGF mRNA levels in different 25 tissues in VLDLR mice. N=03 mice / group. One-way ANOVA was conducted with Graphpad Prism 10. Data are presented as mean ± SD, * = >0.05]. Fig.15B shows a graph of bodyweight (gram) over time in very low density lipoprotein receptor (VLDLR) mice. Folate-ASO drug does not reduce body weight in VLDLR mice. Two- way grouped ANOVA was conducted with Graphpad prism v10. Data are presented as mean ± 30 SD, P value= 0.5551. Fig.16 shows images of the retina in VLDLR mice. Folate-ASO drug reduces abnormal vasculature. Retina is triple-stained with Isolectin IB4, IBA-1 and VEGF. N= 20 images / group. Images were taken at 10x magnification with a Zeiss LSM 900. 670628-02 3220-422529 Fig.17 shows the percent VEGF mRNA knockdown in kidney (left) and retina (right) in C57BL / 6 mice. Folate-ASO drug significantly reduces VEGF mRNA level in different tissues in C57BL / 6 mice. N=03 mice / group. One-way ANOVA was conducted with Graphpad Prism. Data are presented as mean ± SD]. 5 Fig. 18 shows images of kidney sections in C57BL / 6 mice. Folate-ASO drug reduces VEGF protein levels. N=10 sections / group. Images were taken with a Zeiss LSM 900 at 20X magnification with the same instrumental setup. Fig. 19 shows the vessel density in retina in C57BL / 6 mice. Folate-ASO does not suppress normal retinal vasculature in any retinal plexus. N= 03 / group. One-way ANOVA was 10 conducted with Graphpad Prim v.10. Data is presented as mean ± SD. Fig.20 shows images of sections of eyes from Balb-c mice. Folate-ASO is targeted to the RPE layer in the eyes. Representative images are from N=10 sections / group. Images were taken with the same instrumental setup using a Zeiss LSM 900 at 10X magnification. Figs.21A and 21B show images of treated ARPE-19 cells. Folate-ASO is specifically 15 taken up by ARPE-19 cells due to the presence of folate receptor α (FRα). Representative images from N=05-07 sections / group. Images were taken with the same instrumental setup using a Zeiss LSM 900 at 20X magnification. Fig 21A shows Group 1: negative control; Group 2: negative control with 100X competition of folate-glucosamine; Group 3: folate-Cy5: positive control; and Group 4: positive control with 100X competition. Fig.21B shows Group 20 5: folate- ASO-Cy5; Group 6: folate-ASO-Cy5 with 100x competition of folate-glucosamine; Group 7: free ASO-Cy5; and Group 8: free ASO-Cy5 with its competition. Fig. 22 shows the percent VEGF mRNA knockdown in ARPE-19 cells. Folate-ASO suppresses the VEGF mRNA levels at a higher percentage in comparison with the free ASO. N=03 samples / group. 25 Figs. 23A-23F show a sequence alignment of Mus musculus vascular endothelial growth factor A (Vegfa), transcript variant 1, mRNA (SEQ ID NO. 72, NCBI Reference Sequence: NM_001025250.3) as “query” and Homo sapiens vascular endothelial growth factor A (VEGFA), transcript variant 1, mRNA (SEQ ID NO. 83, NCBI Reference Sequence: NM_NM_001025366.3) as “sbjct” (subject). Fig. 23A shows the sequence alignment of 30 nucleotides 1-626 of query and 1-638 of subject. Fig. 23B shows the sequence alignment of nucleotides 627-1340 of query and 639-1358 of subject. Fig. 23C shows the sequence alignment of nucleotides 1341-1989 of query and 1359-2077 of subject. Fig. 23D shows the sequence alignment of nucleotides 1990-2661 of query and 2078-2793 of subject. Fig. 23E shows the sequence alignment of nucleotides 2662-3351 of query and 2794-3480 of subject. 770628-02 3220-422529 Fig. 23F shows the sequence alignment of nucleotides 3352-3547 of query and 3481-3660 of subject. Fig. 24 shows a sequence alignment of nucleotides 1680-1980 (SEQ ID NO. 73) of Mus musculus vascular endothelial growth factor A (Vegfa), transcript variant 1, mRNA (SEQ 5 ID NO. 72, NCBI Reference Sequence: NM_001025250.3) as “query” and nucleotides 1680- 1980 (SEQ ID NO. 84) of Homo sapiens vascular endothelial growth factor A (VEGFA), transcript variant 1, mRNA (SEQ ID NO. 83, NCBI Reference Sequence: NM_NM_001025366.3) as “sbjct” (subject). 10 DETAILED DESCRIPTION The present disclosure is predicated on the development of conjugates, which can be actively transported through the blood retinal barrier (BRB) by targeting folate receptor α (FRα) on the basolateral side of the retinal pigment epithelium (RPE) and which can deliver therapeutic agents, such as oligonucleotides (e.g., small interfering RNAs, antisense 15 oligonucleotides, microRNA, circular RNA, etc.) and small molecule drugs. Specific targeting obviates the need for intravitreal injection. Specific targeting also allows for chemical modification, such as chemical modification of siRNA, e.g., Bevasiranib, to facilitate endosomal escape to improve efficacy in the treatment of ocular diseases, such as ocular neurodegenerative diseases, such as AMD, in particular wet AMD. 20 In view of the above, provided is a method of administering a therapeutic agent to the RPE in a subject in need of a therapeutic agent effective for the treatment of the RPE or adjacent cells. The method comprises administering, by a route other than intravitreal injection, to the subject a conjugate of formula F-L-A, wherein F is a ligand that targets FRα, L is a linker, and A is the therapeutic agent effective for treatment of the RPE. The term “administering” 25 includes any suitable route of administration; desirably, however, the route of administration is other than intravitreal injection. Examples of routes of administration include, but are not limited to, intravenous and intranasal. In some embodiments of the method, the therapeutic agent comprises nucleotides and / or modified nucleotides. In some embodiments of the method, the therapeutic agent 30 comprises nucleotides and / or modified nucleotides, wherein one or more of the nucleotides is modified with a 2’-F sugar, a 2’-O-methyl sugar, a 5-alkylamino base, a 5-allylamino base, a phosphorothioate modification of a nucleotide, a P-alkyl modification of a nucleotide, a phosphonate modification of a nucleotide, a phosphoroselenate modification of a nucleotide, a 870628-02 3220-422529 phosphoroamidate modification of a nucleotide, a modification of a terminal phosphate, or any combination thereof. Nucleotides are composed of a nitrogenous base, a pentose sugar and a phosphate. The nucleotides can include ribonucleotides, deoxyribonucleotides, or a combination thereof. In 5 some embodiments, a ribonucleotide is indicated by a “r” preceding the base, for example, rC may refer to a cytosine ribonucleotide base. In some embodiments, a deoxyribonucleotide is indicated by a “d” preceding the base, for example, dT may refer to a thymine deoxyribonucleotide (2'-deoxy sugar). The nucleotides can form a single strand, a double strand, or a combination thereof. If 10 double-stranded, one strand can be a sense strand and the other strand can be an antisense strand. If single-stranded, antisense can be desirable. The length of a nucleotide strand, also referred to as an oligonucleotide, can comprise from about 15 bases to about 50 bases, such as about 20 bases to about 45 bases, about 25 bases to about 40 bases, about 30 bases to about 35 bases, about 15 bases to about 45 bases, about 15 bases to about 40 bases, about 15 bases to 15 about 35 bases, about 15 bases to about 30 bases, about 15 bases to about 25 bases, or about 15 bases to about 20 bases. In some embodiments, the oligonucleotide comprises 15-25 (e.g., 18-21) nucleotide bases. In some embodiments, the nucleotides form a double strand with a single strand overhang at the 5’ end, the 3’ end or both the 5’ end and the 3’ end. The overhang typically is short, such as a strand comprising from about 2 bases to about 5 bases (about 2 20 bases to 5 bases, 2 bases to about 5 bases, or 2-5 bases), about 2 bases to about 4 bases (about 2 bases to 4 bases, 2 bases to about 4 bases, or 2-4 bases), or 2-3 bases. In some embodiments of the therapeutic agent, the therapeutic agent is an oligonucleotide, an interfering RNA (iRNA), a small interfering RNA (siRNA), an RNA aptamer, a microRNA (miRNA), a ribozyme, a short hairpin RNA, an antisense oligonucleotide 25 (i.e., a single-stranded or double-stranded oligodeoxynucleotide), or an analog or derivative of any of the foregoing. In some embodiments, the therapeutic agent comprises (or consists essentially of or consists of) an siRNA or an antisense oligonucleotide (ASO). In some embodiments, the therapeutic agent comprises (or consists essentially of or consists of) an siRNA or an ASO that targets VEGF (e.g., the gene that expresses VEGF). In some 30 embodiments, the therapeutic agent does not comprise an miRNA (e.g., miRNA-34a). In some embodiments, the therapeutic agent does not comprise an acrolein-scavenging drug (e.g., hydralazine). The bases (nitrogenous bases) of nucleotides can be natural bases, such as A (adenine), T (thymine), G (guanine), C (cytosine), and U (uracil), as well as non-natural analogs and 970628-02 3220-422529 derivatives thereof. In some instances, non-natural analogs of bases and derivatives of bases can stabilize the nucleotide, such as a single or double strand comprising the nucleotide, from degradation (e.g., by a nuclease) or metabolism. In some embodiments, a base is modified with an alkyl group; for example, 5-methylcytosine (5mC) is a modified base of cytosine where a 5 methyl group is bound to the 5th carbon. The pentoses (sugars) of nucleotides can be modified with a 2’-sugar (e.g., a 2’-F sugar, a 2’-O-methyl sugar, a 2’-O-methoxyethyl sugar, or a 2'-deoxy sugar). The phosphates (phosphodiesters or backbones) of nucleotides can be modified (e.g., a phosphorothioate modification of a nucleotide, a P-alkyl modification of a nucleotide, a phosphonate 10 modification of a nucleotide, a phosphoroselenate modification of a nucleotide, a phosphoroamidate modification of a nucleotide, a modification of a terminal phosphate, or any combination thereof). In some embodiments of the therapeutic agent, the therapeutic agent (e.g., an oligonucleotide, such as an siRNA or an ASO) is modified with a 2’-F sugar, a 2’-O-methyl 15 sugar, a 5-alkylamino base, a 5-allylamino base, a phosphorothioate modification of a nucleotide, a P-alkyl modification of a nucleotide, a phosphonate modification of a nucleotide, a phosphoroselenate modification of a nucleotide, a phosphoroamidate modification of a nucleotide, a modification of a terminal phosphate, or any combination thereof. See, e.g., Int’l Pat. App. Pub. No. 2009 / 082606, which is hereby incorporated by reference for its teachings 20 regarding same. In some embodiments of the therapeutic agent, the therapeutic agent (e.g., an oligonucleotide, such as an siRNA or an ASO) is modified with a 2’-sugar (e.g., a 2’-F sugar, a 2’-O-methyl sugar, a 2’-O-methoxyethyl sugar, or a 2'-deoxy sugar), a 5-base (e.g., a 5- alkylamino base or a 5-allylamino base), a backbone modification (e.g., a phosphorothioate modification of a nucleotide, a P-alkyl modification of a nucleotide, a phosphonate 25 modification of a nucleotide, a phosphoroselenate modification of a nucleotide, a phosphoroamidate modification of a nucleotide), a modification of a terminal phosphate, or any combination thereof. In some embodiments of the therapeutic agent, the therapeutic agent is modified with a 2’-O- methoxyethyl sugar, a 2'-deoxy sugar, a phosphorothioate modification of a nucleotide, or any combination thereof. Such modifications can be used in 30 any combination and at any position in a given nucleotide as well as in any nucleotide at any position in a single strand or double strand comprising nucleotides. Methods of synthesis are known in the art and include, for example, the methods described in Trufert et al., Tetrahedron 52:3005 (1996); Martin, Helv Chim Acta 78: 486-504 (1995), and Int’l Pat. App. Pub. No. 2009 / 082606. In some instances, modifications to the nucleotides can stabilize the nucleotide, 1070628-02 3220-422529 such as a single or double strand comprising the nucleotide, from degradation (e.g., by a nuclease) or metabolism. In some embodiments of the therapeutic agent, the therapeutic agent (e.g., an siRNA or an ASO) silences (targets) the gene that expresses vascular endothelial growth factor (VEGF). 5 In some embodiments of the therapeutic agent, the therapeutic agent (e.g., an siRNA or an ASO) targets VEGF messenger RNA (mRNA) by binding to specific mRNA sequences through Watson-Crick base pairing. This binding can lead to the degradation of the mRNA, thus silencing the gene expression, or can interfere with other processes like splicing or translation. 10 In some embodiments, the siRNA comprises (or consists essentially of or consists of) a nucleotide sequence selected from the group consisting of SEQ. ID Nos. 60-71, and any combination thereof. In some embodiments of the siRNA, the siRNA is an 18-21 nucleotide long double-stranded oligonucleotide (e.g., a dsRNA or modified dsRNA). For example, each strand of an 18-21 nucleotide long double-stranded oligonucleotide independently comprises 15 or consists essentially of or consists of 18-21 nucleotides. In some embodiments of the siRNA, the siRNA is an 18-21 nucleotide long double-stranded RNA (dsRNA). In some embodiments, the siRNA is a dsRNA, wherein one strand comprises (or consists essentially of or consists of) a first nucleotide sequence selected from the group consisting of SEQ. ID Nos.60-71, and the other strand comprises (or consists essentially of or consists of) a second nucleotide sequence. 20 In an embodiment of the siRNA, the siRNA is Bevasiranib (Opko Health Inc.; phase 3 clinical trial NCT00499590), which is currently administered by intravitreal injection. The sequences of Bevasiranib are as follows: ACC-UCA-CCA-AGG-CCA-GCA-C-dT-dT [sense strand] (SEQ ID NO. 60) and GUG-CUG-GCC-UUG-GUG-AGG-U-dT-dT [antisense strand] (SEQ ID NO.61). Chemical modifications of the siRNA can include, for example, phosphorothioate 25 (PS) substitutions in the backbone, particularly in bases near the 5’ or 3’ end of the siRNA, and 2’-O-methyl and 2’-fluoro modifications near the middle of the siRNA. The lengths of the sense and antisense strands also can differ (see, e.g., Hwang et al., J Invest Dermatol 136(11): 2305-2313 (2016)). In some embodiments, the siRNA is modified with one or more phosphorothioate (PS) substitutions in the backbone of the nucleotide sequence, one or more 30 2’-sugar substitutions (e.g., a 2’-F sugar, a 2’-O-methyl sugar, a 2’-O-methoxyethyl sugar, or a 2'-deoxy sugar, which can be the same or different) of the nucleotide sequence, or a combination thereof. In some embodiments, the siRNA is Bevasiranib (SEQ. ID No. 60 and SEQ. ID No. 61). In some embodiments, the siRNA is SEQ. ID No. 62 and a second nucleotide sequence. 1170628-02 3220-422529 In some embodiments, the siRNA is SEQ. ID No. 63 and a second nucleotide sequence. In some embodiments, the siRNA is SEQ. ID No.64 and a second nucleotide sequence. In some embodiments, the siRNA is SEQ. ID No. 65 and a second nucleotide sequence. In some embodiments, the siRNA is SEQ. ID No. 66 and a second nucleotide sequence. In some 5 embodiments, the siRNA is SEQ. ID No. 67 and a second nucleotide sequence. In some embodiments, the siRNA is SEQ. ID No. 68 and a second nucleotide sequence. In some embodiments, the siRNA is SEQ. ID No. 68 and SEQ. ID No. 69. In some embodiments, the siRNA is SEQ. ID No.70 and a second nucleotide sequence. In some embodiments, the siRNA is SEQ. ID No.70 and SEQ. ID No.71. In some embodiments, the therapeutic agent does not 10 comprise an siRNA that targets luciferase. For SEQ ID NOs: 60-71, upper case letters represent ribonucleotides, lower case letters represent 2′-O-methyl-nucleotides, upper case letters printed in italics represent 2′-deoxy-2′-fluoro-nucleotides, the asterisk (*) represents the phosphorothioate linkages and dT represents deoxythymidine nucleotides. Table 1. siRNA sequences SEQ. ID No. Sequence (5’-3’) 60 ACC-UCA-CCA-AGG-CCA-GCA-C-dT-dT 15In some embodiments, the ASO comprises (or consists essentially of or consists of) a nucleotide sequence selected from the group consisting of SEQ. ID NOs. 1-59 (e.g., SEQ. ID NOs. 1-52), and any combination thereof. In some embodiments, the ASO is a nucleotide sequence selected from the group consisting of SEQ. ID NOs. 3, 6, 8, 10, 34, 38, 47, 51, and 20 56. In some embodiments, the ASO is a nucleotide sequence selected from the group consisting of SEQ. ID NOs.3, 6, 8, 10, 34, 38, 47, and 51. In some embodiments, the ASO is SEQ. ID NO.10 or 38. In some embodiments of the ASO, the ASO is an 18-21 nucleotide long single-stranded oligonucleotide (e.g., an ssRNA or modified ssRNA). 1270628-02 3220-422529 Chemical modifications of the ASO can include, for example, phosphorothioate (PS) substitutions in the backbone, and 2’-sugar modifications (e.g., 2’-O-methyl, 2’-fluoro, 2’-O- methoxyethyl, or 2’-deoxy modifications). In some embodiments, the ASO is modified with one or more phosphorothioate (PS) substitutions in the backbone of the nucleotide sequence, 5 one or more 2’-sugar substitutions (e.g., a 2’-F sugar, a 2’-O-methyl sugar, a 2’-O- methoxyethyl sugar, or a 2'-deoxy sugar) of the nucleotide sequence, or a combination thereof. In some embodiments, the ASO comprises all phosphorothioate (PS) substitutions in the backbone. In some embodiments, the ASO comprises all 2’-sugar modifications (e.g., 2’-O- methyl, 2’-fluoro, or 2’-deoxy modifications). In some embodiments, the ASO comprises 2’- 10 sugar modifications (e.g., 2’-deoxy modifications) particularly near the middle of the ASO. In some embodiments, the ASO comprises 2’-sugar modifications (e.g., 2’-O-methoxyethyl modifications) particularly near the 5’ and 3’ ends of the ASO. In some embodiments, the ASO comprises (or consists essentially of or consists of) a gapmer. A gapmer, for example, comprises a central region (“gap”) of deoxyribonucleotides 15 (e.g., 2’-deoxy modifications) flanked by regions (“wings”) of modified ribonucleotides (e.g., 2’-sugar modifications, such as 2’-O-methyl, 2’-fluoro, or 2’-O-methoxyethyl modifications). In some embodiments, the ASO comprises (or consists essentially of or consists of) a gapmer comprising all phosphorothioate (PS) substitutions in the backbone. It may be advantageous for an ASO to comprise a gapmer, as a gapmer may provide stability and enhanced binding to 20 target RNA. In some embodiments, the ASO is a 20 nucleotide long single-stranded oligonucleotide that is a 5-10-5 gapmer. A 5-10-5 gapmer, for example, comprises a 10 nucleotide long central gap of deoxyribonucleotides (e.g., 2’-deoxy modifications) flanked by two 5 nucleotide long wings of modified ribonucleotides (e.g., 2’-sugar modifications, such as 2’-O-methyl, 2’-fluoro, or 2’-O-methoxyethyl modifications). Preferably, the two 5 nucleotide25 long wings of a 5-10-5 gapmer comprise (or consist essentially of or consist of) 2’-O- methoxyethyl modifications. Table 2. ASO sequences SEQ. ID No. Sequence (5'-3')1, 2, 3, 41370628-02 3220-422529 SEQ. ID No. Sequence (5'-3')1, 2, 3, 47 GTCTTtccggtgagaGGTCT1470628-02 3220-422529 SEQ. ID No. Sequence (5'-3')1, 2, 3, 448 GCTTGgcgatttagcAGCAG 1 all nucleob ions 2 N: 2'-O-mey y 3 n: 2'-deoxy 4 all C are 5’ methyl 5 In some embodiments, the therapeutic agent further comprises an imaging agent (e.g., a fluorescent dye, such as Cy5 or ATTO647N). In some embodiments when the therapeutic agent comprises an oligonucleotide (e.g., an siRNA or an ASO), the therapeutic agent further comprises an imaging agent covalently bound to the 3’ end of the oligonucleotide. In some 10 embodiments when the therapeutic agent comprises an oligonucleotide (e.g., an siRNA or an ASO), the therapeutic agent further comprises an imaging agent covalently bound to the 5’ end of the oligonucleotide. In some embodiments of the therapeutic agent, the therapeutic agent (e.g., an siRNA or an ASO) targets (e.g., silences) the gene that expresses VEGF (e.g., an mVEGFa gene or an 15 hVEGFa gene) by binding to VEGF messenger RNA (mRNA), such as mRNA transcript SEQ ID NO. 72 (NM_001025250.3) or mRNA transcript SEQ ID NO. 83 (NM_001025366.3). In some embodiments, the therapeutic agent comprises (or consists essentially of or consists of) an oligonucleotide (e.g., an siRNA or an ASO) that is complementary to a region of VEGF mRNA. 20 1570628-02 3220-422529 Table 3. Nucleotides 1684-1963 of mVegfA mRNA transcript (NCBI Reference Sequence: NM_001025250.3) (SEQ ID NO.74) 1684 agcctccctc agggtttcgg gaaccagacc tctcaccgga aagaccgatt aaccatgtca 1744 ccaccacgcc atcatcgtca ccgttgacag aacagtcctt aatccagaaa gcctgacatg gide 5 (e.g., an siRNA or an ASO) that targets a region of the gene that expresses VEGF, such as the region from about nucleotide 1680 to about nucleotide 1980 (SEQ ID NO.73) (e.g., nucleotide 1684 to nucleotide 1963 (SEQ ID NO. 74) of the mVEGFa gene that expresses VEGF (SEQ ID NO. 72). In some embodiments, the therapeutic agent is an 18-21 nucleotide long oligonucleotide that binds to and / or is complementary to a region of VEGF mRNA, such as the 10 region from about nucleotide 1680 to about nucleotide 1980 (SEQ ID NO.73) (e.g., nucleotide 1684 to nucleotide 1963 (SEQ ID NO.74)) of the VEGF mRNA transcript (SEQ ID NO.72)). In some embodiments, the therapeutic agent is an 18-21 nucleotide long oligonucleotide (e.g., an siRNA or an ASO) that targets a region of the gene that expresses VEGF, such as the region from about nucleotide 1684 to about nucleotide 1753 (SEQ ID NO. 75) (e.g., about 15 nucleotide 1713 to about nucleotide 1751 (SEQ ID NO. 76), such as nucleotide 1718 to nucleotide 1737 (SEQ ID NO. 77)) of the mVEGFa gene that expresses VEGF (SEQ ID NO. 72). In some embodiments, the therapeutic agent is an 18-21 nucleotide long oligonucleotide that binds to and / or is complementary to a region of VEGF mRNA, such as the region from about nucleotide 1684 to about nucleotide 1753 (SEQ ID NO.75) (e.g., about nucleotide 1713 20 to about nucleotide 1751 (SEQ ID NO.76), such as nucleotide 1718 to nucleotide 1737 (SEQ ID NO.77)) of the VEGF mRNA transcript (SEQ ID NO.72)). In some embodiments, the therapeutic agent is an 18-21 nucleotide long oligonucleotide (e.g., an siRNA or an ASO) that targets a region of the gene that expresses VEGF, such as the region from about nucleotide 1837 to about nucleotide 1885 (SEQ ID NO. 78) (e.g., about 25 nucleotide 1853 to about nucleotide 1885 (SEQ ID NO. 79), such as nucleotide 1866 to nucleotide 1885 (SEQ ID NO. 80)) of the mVEGFa gene that expresses VEGF (SEQ ID NO. 72). In some embodiments, the therapeutic agent is an 18-21 nucleotide long oligonucleotide that binds to and / or is complementary to a region of VEGF mRNA, such as the region from about nucleotide 1837 to about nucleotide 1885 (SEQ ID NO.78) (e.g., about nucleotide 1853 1670628-02 3220-422529 to about nucleotide 1885 (SEQ ID NO.79), such as nucleotide 1866 to nucleotide 1885 (SEQ ID NO.80)) of the VEGF mRNA transcript (SEQ ID NO.72). In some embodiments, the therapeutic agent is an 18-21 nucleotide long oligonucleotide (e.g., an siRNA or an ASO) that targets a region of the gene that expresses VEGF, such as the 5 region from about nucleotide 1925 to about nucleotide 1963 (SEQ ID NO. 81) (e.g., about nucleotide 1925 to about nucleotide 1958 (SEQ ID NO. 82)) of the mVEGFa gene that expresses VEGF (SEQ ID NO. 72). In some embodiments, the therapeutic agent is an 18-21 nucleotide long oligonucleotide that binds to and / or is complementary to a region of VEGF mRNA, such as the region from about nucleotide 1925 to about nucleotide 1963 (SEQ ID NO. 10 81) (e.g., about nucleotide 1925 to about nucleotide 1958 (SEQ ID NO. 82)) of the VEGF mRNA transcript (SEQ ID NO.72)). In some embodiments, the therapeutic agent is a 15-25 (e.g., 18-21) nucleotide long oligonucleotide (e.g., an siRNA or an ASO) that targets a region of the gene that expresses VEGF, such as the region from about nucleotide 1680 to about nucleotide 1980 (SEQ ID NO. 15 84) of the hVEGFa gene that expresses VEGF (SEQ ID NO. 83). In some embodiments, the therapeutic agent is a 15-25 (e.g., 18-21) nucleotide long oligonucleotide that binds to and / or is complementary to a region of VEGF mRNA, such as the region from about nucleotide 1680 to about nucleotide 1980 (SEQ ID NO.84) of the VEGF mRNA transcript (SEQ ID NO.83). In some embodiments, the therapeutic agent provides greater than about 50% inhibition 20 of VEGF (e.g., reduction in VEGF mRNA). For example, the therapeutic agent may provide greater than about 55% inhibition of VEGF, greater than about 60% inhibition of VEGF, or greater than about 65% inhibition of VEGF. In an embodiment of the RNA aptamer, the RNA aptamer binds VEGF. In an embodiment of the RNA aptamer, the RNA aptamer is Pegaptanib. In an embodiment of the 25 method, the therapeutic agent is a VEGF decoy receptor. In some embodiments of the VEGF decoy receptor, the VEGF decoy receptor is Aflibercept or Conbercept. In an embodiment of the method, the therapeutic agent is an ankyrin repeat protein (DARPin). In an embodiment of the DARPin, the DARPin is Abicipar pegol. In an embodiment of the therapeutic agent, the therapeutic agent is a stress resilience-enhancing drug (SRED). In an embodiment of the 30 SRED, the SRED inhibits a cyclic nucleotide phosphodiesterase (PDE). In some embodiments of the SRED that inhibit a PDE, the SRED is BAY 60-7550, rolipram, or BC 11-38. In some embodiments of the method, the therapeutic agent is a corticosteroid. In some embodiments of the corticosteroid, the corticosteroid is triamcinolone acetonide, dexamethasone, or fluocinolone acetonide. 1770628-02 3220-422529 In some embodiments of the method, the subject has age-related macular degeneration (AMD), diabetic retinopathy (DR), or retinitis pigmentosa (RP). In an embodiment of AMD, the AMD is dry. In an embodiment of AMD, the AMD is wet. In some embodiments, F is a ligand that targets FRα (i.e., a FRα-binding ligand). In 5 some embodiments of F, F is a folate (e.g., folic acid) or a derivative or analog thereof. In some embodiments, the ligand that targets FRα can be folic acid, a folic acid analog, or another FRα- binding molecule. A folate (e.g., folic acid) or a derivative or analog thereof, for example, can include a compound or a radical of formula F1, F2, F3, F4, F5, or a pharmaceutically acceptable salt thereof. In some embodiments, F is folic acid. In some embodiments of F, F is 5- 10 methyltetrahydrofolate (5-MTHF) or an N5,N10-dimethylated derivative of tetrahydrofolic acid (DMTHF). In some embodiments, F is 5-methyltetrahydrofolate (5-MTHF), 5- formyltetrahydrofolate ( 5-formyl-THF), 10-formyltetrahydrofolate (10-formylTHF), a 5,10- methylenetetrahydrofolate (5,10-methylene-THF), a 5,10-methenyltetrahydrofolate (5,10- methenyl-THF), a 5,10-formiminotetrahydrofolate (5,10-formimino-THF), a 5,6,7,8- 15 tetrahydrofolate (THF), or a dihydrofolic acid (DHF). In an embodiment of F, F has or comprises the structure (or a radical thereof): It will be understood that when F has ola F1, the conjugate of formula F-L-A can be represented by the formula: 20 as describeIn an embodiment of F, F has or comprises the structure (or a radical thereof): 1870628-02 3220-422529 O COOH OH O N H 2). It will be understood that when F of formula F2, the conjugate of formulaF-L-A can be represented by the formula: as 5 describeIn an embodiment of F, F has or comprises the structure (or a radical thereof): 3). It will be understood that when Ff formula F3, the conjugate of formula F-L-A can be represented by the formula: 10 c), wherein L and A are as describeIn an embodiment of F, F has or comprises the structure (or a radical thereof): 1970628-02 3220-422529 It will be understood that when F has or c la F4, the conjugate of formula F- L-A canbe represented by the formula: d), wherein L and A are as described 5 herein.In an embodiment of F, F has or comprises the structure (or a radical thereof): 5). It will be understood that when Fof formula F5, the conjugate of 10 formula F-L-A can be represented by the formula: e), wherein L and A are as describeIn some embodiments, F is selected from the group consisting of: 2070628-02 3220-422529 nd 5In some embodiments, F is of the formula (I): O COOH I),, rein10R1and R2, when present, are independently H or alkyl (e.g., methyl), R3is H or alkyl (e.g., methyl), and 2170628-02 3220-422529 wherein each “ ” is independently a single or a double bond.In certain preferred embodiments of formula (I), both “ ” are a double bond, and R1d R2an are absent. In certain preferred embodiments of formula (I), R3is H.In some embodiments, the conjugate of formula F-L-A comprises (or consists 5 essentially of or consists of) a portion of F-L of: , , 1070628-02 3220-422529 a pharmaceutically acceptable salt thereof. In some embodiments, the conjugate of formula F-L-A comprises (or consists essentially of or consists of) a portion of F-L of: or 5In some embodiments, the conjugate of formula F-L-A comprises (or consists essentially of or consists of) a portion of F-L of: , , 10 ,2370628-02 3220-422529 , 5wherein Y comprises (or consists essentially of or consists of) an imaging agent (e.g., a fluorescent dye, such as Cy5). In some embodiments, the conjugate of formula F-L-A comprises (or consists essentially of or consists of) a portion of F-L of: 2470628-02 3220-422529, 2570628-02 3220-422529 N ,2670628-02 3220-422529 , ,5 In some embodiments, F and L are covalently attached by an amide or ester. For example, a carboxylic acid of F can react with L to form an amide or ester. L can be any suitable linker. The linker can comprise one or more linker moieties covalently attached to F and A. The linker can be a chain of atoms selected from C, N, O, S, 2770628-02 3220-422529 Si, and P; C, N, O, S, and P; or C, N, O, and S. In some embodiments, the linker can be a chain of atoms selected from C, N, and O. The conjugates can be synthesized in accordance with methods known in the art. Such methods are exemplified herein. In some embodiments, the linker can be formed via click 5 chemistry / click chemistry-derived. Those of skill in the art understand that the terms “click chemistry” and “click chemistry-derived” generally refer to a class of small molecule reactions commonly used in conjugation, allowing the joining of substrates of choice with specific molecules. Click chemistry is not a single specific reaction but describes a way of generating products that follow examples in nature, which also generates substances by joining small 10 modular units. In many applications, click reactions join a biomolecule and a reporter molecule. Click chemistry is not limited to biological conditions: the concept of a “click” reaction has been used in pharmacological and various biomimetic applications. However, they have been made notably useful in the detection, localization and qualification of biomolecules. Click reactions can occur in one pot, typically are not disturbed by water, can generate minimal 15 byproducts, and are “spring-loaded” — characterized by a high thermodynamic driving force that drives it quickly and irreversibly to high yield of a single reaction product, with high reaction specificity (in some cases, with both regio- and stereo-specificity). These qualities make click reactions suitable to the problem of isolating and targeting molecules in complex biological environments. In such environments, products accordingly need to be 20 physiologically stable and any byproducts need to be non-toxic (for in vivo systems). In some embodiments, L is or comprises a portion formed from a click chemistry reaction (e.g., a strain-promoted alkyne-azide cycloaddition (SPAAC) reaction). The portion formed from a SPAAC reaction, for example, the reaction of a dibenzocyclooctyne and an azide, may comprise a dibenzocyclooctane and a triazole (e.g., a fused dibenzocyclooctane- 25 triazole). In some embodiments, the SPAAC reaction may provide certain benefits over the copper-catalyzed (e.g., CuAAc) In some embodiments of L, L is or comprises the cycloaddition product of an azide and dibenzocylooctyne (DBCO). In some embodiments of L, L is or comprises dibenzocyclooctane. In some embodiments of L, L is or comprises a triazole. A structure 30 including a dibenzocyclooctane and a triazole (e.g., a fused dibenzocyclooctane-triazole) can be represented by: 2870628-02 3220-422529 . es:5 ,, ,70628-02 3220-422529 , ,5 orIn some embodiments, the linker comprises 3070628-02 3220-422529 , , or 5or, as two atoms in the backbone of the linker to as many as 100 or more contiguous atoms in the 10 backbone of the linker. The “backbone” of the linker is the shortest chain of contiguous atoms forming a covalently bonded connection between F and A. In some embodiments, a polyvalent 3170628-02 3220-422529 linker has a branched backbone, with each branch serving as a section of backbone linker until reaching a terminus. The linker can range in length from about 7 to about 100 atoms (such as about 7 to 100 atoms, 7 atoms to about 100 atoms, or 7 to 100 atoms). In some embodiments, the linker is at 5 least about 10 atoms in length. In some embodiments, the linker is at least about 14 atoms in length. In some embodiments, the linker is between about 7 and about 31 atoms (such as, about 7 to 31, 7 to about 31, or 7 to 31), between about 7 and about 24 atoms (such as, about 7 to 24, 7 to about 24, or 7 to 24), or between about 7 and about 20 atoms (such as, about 7 to 20, 7 to about 20, or 7 to 20) atoms. In some embodiments, the linker is between about 14 and about 10 31 atoms (such as, about 14 to 31, 14 to about 31, or 14 to 31), between about 14 and about 24 atoms (such as, about 14 to 24, 14 to about 24, or 14 to 24), or between about 14 and about 20 atoms (such as, about 14 to 20, 14 to about 20, or 14 to 20). In some embodiments, the linker has a chain length of at least 7 atoms, at least 14 atoms, at least 20 atoms, at least 25 atoms, at least 30 atoms, or at least 40 atoms; or from 1 to 15 atoms, 1 to 5 atoms, 5 to 10 atoms, 5 to 20 15 atoms, 10 to 40 atoms, or 25 to 100 atoms. The preceding ranges are inclusive of the stated end points and all one-atom increments within the specified ranges. The atoms used in forming the linker can be combined in all chemically relevant ways, such as chains of carbon atoms forming alkylene groups, chains of carbon and oxygen atoms forming polyoxyalkylene groups, chains of carbon and nitrogen atoms forming polyamines, 20 and others. The bonds connecting atoms in the chain can be either saturated or unsaturated, such that for example, alkanes, alkenes, alkynes, cycloalkanes, arylenes, imides, and the like may be divalent radicals that are included in the linker. In certain embodiments, the atoms forming the linker are cyclized upon each other to form divalent cyclic radicals in the linker. In each of the foregoing embodiments and other linkers described herein the chain forming the 25 linker can be substituted with a wide variety of groups. The linker can comprise at least one carbon-carbon bond and / or at least one amide bond. The linker can comprise one or more L- or D-configurations, natural or unnatural amino acids, a polyethylene glycol (PEG) monomer, a PEG oligomer, a PEG polymer, or a combination of any of the foregoing. For a linker that comprises one or more PEG units, all carbon and oxygen 30 atoms of the PEG units are part of the backbone, unless otherwise specified. The linker can comprise an alkyl group (e.g., ethylene, propylene, butylene, pentylene, or hexylene), a polyethylene glycol (PEG), a peptide, an aryl group (e.g., a phenyl or a phenoxy), a heteroaryl group (e.g., a triazole), or a combination of two or more thereof. Each of these groups can be linked together or to the rest of the molecule through various functional groups, including 3270628-02 3220-422529 ethers, esters, amines, amides, carbonyls, phosphates, phosphonates, phosphorothioates, phosphoroselenates, phosphoroamidates, and others. For example, in some embodiments, the linker comprises ethylene, propylene, butylene, pentylene, hexylene, , , 5 , ionThe linker can comprise an oligomer of peptidoglycans, glycans, anions, or a10 combination of any of the foregoing. The linker can comprise at least one 2,3- diaminopropionic acid group, at least one glutamic acid group, at least one cysteine group, or a combination of two or more of the foregoing. In certain embodiments, the linker comprises one or more (e.g., two or more, such as two, three, four, or five) amino acids. In some embodiments, the linker can comprise an amino 15 acid selected from the group consisting of Lys, Asn, Thr, Ser, He, Met, Pro, His, Gin, Arg, Gly, Asp, Glu, Ala, Val, Phe, Leu, Tyr, Cys, and Trp. In some embodiments, the linker does not comprise an amino acid (e.g., cysteine or glutamic acid). In some embodiments, the linker does not comprise cysteine or homocysteine. In certain embodiments, the linker comprises an amino acid linker (e.g., a lysine (Lys) linker). In certain embodiments, the linker comprises two 20 amino acid linkers (e.g., a Lys-Lys linker). In some embodiments, the linker comprises 3370628-02 3220-422529 , 5 ,70628-02 3220-422529 wherein Y comprises (or consists essentially of or consists of) an imaging agent (e.g., a fluorescent dye, such as Cy5). In some embodiments, the linker comprises , 53570628-02 3220-422529 ,3670628-02 3220-422529 ,ker. The linker can, in certain embodiments, include at least one slow-release linker. The term “quick- release” in the context of a linker means a linker that includes at least one bond that is releasable 5 as is known in the art and / or that can be cleaved to varying degrees under certain conditions and, in particular, can be fragmented or cleaved in less than about 48 hours when under, or otherwise exposed to, certain metabolic, physiological, or cellular conditions (e.g., a pH-labile, acid-labile, oxidatively-labile, or enzyme-labile bond) that may initiate a cascade of fragmentation or bond cleavage (which may, for example, result in the release of one or more10 of the moieties connected through one or more portions of the linker. For example, a quick- release linker can be fragmented or cleaved in about 1 hour to about 48 hours (such as 1-48 hours), in about 2 to about 40 hours (such as 2-40 hours), in about 5 to about 35 hours (such as 5-35 hours), in about 10 to about 30 hours (such as 10-30 hours), in about 15-25 hours (such as 15-25 hours), or in about 20 hours when under, or otherwise exposed to, certain metabolic, 15 physiological, or cellular conditions that can initiate a cascade of fragmentation or bond cleavage. The aforementioned ranges are inclusive of the stated end points and all 15-minute increments included therein. Bond cleavage can occur by standard chemical hydrolysis reactions that occur, for example, at physiological pH, or as a result of compartmentalization into a cellular organelle 20 such as an endosome having a lower pH than cytosolic pH. Bond cleavage can also occur by acid-catalyzed elimination. Illustratively, the quick-release linkers can undergo cleavage under other physiological or metabolic conditions, such as by the action of a glutathione mediated mechanism. Alternatively, fragmentation can be initiated by a nucleophilic attack on a disulfide 3770628-02 3220-422529 group of the quick-release linker, causing cleavage to form a thiolate, for example. In any of these cases, the quick-release nature of such linkers can be realized by whatever mechanism is relevant to the chemical, metabolic, physiological, or biological conditions present. In certain embodiments, a quick-release linker can comprise one or more sulfide bridges. 5 The quick-release bond or bonds can be present in the interior of a quick-release linker and / or at one or both ends of a quick-release linker. The lability of the quick-release bond can be adjusted by including functional groups or fragments within the releasable linker that are able to assist or facilitate such bond breakage (i.e., anchimeric assistance). The lability of the quick-release bond can also be adjusted by, for example, substitutional changes at or near the 10 quick-release bond, such as including alpha branching adjacent to a cleavable disulfide bond, increasing the hydrophobicity of substituents on silicon in a moiety having a silicon-oxygen bond that can be hydrolyzed, homologating alkoxy groups that form part of a ketal or acetal that can be hydrolyzed, and the like. In addition, additional functional groups or fragments can be included within the quick-release linker that are able to assist or facilitate additional 15 fragmentation of the conjugates after bond breaking of the quick-release linker. A quick-release linker can release A from the conjugate relatively quickly, for example, when subjected to physiological conditions. Examples of quick-release linkers include, but are not limited to, ester, disulfide, and thiol. In certain embodiments, the linker can comprise an ester. In certain embodiments, the linker can comprise a thioester. In certain embodiments, the 20 linker can comprise an oxime ester. In certain embodiments, the linker can comprise a hydrazone. In certain embodiments, the linker can comprise an acetal. In certain embodiments, the linker can comprise a ketal. In certain embodiments, the linker can comprise a para- methoxybenzyl ether (PMB). In some embodiments, the linker does not comprise a hydrazone, a hydrazide, or a disulfide. In some embodiments, the linker does not comprise a disulfide. In 25 some embodiments, the linker does not comprise a maleimide. In some embodiments, L does not comprise a disulfide, a maleimide, or an amino acid (e.g., cysteine or glutamic acid). The linker can comprise a biodegradable, pH-sensitive, self-immolative, peptidase- sensitive, or hydrolysable linker. Examples of these linkers include, but are not limited to, a β- glucuronide linker, a maleimide-based thiol linker, a cathepsin K-sensitive linker, a cathepsin 30 B-sensitive linker, a matrix metalloproteinase-sensitive linker, and a brush border membrane (BBM)-cleavable linker. In certain embodiments, the linker can comprise a peptide. Quick- release groups also include photochemically cleavable groups. Examples of photochemically- cleavable groups include 2-(2-nitrophenyl)-ethan-2-ol groups and linkers containing o- nitrobenzyl, desyl, trans-o-cinnamoyl, m-nitrophenyl or benzylsulfonyl groups (see, for 3870628-02 3220-422529 example, Dorman and Prestwich, Trends Biotech.18: 64-77 (2000); Greene & Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, New York (1991)). In some embodiments, the linker can be conjugated to either end of A. In certain embodiments, the quick-release linker is cleavable by a reducing agent. In 5 certain embodiments, the reducing agent is glutathione. In certain embodiments, the reducing agent is present within an endosome of a cell. In certain embodiments, the quick-release linker is cleavable by a reductive condition in an endosome of a cell. In certain embodiments, the quick-release linker is cleavable by an enzyme such as, and without limitation, a brush border cleavable enzyme, a lysosomal enzyme, a matrix metalloproteinase enzyme, a cathepsin, a 10 furin, and / or a glucuronidase. In certain embodiments, the quick-release linker is cleavable in a lysosome of a cell. In certain embodiments, the quick-release linker is cleavable under acidic pH. The quick-release linker can comprise at least one disulfide bond. In certain embodiments, the linker comprises at least one quick-release linker that is not a disulfide. In 15 other embodiments, the linker does not include a quick-release linker. Quick-release linkers can be used when the drug to be delivered is advantageously liberated from the binding ligand-linker conjugate so that the free drug will have the same or nearly the same effect at the target as it would when administered without the targeting provided by the conjugate. 20 The linker can comprise one or more slow-release linkers. In contrast to “quick- release,” “slow-release” in the context of a linker means a linker that includes at least one bond that is not easily or quickly broken (i.e. the bond does not cleave) and, while potentially cleavable or fragmentable to varying degrees under certain conditions, does not cleave, fragment, or otherwise release one or more of the moieties connected through one or more 25 portions of the linker when subjected to certain metabolic, physiological, or cellular conditions that may initiate a cascade of fragmentation (e.g., after administration to a subject) for more than about 48 hours (e.g., 48 hours), more than about 1 week (e.g., 1 week), more than about 1 month (e.g., 1 month), more than about 4 months (e.g., 4 months), more than about 6 months (e.g., 6 months), or more than about 1 year (e.g., 1 year). In certain embodiments, the slow- 30 release linker cleaves, fragments, or otherwise releases one or more of the moieties connected through one or more portions of the linker (e.g., B and D) only when subjected to certain metabolic, physiological, or cellular conditions that may initiate a cascade of fragmentation (e.g., after administration to a subject) for about 48 hours to about 1 week (e.g., 48 hours to 1 week), about 1 week to 1 month (e.g., 1 week to 1 month), about 1 month to about 4 months 3970628-02 3220-422529 (e.g., 1 month to 4 months), or about 4 months to about 6 months (e.g., 4-6 months). The aforementioned ranges are inclusive of the stated end points and all pne-day increments therein. In certain embodiments, a slow-release linker can comprise one or more amide bonds. Slow-release linkers can be advantageous, for example, when the therapeutic agent (A) is 5 advantageously retained by the conjugate. In some embodiments, a slow-release linker comprises a backbone that is stable under physiological conditions (e.g., the backbone is not susceptible to hydrolysis (e.g., aqueous hydrolysis or enzymatic hydrolysis)). In some embodiments, a slow-release linker does not release any component to which it is conjugated. In some embodiments, the slow-release linker 10 lacks a disulfide bond (e.g., S-S) or an ester in the backbone. In some embodiments, parts of the linker are connected by a backbone that is substantially stable for the entire duration of the composition’s circulation (e.g., in vivo). The slow-release linker can comprise an alkyl(ene), anhydride, amide, ester, ether, amine, and / or thioether (e.g., thio-maleimide). Any slow- release linker can be used provided at least one bond that is not easily or quickly broken under 15 physiological conditions is formed. In certain embodiments, the linker comprises an amide. In some embodiments, a non-releasable linker comprises a linker that, at a neutral pH, for example, less than ten percent (10%) (e.g., less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1%, less than 0.01%, or less than 0.001%) will hydrolyze in an aqueous (e.g., buffered (e.g., phosphate buffer)) solution within a period of time (e.g., 24 20 hours). In some embodiments, where a slow-release linker is employed, less than about ten percent (10%), and preferably less than five percent (5%) or none, of the conjugate administered releases D (e.g., in systemic circulation prior to uptake by the targeted cells / tissue). In some embodiments, within one (1) hour of administration, less than five percent (5%) of D is released from the conjugate while the compound is in systemic circulation. 25 In some embodiments, the linker can comprise portions that are neutral under physiological conditions. In some embodiments, the linker can comprise portions that can be protonated or deprotonated to carry one or more positive or one or more negative charges, respectively. In some embodiments, the linker can comprise neutral portions and portions that can be protonated to carry one or more positive charges. Examples of neutral portions include 30 polyhydroxyl groups, such as sugars, carbohydrates, saccharides, inositols, and the like, and / or polyether groups, such as polyoxyalkylene groups, including polyoxyethylene, polyoxypropylene, and the like. Examples of portions that can be protonated to carry one or more positive charges include amino groups, such as polyaminoalkylenes, including ethylene diamines, propylene diamines, butylene diamines and the like, and / or heterocycles, including 4070628-02 3220-422529 pyrrolidines, piperidines, piperazines, and other amino groups, each of which can be optionally substituted. In certain embodiments, the linker can comprise a positive portion comprising one or more lysine residues. Examples of portions that can be deprotonated to carry one or more negative charges include carboxylic acids, such as aspartic acid, glutamic acid, and longer- 5 chain carboxylic acid groups, and sulfuric acid esters, such as alkyl esters of sulfuric acid. Alternatively, or in addition to chain length, in some embodiments, the linker has suitable substituents that can affect hydrophobicity or hydrophilicity. Thus, for example, a linker can have a hydrophobic side chain group, such as an alkyl, cycloalkyl, aryl, arylalkyl, or like group, each of which is optionally substituted. If a linker were to include one or more 10 amino acids, the linker can contain hydrophobic amino acid side chains, such as one or more amino acid side chains from Phe and Tyr, including substituted variants thereof, and analogs and derivatives of such side chains. In certain embodiments, the linker comprises an oligoethylene glycol linker. In certain embodiments, the linker comprises a (PEG)n, wherein n is 0-36. In certain embodiments, the 15 linker comprises an alkyl. In certain embodiments, the linker comprises an ether. In certain embodiments, the linker comprises a rigid linker. In certain embodiments, the rigid linker comprises polyproline or polypiperdine. Both quick-release and slow-release linkers can be engineered to optimize biodistribution, bioavailability, and PK / PD (e.g., of the A) and / or to increase uptake (e.g., of 20 A) into the targeted tissue pursuant to methodologies commonly known in the art or hereinafter developed, such as through PEGylation and the like. In some embodiments, the linker is configured to avoid significant release of a pharmaceutically active amount of A in circulation prior to capture by a cell. The linker can comprise a spacer (e.g., be conjugated with and / or include a spacer). 25 The spacer can be any suitable spacer. A length of a spacer can range from 1 to 30 (e.g., 1 to 30 carbon atoms, a PEG with 1-30 units, about 2 to about 20 atoms (e.g., 2-20 atoms, about 2 to 20 atoms, or 2 to about 20 atoms), etc.). Lower molecular weight linkers (i.e., those having an approximate molecular weight of about 30 to about 300) are also contemplated. A spacer in the linker can comprise hydrophilic, hydrophobic, amphipathic, non- 30 peptidic, peptidic, and / or aromatic monomers. Examples of hydrophilic spacers include, but are not limited to, polyethylene glycol polymers and derivatives thereof. Examples of hydrophobic spacers include, but are not limited to, pure or mixed branched hydrocarbons, fluorocarbons, alkane, alkene, and / or alkyne polymers. Examples of amphipathic spacers include, but are not limited to, pure or mixed phospholipids and / or derivatives thereof. 4170628-02 3220-422529 Examples of peptidic spacers include, but are not limited to, pure and mixed single, branched, L- or D-configurations, essential, nonessential, natural, and unnatural amino acids and derivatives thereof. Examples of aromatic spacers include, but are not limited to, pure and mixed repeated quinoids. 5 In certain embodiments, a PK parameter of circulation half-life (CL1 / 2) of the conjugate can be prolonged. The PK parameter of total exposure as measured by area under the curve (AUC) in vivo can be increased. For example, the conjugate can comprise an albumin or a hapten. In certain embodiments, a hapten can be preferred over an albumin. Examples of haptens include, without limitation, nitrophenol, dinitrophenol, trinitrophenol, and rhamnose. 10 The albumin or the hapten(s) can be attached to the linker of the conjugate using routine chemistry. In embodiments of L, L is a quick-release linker, such as a quick-release linker comprising at least one disulfide bond. In embodiments of L, L is cleavable by an enzyme. In embodiments of L, L is a slow-release linker. In some embodiments, L is not releasable and 15 does not include a releasable moiety (e.g., a disulfide bond). In some embodiments, L comprises an imaging agent. In some embodiments, the imaging agent is an optical imaging agent. In some embodiments, the optical imaging agent is a fluorescent dye. In some embodiments, the fluorescent dye is Cyanine5 (Cy5) or ATTO 647N. In some embodiments, the imaging agent is a radionuclide for positron emission tomography 20 (PET) or single-photon emission computed tomography (SPECT). In some embodiments, the imaging agent is a paramagnetic agent or a superparamagnetic agent for magnetic resonance imaging (MRI). In some embodiments, the paramagnetic agent comprises dysprosium (Dy+3), gadolinium (Gd+3), or manganese (Mn+2). In some embodiments, the imaging agent is a nanoparticle. In some embodiments, the imaging agent enables multimodal imaging. In some 25 embodiments, the multimodal imaging is PET / MRI, PET / computed tomography (PET / CT), or photoacoustic microscopy (PAM). In some embodiments, L does not comprise an imaging agent. In some embodiments, L does not comprise an optical imaging agent, a fluorescent dye (e.g., a near-infrared (NIR) dye, such as Cy5, ATTO 647N, or S0456), a radionuclide for positron emission tomography 30 (PET) or single-photon emission computed tomography (SPECT), a paramagnetic agent or a superparamagnetic agent for magnetic resonance imaging (MRI), or a nanoparticle. In some embodiments, the conjugate is selected from the group consisting of: 4270628-02 3220-4225295 (Folate-ASO), and 4370628-02 3220-422529(Folate-ASO-Cy5), or a pharmaceutically acceptable sat thereof. In some embodiments, the conjugate is: 5A is a therapeutic agent, such as an siRNA, and 10 X is O or S. In some embodiments, the conjugate is:, , A is a therapeutic agent, such as an siRNA or an ASO, and 15 X is O or S. In some embodiments, the conjugate is: 4470628-02 3220-422529 , 5, 10 X is O or S. In some embodiments, the conjugate is:p y p , 4570628-02 3220-422529 A is an oligonucleotide, such as or 5 , 10 or .70628-02 3220-422529 .or 5 X is O. Furtherprovided are conjugates of formula F-L-A. In an embodiment of F-L-A, F is a ligand that targets FRα, L is a linker, and A is Bevasiranib; in embodiments thereof, L is or comprises dibenzocyclooctane. In some embodiments of F-L-A, F is a ligand that targets FRα, L is a linker, and A is Pegaptanib. In some embodiments of F-L-A, F is a ligand that targets FRα, L 10 is a linker, and A is Aflibercept or Conbercept. In some embodiments of F-L-A, F is a ligand that targets FRα, L is a linker, and A is Abicipar pegol. In some embodiments of F-L-A, F is a ligand that targets FRα, L is a linker, and A is BAY 60-7550, rolipram, or BC 11-38. In some embodiments of F-L-A, F is a ligand that targets FRα, L is a linker, and A is triamcinolone acetonide or fluocinolone acetonide. 15 In some embodiments, when the conjugate of formula F-L-A comprises an imaging agent, the imaging agent is covalently bound to the therapeutic agent (e.g., an siRNA or an ASO). In some embodiments of the conjugate of formula F-L-A, F is of the formula (I): O COOH is 20 e.g., a non-releasable linker).g., the cycloaddition product from a SPAAC), alkylene groups (e.g., C1-C6 alkylene groups such as ethylene, 4770628-02 3220-422529 pentylene, hexylene etc.), one or more amides, optionally carboxylates or esters, and optionally a phosphate to couple with the therapeutic agent (A), which may be an oligonucleotide (e.g., an siRNA or ASO of about 10-30 bp in length), that operates to decrease the expression of a target (e.g., a growth factor such as VEGF). The conjugate may be used to treat a condition in 5 the eye but is not administered by direct injection into the eye. In some embodiments, the conjugate of formula F-L-A does not comprise an imaging agent. In some embodiments, the conjugate of formula F-L-A does not comprise an optical imaging agent, a fluorescent dye, a radionuclide for positron emission tomography (PET) or single-photon emission computed tomography (SPECT), a paramagnetic agent or a 10 superparamagnetic agent for magnetic resonance imaging (MRI), or a nanoparticle. In some embodiments, the conjugate of formula F-L-A does not comprise an ionophore (e.g., nigericin or salinomycin). In some embodiments, the conjugate of formula F-L-A does not comprise an acrolein-scavenging drug (e.g., hydralazine). In some embodiments, the conjugate of formula F-L-A is not: 15 ,4870628-02 3220-422529 , ,, 5 or a pharmaceutically acceptably salt thereof. 4970628-02 3220-422529 The above conjugates can be synthesized using methods known in the art and exemplified herein. In each of the foregoing and following embodiments, the formulae include and represent not only all pharmaceutically acceptable salts of the compounds in the conjugates, 5 but also include any and all hydrates and / or solvates of the formulae. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and / or coordination compounds with water and / or various solvents, in the various physical forms of the compounds in the conjugates described herein. Accordingly, the formulae described herein are to be understood to include and represent those various hydrates and / or solvates. 10 The conjugates hereof can be “deuterated,” meaning one or more hydrogen atoms can be replaced with deuterium. As deuterium and hydrogen have nearly the same physical properties, deuterium substitution is the smallest structural change that can be made. Deuteration is well known to those of ordinary skill in the art. In each of the embodiments, it is also to be understood that the formulae include and 15 represent each possible isomer, such as stereoisomers and geometric isomers, both individually and in any and all possible mixtures. The components of the conjugates described herein can contain one or more chiral centers or can otherwise be capable of existing as multiple stereoisomers. For each embodiment, unless expressly specified otherwise, the conjugates are not limited to any 20 particular stereochemical requirement, and can be optically pure, or can be any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. Such mixtures of stereoisomers can also include a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers. 25 Similarly, the ligands and conjugates hereof can include geometric centers, such as cis, trans, E, and Z double bonds. The ligands and conjugates are not limited to any particular geometric isomer requirement, and that the conjugates can be pure, or can be any of a variety of geometric isomer mixtures. Such mixtures of geometric isomers can include a single configuration at one or more double bonds, while including mixtures of geometry at one or 30 more other double bonds. Still further provided is a pharmaceutical composition. The pharmaceutical composition comprises a conjugate of formula F-L-A and a pharmaceutically acceptable carrier. In the conjugate of formula F-L-A, F is a ligand that targets FRα, L is a linker, and A is Bevasiranib, Pegaptanib, Aflibercept, Conbercept, Abicipar pegol, BAY 60-7550, rolipram, 5070628-02 3220-422529 BC 11-38, triamcinolone acetonide, or fluocinolone acetonide. Desirably, the pharmaceutical composition comprises the conjugate in an effective amount. An “effective amount” is an amount that is sufficient to achieve the desired result or to have a desired effect on a disease condition. The specific amount will depend on a variety of factors, including the 5 disease / condition being treated, the severity of the disease / condition, the specific composition and / or conjugate employed, the route of administration, characteristics of the subject to whom the composition is administered, responsiveness of the subject to treatment, time of administration, duration of treatment, and the like as well-known to those skilled in the medical arts. 10 For example, it is well within the skill of the art to start doses of a conjugate / composition at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective amount can be divided into multiple doses for purposes of administration. Consequently, single dose conjugates / compositions can contain such amounts or submultiples 15 thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of the antigen or composition) information about a particular patient can affect the dosage used to achieve an effective amount. Depending upon the route of administration, a wide range of permissible dosages is 20 contemplated. For example, the effective amount of the conjugate and / or pharmaceutical composition can range from about 0.1 µg / kg / day, such as 0.5 µg / kg / day, 0.7 µg / kg / day, or 0.01 mg / kg / day up to about 1,000 mg / kg / day. Intravenous doses can be several orders of magnitude lower. The conjugates and pharmaceutical compositions can be administered in unit dosage forms and / or compositions. 25 For methods described herein, the conjugate(s) and compositions can be administered in a single dose, or via a combination of multiple dosages, which can be administered by any suitable means, contemporaneously, simultaneously, sequentially, or separately. Where the dosages are administered in separate dosage forms, the number of dosages administered per day for each compound or composition can be the same or different. The conjugate and / or 30 composition dosages can be administered via the same or different routes of administration. The conjugates or compositions can be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms. Desirably, administration does not involve intravitreal injection. 5170628-02 3220-422529 Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for 5 prevention of a disease or condition. The compositions can be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and / or other morphological forms of the conjugates, and the compositions can be prepared from isolated conjugates or from salts, solutions, hydrates, solvates, and other forms of the conjugates. Accordingly, such pharmaceutical compositions 10 can include each of, or any combination of, or individual forms of, the various morphological forms and / or solvate or hydrate forms of the conjugates. The conjugate / composition can be administered more than once, such as daily (1-3 or more times per day; q.d. (once a day), b.i.d. (twice a day), t.i.d. (three times a day)), weekly (including 1-3 or more times on a given day), bi-weekly (including 1-3 or more times on a15 given day), monthly (including 1-3 or more times on a given day), or bimonthly (including 1- 3 or more times on a given day). In each case it is understood that the effective amounts described herein correspond to the instance of administration, or alternatively to the total daily, weekly, month, or quarterly dose, as determined by the dosing protocol. The pharmaceutical composition can comprise one or more pharmaceutically 20 acceptable carriers, adjuvants, diluents, excipients, and / or vehicles (e.g., conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles), and combinations thereof. Any pharmaceutically acceptable carriers and excipients as known in the art can be used. Examples include, but are not limited to, an excipient, a color additive, a preservative, and a stabilizer. More specific examples include crystal cellulose, calcium carmellose, sodium carmellose, 25 hydropropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, and magnesium stearate. Solutions of the active conjugate or pharmaceutical composition can be aqueous, optionally mixed with a nontoxic surfactant, and / or can contain carriers or excipients, such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9), but, for some applications, they can be more suitably formulated as a sterile non-aqueous solution or as a 30 dried form to be used in conjunction with a suitable vehicle, such as sterile, pyrogen-free water, or phosphate-buffered saline. For example, dispersions can be prepared in glycerol, liquid PEGs, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can further contain a preservative to prevent the growth of microorganisms. 5270628-02 3220-422529 The conjugates can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms adapted to the chosen route of administration. The pharmaceutical compositions can be formulated, e.g., for a given route of administration, and manufactured in accordance with methods in the art and described, for 5 example, in Remington, The Science and Practice of Pharmacy, 22ndedition (2012). The composition can be an infusion or an injectable composition, such as a composition that can be injected subcutaneously or intravenously. The pharmaceutical composition can be administered to a mammalian host, such as a human patient, in a variety of forms adapted to the chosen route of administration. In certain 10 embodiments, the pharmaceutical composition is formulated to be administered subcutaneously. In certain embodiments, the pharmaceutical composition is formulated to be administered orally. In certain embodiments, the pharmaceutical composition is formulated to be administered intramuscularly, intravenously, intraarterially, intraperitoneally, or as any other art-recognized route of parenteral administration. 15 In certain embodiments, the pharmaceutical composition is systemically administered in combination with a pharmaceutically acceptable vehicle. The percentages of the components of the compositions and preparations can vary and can be between about 1 to about 99% weight of the active ingredient(s) (e.g., the conjugate) and a binder, an excipient, a disintegrating agent, a lubricant, and / or a sweetening agent (as are known in the art). The 20 amount of active conjugate in such therapeutically useful compositions is such that an effective dosage level can be obtained (e.g., in the serum or targeted tissue). Illustrative means of parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques, as well as any other means of parenteral administration recognized in the art. Parenteral formulations are typically aqueous solutions, 25 which can contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH in the range from about 3 to about 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can readily be 30 accomplished using standard pharmaceutical techniques well-known to those skilled in the art. The pharmaceutical dosage forms suitable for administration can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredients that are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes, nanocrystals, or polymeric nanoparticles. In 5370628-02 3220-422529 all cases, the ultimate dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example and without limitation, water, electrolytes, sugars, ethanol, a polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable 5 oils, nontoxic glyceryl esters, and / or suitable mixtures thereof. In at least one embodiment, the desired fluidity can be maintained by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. Sterile injectable solutions can be prepared by incorporating the pharmaceutical compositions in the required amount of the appropriate solvent with one or more of the other 10 ingredients set forth above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, vacuum-drying and freeze-drying techniques can be employed, which can yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. ALTERNATIVE EMBODIMENTS 15 1. A method of administering a therapeutic agent to the retinal pigment epithelium (RPE) in a subject in need of a therapeutic agent effective for the treatment of the RPE or adjacent cells, which method comprises administering, by a route other than intravitreal injection, to the subject a conjugate of formula F-L-A, wherein 20 F is a ligand that targets folate receptor α (FRα), L is a linker, and A is the therapeutic agent effective for treatment of the RPE, whereupon the therapeutic agent is administered to the RPE in the subject. 2. The method of clause 1, wherein the therapeutic agent comprises nucleotides 25 and / or modified nucleotides. 3. The method of clause 2, wherein the therapeutic agent comprises an oligonucleotide, an interfering RNA (iRNA), a small interfering RNA (siRNA), an RNA aptamer, a microRNA, a ribozyme, a short hairpin RNA, an antisense oligonucleotide, or an analog or derivative of any of the foregoing. 30 4. The method of clause 2 or 3, wherein the therapeutic agent is modified with a 2’-F sugar, a 2’-O-methyl sugar, a 2’-O- methoxyethyl sugar, a 2'-deoxy sugar, a 5-alkylamino base, a 5-allylamino base, a phosphorothioate modification of a nucleotide, a P-alkyl modification of a nucleotide, a phosphonate modification of a nucleotide, a 5470628-02 3220-422529 phosphoroselenate modification of a nucleotide, a phosphoroamidate modification of a nucleotide, a modification of a terminal phosphate, or any combination thereof. 5. The method of clause 2, 3 or 4, wherein the therapeutic agent is modified with a 2’- O- methoxyethyl sugar, a 2'-deoxy sugar, a phosphorothioate modification of a nucleotide, or 5 any combination thereof. 6. The method of clause 3, 4 or 5, wherein the therapeutic agent silences the gene that expresses vascular endothelial growth factor (VEGF). 7. The method of clause 6, wherein the therapeutic agent comprises an siRNA (e.g., an 18-21 nucleotide long double-stranded RNA (dsRNA)). 10 8. The method of clause 7, wherein the siRNA comprises a nucleotide sequence selected from the group consisting of SEQ. ID Nos.60-71, and any combination thereof. 9. The method of clause 7 or 8, wherein the siRNA is Bevasiranib (SEQ. ID No.60 and SEQ. ID No.61). 10. The method of clause 5 or 6, wherein the therapeutic agent is an antisense 15 oligonucleotide (ASO) (e.g., an 18-21 nucleotide long single-stranded oligonucleotide). 11. The method of clause 10, wherein the ASO comprises a nucleotide sequence selected from the group consisting of SEQ. ID Nos.1-59, and any combination thereof. 12. The method of clause 10 or 11, wherein the ASO is a nucleotide sequence selected from the group consisting of SEQ. ID Nos.3, 6, 8, 10, 34, 38, 47, 51, and 56. 20 13. The method of clauses 10, 11 or 12, wherein the ASO is SEQ. ID No.10 or 38. 14. The method of clause 3, wherein the RNA aptamer binds VEGF. 15. The method of clause 14, wherein the RNA aptamer is Pegaptanib. 16. The method of clause 1, wherein the therapeutic agent is a VEGF decoy receptor. 17. The method of clause 16, wherein the VEGF decoy receptor is Aflibercept or 25 Conbercept. 18. The method of clause 1, wherein the therapeutic agent is an ankyrin repeat protein (DARPin). 19. The method of clause 18, wherein the DARPin is Abicipar pegol. 20. The method of clause 1, wherein the therapeutic agent is a stress resilience- 30 enhancing drug (SRED). 21. The method of clause 20, wherein the SRED inhibits a cyclic nucleotide phosphodiesterase (PDE). 22. The method of clause 21, wherein the SRED is BAY 60-7550, rolipram, or BC 11-38. 5570628-02 3220-422529 23. The method of any one of clauses 1-22, wherein the subject has age-related macular degeneration (AMD), diabetic retinopathy (DR), or retinitis pigmentosa (RP). 24. The method of clause 23, wherein the AMD is wet. 25. The method of any one of clauses 1-24, wherein F is selected from the group 5 consisting of a folate, a folate derivative, a folate analog, or a radical thereof that binds to a folate receptor. 26. The method of clause 25, wherein F is 5-methyltetrahydrofolate (5-MTHF) or an N5,N10-dimethylated derivative of tetrahydrofolic acid (DMTHF). 27. The method of clause 25, wherein F has or comprises the structure (or a radical 10 thereof): O COOH OH O N .omprises the structure (or a radical thereof): . 15omprises the structure (or a radical thereof): .. e e o o c ause , w e e as or comprises the structure (or a radical thereof): 5670628-02 3220-422529 . r comprises the structure (or a radicalthereof): . 5erein L is or comprises a portion formed from a strain-promoted alkyne-azide cycloaddition (SPAAC) reaction (e.g., a fused dibenzocyclooctane-triazole). 33. The method of clause 32, wherein L comprises: . 10in L comprises: ethylene, propylene, butylene, pentylene, hexylene ,, . 15. , disulfide, a maleimide, or an amino acid (e.g., cysteine or glutamic acid). 5770628-02 3220-422529 35. The method of clause 1, wherein the conjugate is selected from the group consisting of: 570628-02 3220-422529(Folate-ASO-Cy5), or a pharmaceutically acceptable sat thereof. 36. A conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α 5 (FRα), L is a linker, and A comprises an oligonucleotide (e.g., an interfering RNA (iRNA), a small interfering RNA (siRNA), an RNA aptamer, a microRNA, a ribozyme, a short hairpin RNA, or an antisense oligonucleotide (ASO). 37. The conjugate of clause 36, wherein A is an siRNA. 38. The conjugate of clause 37, wherein the siRNA comprises a nucleotide sequence 10 selected from the group consisting of SEQ. ID Nos.60-71, and any combination thereof. 39. The conjugate of clause 37 or 38, wherein the siRNA is Bevasiranib (SEQ. ID No. 60 and SEQ. ID No.61). 40. The conjugate of clause 36, wherein A is an ASO. 41. The conjugate of clause 40, wherein the ASO comprises a nucleotide sequence 15 selected from the group consisting of SEQ. ID Nos.1-59, and any combination thereof. 42. The conjugate of clause 40 or 41, wherein the ASO is a nucleotide sequence selected from the group consisting of SEQ. ID Nos.3, 6, 8, 10, 34, 38, 47, 51, and 56. 43. The conjugate of clause 40, 41 or 42, wherein the ASO is SEQ. ID No.10 or 38. 44. The conjugate of any one of clauses 36-43, wherein F is selected from the group 20 consisting of a folate, a folate derivative, a folate analog, or a radical thereof that binds to a folate receptor (e.g., FRα). 45. The conjugate of clause 44, wherein F is of the formula (I): O COOH I),, rein 25 R1and R2, when present, are independently H or alkyl (e.g., methyl), 5970628-02 3220-422529 R3is H or alkyl (e.g., methyl), and wherein each “ ” is independently a single or a double bond.46. The conjugate of any one of clauses 36-45, wherein L is or comprises a portionformed from a strain-promoted alkyne-azide cycloaddition (SPAAC) reaction (e.g., a fused 5 dibenzocyclooctane -triazole). 47. The conjugate of clause 46, wherein L comprises: . rein L comprises: ethylene, propylene,, 10 ,, or any combination thereof., , wherein L does not comprise a disulfide, a maleimide, or an amino acid (e.g., cysteine or glutamic acid). 15 50. The conjugate of clause 36, wherein the conjugate is selected from the group consisting of: 6070628-02 3220-4225295 (Folate-ASO), and 6170628-02 3220-422529(Folate-ASO-Cy5), or a pharmaceutically acceptable sat thereof. 51. A conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α 5 (FRα), L is a linker, and A is Pegaptanib. 52. A conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α (FRα), L is a linker, and A is Aflibercept or Conbercept. 53. A conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α 10 (FRα), L is a linker, and A is Abicipar pegol. 54. A conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α (FRα), L is a linker, and A is BAY 60-7550, rolipram, or BC 11-38. 55. A pharmaceutical composition comprising the conjugate of any one of clauses 36- 50 and a pharmaceutically acceptable carrier. 15 EXAMPLES The following examples serve to illustrate the present disclosure. The examples are not intended to limit the scope of the claimed invention in any way. Materials: Isopentane [Fisher Scientific, cat: AA19387AP], ProLong™ Gold Antifade 20 Mounting with DNA Stain DAPI [Thermofisher Scientific, cat: P36931], ELISA MAS Deluxe Set Human VEGF [Biolegend, car:446504], RPMI medium 1640 [Gibco, cat: 27016-021], Triton X-100 [Acros Organics, cat: 21568-2500], Tissue Plus OCT Compound [Fisher, cat: 23- 730-571], PBS [Corning], Cobalt Chloride [Sigma, cat: C8661], ZO-1 antibody [Genetex, cat: GTX108592], Goat anti-Rabbit IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa 25 Fluor™ 568 [Thermofisher, cat: A-11011], DMEM F-12 Media [Thermofisher, cat: 11320033] [These materials have been used in all the described experiments except the chemical conjugation reactions]. Synthetic Methods: All reactions were carried out in oven-dried glassware. Reactions requiring an inert atmosphere were carried out under an argon atmosphere. Amino acids and 6270628-02 3220-422529 resins for peptide synthesis were purchased from Chem-Impex International (Chicago, IL) and Aapptec (Louisville, KY). NHS-DBCO (N-hydroxysuccinimidyl ester-dibenzocyclooctyne) was purchased from Broadpharm (San Diego, CA), cyanine5 (Cy5) NHS ester dye was purchased from Aablocks (San Diego, CA), and all other chemical reagents were purchased 5 from Sigma-Aldrich (St. Louis, MO). All conjugates were purified by preparative reverse phase (RP)-HPLC (Agilent), and LC / MS analyses were obtained using an Agilent mass spectrometer coupled with a UV diode array detector. Oligonucleotide sequences were customized and purchased from Integrated DNA technologies (Coralville, IA). Oligo Clean & Concentrator kit was purchased from Zymo Research. 10 EXAMPLE 1 Folate-conjugated fluorescent probes targeted folate receptor α (FRα) on the basolateral side of the RPE Female Swiss outbred mice [Jax:034608] were administered 10 nanomoles of folate- 15 cyanine-5 multiple times. The mice were euthanized, and the eyes were collected for further processing. The eyes were fixed in 4% PFA [paraformaldehyde] and then submerged in cryoprotectant solution [30% sucrose] for 24 hours. Then the eyes were flash frozen in OCT medium using dry ice and isopentane. The frozen eye was sectioned into 25 micrometer sections. The eye sections were permeabilized in PBST [PBS with Triton X-100] solution for 20 30 minutes and then blocked in 10% serum solution for one hour to block non-specific antibody binding. After blocking, the sections were mounted with DAPI mounting medium and were left overnight at room temperature for drying. The slides were imaged with a widefield confocal microscope, A1Rsi. The results are shown in Fig.1. The fluorescence of cyanine 5 was visible in the RPE 25 cell layer situated between the choroid capillaries and the photoreceptor layers. This indicates that the folate conjugated moieties can reach the RPE layer in the eye. EXAMPLE 2 Folate-DBCO synthesis 30 2.1 N10-(trifluoroacetyl)pteroic acid synthesis:70628-02 3220-422529 To vacuum-dried pteroic acid (1 g, 3.2 mmol) in a round bottom flask trifluoroacetic anhydride (23.16 mL, 170 mmol) was added dropwise under argon gas. The round bottom flask was covered with aluminum foil, and the contents in the flask were stirred for four days under argon gas. LC-MS. monitored the progress of the reaction After the complete 5 consumption of pteroic acid, excess trifluoroacetic anhydride was removed by a rotary evaporator. Trifluoroacetic acid (25 mL of 3%) was added to the flask, and the contents were stirred for two days at room temperature. After this time, 20 mL of HPLC-grade water were added to the flask, and the contents of the flask were transferred into centrifuge tubes and centrifuged at 3,000 rpm for 20 minutes. The resultant pellet was washed with HPLC grade 10 water (3x) followed by centrifugation. The supernatant layer was discarded, and the pellet was lyophilized. The resultant yellow solid (N10-trifluoroacetylpteroic acid) was stored in an amber vial. 2.2 Folate-EDA (ethylene diamine) synthesis: O NHFmoc HO H O HN NHFmo N c 1,2resinO O N OH 156470628-02 3220-422529Folate-dibenzocyclooctane (DBCO) conjugate was synthesized starting from folate ethylenediamine (EDA) conjugate. Briefly, folate-EDA conjugate was synthesized by 5 following the Fmoc-solid phase peptide synthesis procedure. In a solid phase peptide synthesis vessel, ethylenediamine polymer-bound resin (200-400 mesh, 0.5 g, 0.9 mmol / g, 1 eq.) was swollen with 10 mL of dichloromethane followed by 10 mL of dimethylformamide for 30 minutes each. A solution of Fmoc-Glu-OtBu solution (0.5 g, 1.125 mmol, 2.5 eq), (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluoro phosphate (PyBOP, 0.6 g, 1.125 10 mmol, 2.5. eq.) and N, N-diisopropylethylamine (DIPEA, 0.481 mL, 2.7 mmol, 3 eq.) in DMF (15 mL) was added. Argon was bubbled for 12 hours, after which the coupling solution was drained, and the resin was washed with DMF (3x10 mL) and iPrOH (3x10 mL). The efficiency of coupling was monitored by pilot resin cleavage. The Fmoc group was removed with a piperidine solution (20% in DMF, 3x 10 ml), and the resin was washed with DMF (3 x 15 mL) 15 and iPrOH (3x15 mL). The coupling reaction sequence was repeated with TFA (trifluoro acetyl)-pteroic acid (0.414 g, 0.9 mmol), pyBOP (0.468 g, 0.9 mmol), and DIPEA (160 uL, 0.9 mmol). After 12 hours, the coupling solution was drained, and the resin was washed with DMF (3x10 mL) and iPrOH (3x10 mL). The resin was treated with 50% NH4OH in DMF solution (3x15 mL) for two hours each time. After the 50% NH4OH treatment, the resin was washed 20 with DMF (3x15 mL) and iPrOH (3x15 mL). The resin was dried for 30 minutes. Folate peptide was cleaved from the resin using a cocktail cleavage solution containing 92.5% 6570628-02 3220-422529 trifluoroacetic acid, 2.5% water, and 2.5% triisopropylsilane (3x15 mL) and was bubbled for 2 hours. The cleavage mixture was collected in a clean round bottom flask, and the combined mixture was concentrated under reduced pressure to a smaller volume. The concentrated product was precipitated in diethyl ether. The precipitate was collected by centrifugation, 5 washed with ethyl ether (3x50 mL), and dried under a vacuum. The crude conjugate was purified by RP-HPLC [A = 20 mM ammonium acetate buffer (pH 7.0), B = acetonitrile, solvent gradient: 5% B to 95% B in 60 min] to yield folate-EDA compound as yellow solid (38 % yield). LC-MS (A = 20 mM ammonium bicarbonate, pH = 7; organic phase B = acetonitrile; method: 0% B to 30% B in 12 minutes) RT = 3.26 min (M+H+= 484.0). 10 2.3 Folate-DBCO conjugate synthesis:NHS-DBCO (0.0091 g, 0.0227 mmol, 1.1 eq.) and DIPEA (2 uL, 0.0309 mmol, 2 eq.) were added under an inert atmosphere to a solution of Folate-EDA (0.010 g, 0.0206 mmol, 1 15 eq.) in anhydrous DMSO. The reaction mixture continued with stirring at room temp. The progress of the reaction was monitored by LC-MS. After the complete conversion of folate- EDA, the crude reaction mixture was purified by RP-HPLC (mobile phase A = 20mM ammonium acetate, pH = 7; organic phase B = acetonitrile; method: 0% B to 50% B in 35 minutes at 13 mL / min) and furnished Folate-DBCO with 82% yield. LC-MS (A = 20 mM 20 ammonium bicarbonate, pH = 7; organic phase B = acetonitrile; method: 0% B to 100% B in 7 minutes) RT = 3.2 min (M+H+) = 771.3. 6670628-02 3220-422529 EXAMPLE 3 Folate-Cy5-DBCO conjugate synthesis 3.1 Folate Cy5-lysine (Folate-Cy5) synthesis:56770628-02 3220-422529Folate-Cy5-DBCO conjugate was synthesized starting from folate Cy5-lysine conjugate. Briefly, folate Cy5-lysine conjugate was synthesized by following the Fmoc-solid phase peptide synthesis procedure. In a solid phase peptide synthesis vessel, 2-chlorotrityl 5 polymer bound resin (100-200 mesh, 0.5 g, 1.5 mmol / g, 1 eq.) was swollen with 10 mL of dichloromethane followed by 10 mL of dimethylformamide for 30 mins each. A solution of Fmoc-lys-OtBu (1.125 mmol, 2.5 eq), and N, N-diisopropylethylamine (DIPEA, 0.481 mL, 2.7 mmol, 3 eq.) in DMF (15 mL) was added. Argon was bubbled for 4 hours, after which the solvent was drained, and the resin was washed with DMF (3x10 mL) and iPrOH (3x10 mL). 10 The efficiency of coupling was monitored by pilot resin cleavage. The Fmoc group was removed with a piperidine solution (20% in DMF, 3x 10 ml), and the resin was washed with DMF (3 x 15 mL) and iPrOH (3x15 mL). To the free amine-containing resin, a solution of Fmoc-Lys (Dde)-OH (1.125 mmol, 2.5 eq.), (Benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluoro phosphate (PyBOP, 0.6 g, 1.125 mmol, 2.5. eq.) and 15 DIPEA (0.481 mL, 2.7 mmol, 3 eq.) in DMF (15 mL) was added. Argon was bubbled for 4 hours, after which the solvent was drained, and the resin was washed with DMF (3x10 mL) and iPrOH (3x10 mL). The efficiency of coupling was monitored by pilot resin cleavage. The Fmoc group was removed with a piperidine solution (20% in DMF, 3x10 mL), and the resin was washed with DMF (3 x 15 mL) and iPrOH (3x15 mL). The coupling reaction sequence 6870628-02 3220-422529 was repeated with Fmoc-Glu-OtBu (1.125 mmol, 2.5 eq.), TFA (trifluoro acetyl)-pteroic acid (0.9 mmol), pyBOP (0.468 g, 0.9 mmol), and DIPEA (160 uL, 0.9 mmol). After 12 hours, the coupling solution was drained, and the resin was washed with DMF (3x10 mL) and iPrOH (3x10 mL). The resin was treated with 50% NH4OH in DMF solution (3x15 mL) for two hours 5 each time. After the 50% NH4OH treatment, the resin was washed with DMF (3x15 mL) and iPrOH (3x15 mL). A solution of Cy5-NHS ester (0.1623 mmol, 1 eq.) and DIPEA (0.481 mL, 2.7 mmol, 3 eq.) in DMF (15 mL) was added. After 12 hours in the dark, the reaction solution was drained, and the resin was washed with DMF (3 x 15 mL). The resin was dried for 30 minutes. Folate peptide was cleaved from the resin using a cocktail cleavage solution 10 containing 92.5% trifluoroacetic acid, 2.5% water, and 2.5% triisopropylsilane (3x15 mL) and was bubbled for 2 hours. The cleavage mixture was collected in a clean round bottom flask, and the combined mixture was concentrated under reduced pressure to a smaller volume. The concentrated product was precipitated in diethyl ether. The precipitate was collected by centrifugation, washed with ethyl ether (3x50 mL), and dried under a vacuum. The crude 15 conjugate was purified by RP-HPLC [A = 20 mM ammonium acetate buffer (pH 7.0), B = acetonitrile, solvent gradient: 5% B to 35% B in 60 min] to yield folate-Cy5-lysine compound as a blue solid (22 % yield). LC-MS (A = 20 mM ammonium bicarbonate, pH = 7; organic phase B = acetonitrile; method: 0% B to 30% B in 12 minutes) RT = 3.26 min (M+H+= 1163.0). 20 3.2 Folate-Cy5-DBCO conjugate synthesis: 6970628-02 3220-422529, 3 eq.) were added under an inert atmosphere to a solution of folate-Cy5-lysine (0.006 g, 0.0048 mmol, 1 eq.) in anhydrous DMSO. The reaction mixture continued with stirring at room temperature. 5 The progress of the reaction was monitored by LC-MS. After the complete conversion of folate-Cy5-lysine, the crude reaction mixture was purified by RP-HPLC (mobile phase A = 20mM ammonium acetate, pH = 7; organic phase B = acetonitrile; method: 5% B to 35% B in 60 minutes at 8 mL / min) and furnished folate-Cy5-DBCO with 40% yield. LC-MS (A = 20 mM ammonium bicarbonate, pH = 7; organic phase B = acetonitrile; method: 5% B to 95% B 10 in 7 minutes) RT = 4.53 min (M+H+) = 1449.7. EXAMPLE 4 Conjugation of oligonucleotides to folate-DBCO conjugates Folate-conjugated molecules were prepared using click chemistry reaction as 15 previously used to prepare FolamiR molecules (Abdelaal et al., Oncogene 42(40): 2985-2999 (2023)), as shown in Figs.2A and 2B. In brief, Bevasiranib sense strand was annealed with anti-sense strand at (1:1) molar ratio in the presence of annealing buffer (10 mM Tris buffer, pH 7, 50 mM NaCl, and 1 mM 7070628-02 3220-422529 EDTA), followed by incubation at 95°C for 5 minutes and cooling to room temperature for 1 hour. Folate-DBCO or folate-Cy5-DBCO were mixed at a 1:10 molar ratio with bevasiranib duplex (including an azide linker) in water at room temperature for 10 hours followed by cooling to 4°C for 4 hours to make folate-Bevasiranib or folate-Cy5-bevasiranib (Fig. 3A). 5 Folate-DBCO was mixed at a 1:10 molar ratio with ASO or ASO-Cy5 (each including an azide linker) in water at room temperature for 10 hours followed by cooling to 4°C for 4 hours to make folate-ASO (Fig.3B). or folate-ASO (Fig.3B). Unconjugated folate ligand was cleaned from the reaction using Oligo Clean & Concentrator kit per manufacturer’s instructions. Successful conjugation was verified by running 15% polyacrylamide gel (PAGE) followed by 10 gel red staining. EXAMPLE 5 Targeting of folate-Bevasiranib conjugate to ARPE-19 cells (Figs.5A-5E) ARPE (Arising Retinal Pigment Epithelium), a human RPE cell line was purchased 15 from ATCC [Cat: CRL-2302] and passaged in DMEM F-12 media containing 1% streptomycin-penicillin and 10% FBS for initial passages. This cell line was transduced with human FRα (folate receptor α). The transduced cell line has been passaged in folate-deficient RPMI medium containing 0.01% streptomycin and 0.1% FBS. Cells (50,000) were seeded per well in a 6-well plate with lysine coverslips placed in the bottom of the wells. The next day, 20 the medium was removed, and cells were washed with 1X PBS. New medium was added to each well, and the sample well was treated with 50 nM folate-Bevasiranib (folate-Bevasiranib- atto647) (Fig.3A) for 1 hour at 37 °C. For positive control, the same concentration of folate- Cy5 was used. After incubation, the medium was removed, and the wells were washed with PBS. The cells were fixed with 4% PFA [paraformaldehyde] for 20 minutes. After fixation, 25 the wells were washed with PBS and permeabilized with PBST [PBS with Triton X-100] solution for 20 minutes. Then cells were blocked by immunofluorescence buffer for 1 hour. Then the coverslips were carefully rinsed with PBS and mounted on slides with antifade mounting medium containing DAPI. The slides were kept at room temperature to dry overnight. Images were taken with an A1RSi microscope at 20X magnification at the same 30 instrumental setup for all the imaging (Figs.5A-5E). Images show that folate-Bevasiranib was targeted to the ARPE-19 cells. The fluorescence signal was evident in the folate-siRNA treated cells compared to negative controls. The results show that the folate-siRNA (folate- Bevasiranib) is taken up by the ARPE-19 cells. The positive control used Cy5 fluorescent dye, 7170628-02 3220-422529 and the siRNA was attached to atto647 dye. Although the fluorescent probes have similar excitation wavelength, Cy5 is a more vibrant fluorescent dye. EXAMPLE 6 5 Targeting of folate-Bevasiranib conjugate in vivo (Figs.6A-6C) Female Swiss outbred mice were injected with 2.6 nanomoles of folate-Bevasiranib (folate conjugated to Bevasiranib-atto647) (Fig.3A). For a positive control, mice were injected 2 nanomole folate-Cy5, and for a negative control, non-injected mice were used. The mice were euthanized, and eyes were enucleated and fixed in PFA solution. After fixation, the eyes 10 were submerged in cryoprotectant solution [30% sucrose solution] for at least 24 hours. Then the eyes were flash-frozen in OCT medium with dry ice-isopentane and stored in -80 °C until further processing. The embedded eyes were sectioned into 25 micrometer thin sections. The eye sections were permeabilized in PBST solution for 30 minutes and then blocked in 10% serum solution for one hour to block non-specific antibody binding. After blocking, the 15 sections were mounted with DAPI mounting medium and were left overnight at room temperature for drying. The slides were imaged with an A1RSi microscope at 20X magnification at the same instrumental setup for all the imaging (Figs.6A-6C). Fluorescence signal was visible at the RPE. The animal data confirm the specific uptake of folate- Bevasiranib (folate-conjugated siRNA) in the RPE of the eye. 20 EXAMPLE 7 Competitive study between folate-Bevasiranib and folate-glucosamine (Figs.7-9) In a 12 well-plate, 50,000 cells were seeded. The next day, the medium was removed, and new medium was added to the wells. Folate-Bevasiranib (50 nM) (Fig. 3A) and folate- 25 Bevasiranib (50 nM) + 5,000 nM folate-glucosamine (5,000 nM) were added to the only Bevasiranib-treated and Bevasiranib-competition wells, respectively. The same concentration of folate Cy-5 and its corresponding competition were done simultaneously. After 1 hour of incubation, the medium was removed, and PBS washes were conducted followed by fixation, permeabilization and blocking. Then ZO-1 antibody was added to the wells for overnight 30 incubation at 4 °C. The next day, secondary antibody, Alexa-568 was added and incubated at room temperature for 1 hour. Afterwards, the cells were washed and mounted on slides with DAPI medium. The images were taken at 20x magnification with Zeiss LSM 900 at the same time with same instrumental setup (Figs. 7-9). The ‘only Bevasiranib’-treated well shows bright fluorescence, indicative of the folate-Cy5-bevasiranib (folate-bevasiranib-Cy5) uptake, 7270628-02 3220-422529 whereas the competition study shows no or very dim fluorescence. This ascertains the role of receptor-mediated endocytosis as the primary route of Folate-Bevasiranib (folate-conjugated siRNA) uptake in the ARPE-19 cells. 5 EXAMPLE 8 Efficacy of folate-Bevasiranib in reducing VEGF levels in ARPE-19 cells (Fig.10) Cells (0.1 million) were seeded. The next day, the medium was replaced with serum- free fresh medium, and folate-Bevasiranib (Fig.3A) was added at a final concentration of 470 nM. After pre-treatment with Folate-Bevasiranib (folate-siRNA), hypoxic conditions were 10 created by either a chemical inducer [Cobalt Chloride II] or a hypoxic chamber containing 0.1% oxygen to induce increased VEGF production. The cells were incubated for 72 hours. The spent media was collected from the wells and centrifuged to remove any dead cell debris. Supernatants were stored in -20 °C before assay. The VEGF quantification was conducted with ELISA (Fig.10). The wells pre-treated with folate-Bevasiranib showed reduced VEGF levels15 compared to their no-treatment counterparts. The data indicate that Folate-Bevasiranib (folate- siRNA) treatment was successful in reducing VEGF levels. EXAMPLE 9 Development and screening of in-silico-designed ASOs in AML12 cells (Figs.11 and 12) 20 A library of 52 in-silico-designed ASOs (SEQ. ID Nos. 1-52) was designed. NM_001025250.3 [ mRNA transcript] was used to generate the targeting ASO sequences and the generated ASO sequences target the 1684-1963 region of the mVEGFa gene. The 1684- 1963 region is conserved across several high-quality and representative transcripts (NCBI annotation: NM_001025250.3; Ensembl annotation: ENSMUST00000142351.9， 25 ENSMUST00000071648.12，ENSMUST00000024747.14). And because of this, this particular region was the interest for generating the ASOs. A primary screening of ASOs was performed in AML12 cells treated with 33 nM ASO. The relative remain of mVegf mRNA (%) in treated cells is shown in Fig.11. The cytotoxicity of ASOs in treated cells is shown in Fig.12.8 of 52 in-silico-designed ASOs showed significant 30 efficacy in primary screening. ASOs of SEQ. ID No.10 and 38 were the top 2 effective ASOs, while ASO of SEQ. ID No.38 exhibited slight cytotoxicity, as shown in Table 4. 7370628-02 3220-422529 Table 4. SEQ. ID. No. Inhibition rate % Cell viability % 56 33.12 85.5 EXAMPLE 10In vivo efficacy of ASO (Figs.13 and 14) 5 The efficacy of ASO of SEQ. ID NO.10 was confirmed in an in vivo model. C57BL / 6 mice were treated with 60 mg / kg of ASO subcutaneously (SC) on day 1 (D1) of study. On day 4 (D4) mice were sacrificed, and livers were collected for qPCR evaluation. The relative remain of mVEGF mRNA (%) in the liver is shown in Fig. 13. Azide linker modification of ASO of SEQ. ID No.10 did not significantly influence the efficacy of the ASO (Fig.14). The 10 ASO including SEQ. ID No.10 and an azide linker (N3-10 or azide-ASO) is shown in Fig.4. EXAMPLE 11 Efficacy of folate-ASO (folate-conjugated ASO of SEQ. ID NO. 10) in treating abnormal vascularization in a wet AMD mouse model, VLDLR (Figs.15A and 15B) 15 The aim of this efficacy experiment was to assess the efficacy of folate-ASO (Fig.3B) in suppressing abnormal vascularization in an abnormal vascularization model. B6;129S7-Vldlrtm1Her / J mice [IMSR_JAX:002529] was purchased from Jax lab and bred in house. Before the start of experiment, the mice have been put on folate free chow for at least two weeks. The mice were divided into three groups [no treatment, ASO, folate-ASO]. 20 The ASO and folate-ASO mice received 15 nanomole of respective drugs via subcutaneous [SC] route for one month [dosing frequency: Day 01, 03, 06, 09, … Day 30]. After the last dose, the mice were euthanized, and the tissue [eye, liver and kidney] were collected for subsequent RT-PCR experiments. Each week, the body weight of the mice was measured to assess any drug related toxic effects on mouse weight. 25 The tissues were stored in RNA-protect Tissue Reagent [Qiagen Catalog: 76104] in 4 °C until they were used for RNA isolation. RNA was isolated from liver and kidney tissues 7470628-02 3220-422529 using the Qiagen RNeasy kit [Catalog: 74104] following the manufacturer’s protocol with minor modifications. The eye was dissected to remove the lens and sclera. RNA from the RPE- retina was isolated using Qiagen RNeasy Micro kit

[74004] following manufacturer’s guide with modifications. The RNA amount and the purity of each sample were quantified using the 5 Nanodrop. RT-PCR was conducted using ‘iTaq Universal SYBR Green One step Kit’ [Biorad, catalog: 172-5151] with 20 nanogram template in each sample. Each sample was run in triplicate and the average Cq value was used for the delta-delta Ct calculation. VEGF was normalized to GAPDH gene. One-way ANOVA was employed to see the statistical differences 10 among groups. The VEGF mRNA knockout was significantly higher in the RPE-retina and kidney tissue in the folate-ASO treated group (Fig.15). This data is indicative of the targeted effect of the folate-ASO drug in suppressing the VEGF mRNA levels in tissues with folate receptor expression. The body weight was also consistent throughout the study length and there was no 15 significant difference according to two-way ANOVA analyses (Fig.15B). Immunostaining of vasculature in the retina of VLDLR mice is shown in Fig.16 One eye / mouse was collected to assess the drug’s ability to reduce abnormal vasculature. The enucleated eye was fixed in 4% formalin buffer and then the retina was dissected. The retina was then permeabilized followed by an incubation step with a blocking 20 buffer for 2 hours. Then the retina was incubated with Isolectin GS IB4-488 [Invitrogen, catalog: I21411], IBA-1 [Genetex, Catalog: GTX100042] and VEGF [Invitrogen, catalog: MA5-13182] antibodies for 24 hours. This step was followed by an incubation step with secondary antibodies, Goat anti-Mouse IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 647 [Invitrogen, catalog: A-21235] and Goat anti-Rabbit IgG (H+L) Cross- 25 Adsorbed Secondary Antibody, Alexa Fluor™ 568 [Invitrogen, catalog: A-11011] for overnight. After the secondary incubation, the whole retina was washed in PBS and then flat mounted on microscopic slides with Fluoromount G mounting medium [SouthernBiotech, catalog: 0100-01]. The abnormal vasculature was imaged across the retina at 10X magnification with the same instrumental setup at the Zeiss LSM 900. 30 As shown in Fig.16, the region of abnormal vasculature was smaller in the folate-ASO treated group of mice compared to the ASO treated mice. The abnormal regions of vasculature were the most prominent in the control group. The fluorescent signal for inflammation around the abnormal vasculature and the signal for VEGF expression were also the lowest in the folate- 7570628-02 3220-422529 ASO group. These data indicates that the targeted ASO drug is effective in reducing the VEGF proteins level and consequently in suppressing the abnormal vasculature. EXAMPLE 12 5 In-vivo efficacy testing of folate-ASO in healthy C57BL / 6 mice (Figs.17, 18, and 19) The aim of this experiment was to assess the efficacy of folate-ASO (Fig. 3B) in reducing VEGF mRNA levels in healthy mice. C57BL / 6 [Vendor: Charles River] was purchased, and they were on folate -free chow before the experiment started. The mice were treated for 3 weeks [Dosing frequency: Day 1,3, 6, 9,12, … day-21]. After sacrificing the mice, 10 the liver and kidney tissue were similarly preserved in RNA-protect as described in Example 11. RNA isolation and RT-PCR were also conducted followed by the same method. The VEGF mRNA suppression was significantly higher in the kidney of the folate-ASO treated mice group (Fig.17). This experiment validated the efficacy of the folate-ASO drug in targeted tissue with folate receptor expression. 15 One kidney / mouse was preserved in fixative buffer [4% formalin] followed by cryopreservation in sucrose solution. Then the tissue was frozen in OCT gum using dry ice- isopentane slurry. With Cryostat machine, 25-micron sections of the kidney were sectioned. These sections underwent the process of permeabilization with subsequent 0.1% PBST and 1.5% PBST washes. Then the tissue was incubated with VEGF antibody [Invitrogen, catalog: 20 MA5-13182] for 24 hours followed by a secondary incubation with Goat anti-Mouse IgG (H+L) antibody [Invitrogen, catalog: A-21235]. The tissue sections were mounted with antifade gold DAPI mounting medium. The images were taken with the Zeiss LSM 900 at 20X magnification with the same instrumental set up. The fluorescent signal for VEGF levels were significantly lower in the folate-ASO mice kidney in comparison to control and ASO treated 25 mice kidneys (Fig.18). The eyes of the mice were also collected to assess the change in vasculature in the healthy eyes. The eyes were enucleated after euthanasia and fixed in formalin solution. Then the whole retina was dissected and stained with Isolectin GS IB4-488 [Invitrogen, catalog: I21411]. After 24 hours of incubation, the retina was flat-mounted and imaged at 20X 30 magnification. There was no significant difference in vasculature in the healthy retina (Fig. 19). This data is indicative of the fact that the targeted ASO drug did not repress the healthy vasculature in the mouse retina. 7670628-02 3220-422529 EXAMPLE 13 In-vivo targeting of folate-ASO to the Retinal Pigmented Epithelial (RPE) cells (Fig.20) The aim of the study was to validate the specific targeting of folate-ASO (Fig. 3B) entities to the RPE cells in the eye. 5 Female Balb-c mice [IMSR_JAX:000651] was purchased and acclimatized on folate free chow to normalize the blood folate level before conducting the experiment. There were three groups [negative control, Folate-ASO conjugated to Cyanine 5 and ASO conjugated to Cyanine 5]. The mice were administered 10 nanomole of the compounds once via subcutaneous route. After 2 hours the mice were euthanized, and the eyes were collected for 10 further processing. The eyes were fixed in 4% PFA and then submerged in cryoprotectant solution [30% Sucrose] for 24 hours. Then the eyes were flash frozen in OCT medium using dry ice and isopentane. The frozen eye was sectioned into 25 micrometer sections using cryostat machine. The eye sections were permeabilized in PBST [PBS with Triton X-100] solution for 30 minutes and then blocked in 10% serum solution for 1 hour to block non-specific 15 antibody binding. After blocking the sections were mounted with DAPI mounting medium and were left overnight at room temperature for drying. The slides were imaged with Zeiss LSM 900. The corresponding fluorescence of cyanine 5 was visible in the RPE cell layer situated between the choroid capillaries and the photoreceptor layers in the folate-ASO-Cy5 mice. This 20 indicates that folate conjugated ASO moieties can reach the RPE layer in the eye (Fig.20). EXAMPLE 14 In vitro uptake of the folate-ASO (Figs.21A and 21B) The aim of the study was to assess the uptake of folate-ASO (Fig. 3B) in the Folate 25 Receptor-alpha [FR-α] transduced ARPE-19 cells. There were 8 groups [Group 1: negative control, Group 2: negative control with 100X competition of folate-glucosamine, Group 3: folate-Cy5: positive control, Group 4: positive control with 100X competition, Group 5: folate-- ASO-Cy5, Group 6: folate-- ASO-Cy5 with 100x competition of folate-glucosamine, Group 7: free ASO-Cy5 and Group 8: free ASO-Cy5 30 with its competition]. The cells were seeded at a 50000 / well density in a 6 well plate with adherent coverslips in them. The next day the old media was replaced with new media and groups 3, 5 and 7 were treated with 10 nanomolar concentration of respective molecules for 1 hour. The groups 2, 4, 6 and 8 were treated with 10 nanomolar folate-Cy5 and 1000 nanomolar folate-glucosamine for the same length of time. After the incubation, the cells were washed to 7770628-02 3220-422529 remove any excess non-specific molecules and then fixed in 4% PFA. The fixed cells were washed with PBS and then the coverslips were mounted on microscopic slides for imaging. The results showed that the folate-ASO treated cells showed fluorescent signals corresponding to Cy5 as an indication of the cellular uptake of the folate-ASO- Cy5 probe 5 (Figs. 21A and 21B). But the competition with 100X folate-glucosamine did not show the fluorescent signal. This represented that the specific uptake is because of the presence of the folate receptor alpha which was saturated by the excess amount of competition present. The free ASO-Cy5 probe did not fluoresce. 10 EXAMPLE 15 In-vitro efficacy of folate-ASO in suppression of VEGF mRNA levels (Fig.22) The goal of this experiment was to assess the efficacy of folate-ASO (Fig. 3B) in knocking down VEGF mRNA levels of the ARPE-19 cells. 0.5 million cells were seeded in each group. There were three different groups [Group 15 1: no treatment, group 2: folate-ASO treated and group 3: free ASO treated]. The next day the groups were treated with respective drugs at 125 nanomolar concentration for 1 hours and 45 minutes. After the incubation, the cells were washed with PBS to remove any excess drug present in the media. After 72 hours, the RNA was isolated from the cells following the manufacturer’s protocol of Quick RNA Microprep Kit [Zymo Research, catalog: R1050] with 20 minor changes. The RT-PCR was conducted at the Bio-rad CFX Connect machine using the Itaq universal kit following the RT-PCR workflow. The VEGF levels were normalized to the expression of housekeeping gene, GAPDH. The folate-ASO group has shown to suppress the VEGF mRNA with higher efficacy (Fig.22). 25 EXAMPLE 16 Sequence alignment between mouse and human VEGF genes (Figs.23A-23F and Fig.24) Homo sapiens vascular endothelial growth factor A (VEGFA), transcript variant 1, mRNA ( SEQ ID NO.83, NM_001025366.3) can be used for designing ASOs targeting human VEGF A sequence. This sequence has also been found to be highly conserved according to 30 different databases such as ENSP00000361125.5, ENST00000372055.9. Pairwise sequence alignment of human transcript (SEQ ID NO.83, NM_001025366.3) with whole mouse transcript (SEQ ID NO. 72, NM_001025250.3) shows 81% sequence alignments (Figs.23A-23F). ASOs designed against these homologous sequences can be used to generate ASO sequences that have the potential to target both species. ASO generation for 7870628-02 3220-422529 multiple species (not only limited to humans and mice) can be done in a similar manner following the example provided here. The query and subject sequences belong to the mouse and human VEGF transcripts, respectively. One example for generating such ASO targets can be focused, but not limited to, 5 the aligned query sequence [510-569] and subject sequence [519-578] (Fig. 23A). Sequence alignment of mouse sequences [1680-1980] and similar human sequences show 55% similarity (Fig.24). The ASO sequences (e.g., SEQ ID Nos. 1-52) described herein are unique only to the VEGF gene and do not show similarity with any other genes according to the BLAST results. 10 The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range. Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include 15 all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range were explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about 20 X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise. In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive 25 “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings and subheadings is solely for ease of reference and is not intended to limit any disclosure made in one section to that section only; rather, any disclosure 30 made under one section heading or subheading is intended to constitute a disclosure under each and every other section heading or subheading. Various modifications and variations of the described compositions, methods, and uses of the technology will be apparent to those skilled in the art without departing from the scope and spirit of the technology as described. Although the technology has been described in 7970628-02 3220-422529 connection with specific exemplary embodiments, the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the following claims. 5 The terms and expressions, which have been employed, are used as terms of description and not of limitation. In this regard, where certain terms are defined and are described or discussed elsewhere, the definitions and all descriptions and discussions are intended to be attributed to such terms. There also is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof. 10 Further, all publications and patents mentioned herein are incorporated by reference in their entireties for all purposes. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls. 15 80

Claims

70628-02 3220-422529 WHAT IS CLAIMED IS:

1. A method of administering a therapeutic agent to the retinal pigment epithelium (RPE) in a subject in need of a therapeutic agent effective for the treatment of the RPE or adjacent cells, which method comprises administering, by a route other than intravitreal injection, to the subject a conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α (FRα), L is a linker, and A is the therapeutic agent effective for treatment of the RPE, whereupon the therapeutic agent is administered to the RPE in the subject.

2. The method of claim 1, wherein the therapeutic agent comprises nucleotides and / or modified nucleotides.

3. The method of claim 2, wherein the therapeutic agent comprises an oligonucleotide, an interfering RNA (iRNA), a small interfering RNA (siRNA), an RNA aptamer, a microRNA, a ribozyme, a short hairpin RNA, an antisense oligonucleotide, or an analog or derivative of any of the foregoing.

4. The method of claim 3, wherein the therapeutic agent is modified with a 2’-F sugar, a 2’- O-methyl sugar, a 2’-O- methoxyethyl sugar, a 2'-deoxy sugar, a 5-alkylamino base, a 5-allylamino base, a phosphorothioate modification of a nucleotide, a P-alkyl modification of a nucleotide, a phosphonate modification of a nucleotide, a phosphoroselenate modification of a nucleotide, a phosphoroamidate modification of a nucleotide, a modification of a terminal phosphate, or any combination thereof.

5. The method of claim 4, wherein the therapeutic agent is modified with a 2’-O- methoxyethyl sugar, a 2'-deoxy sugar, a phosphorothioate modification of a nucleotide, or any combination thereof.

6. The method of claim 5, wherein the therapeutic agent silences the gene that expresses vascular endothelial growth factor (VEGF).

7. The method of claim 6, wherein the therapeutic agent comprises an siRNA (e.g., an 18-21 nucleotide long double-stranded RNA (dsRNA)). 8170628-02 3220-422529 8. The method of claim 7, wherein the siRNA comprises a nucleotide sequence selected from the group consisting of SEQ. ID Nos.60-71, and any combination thereof.

9. The method of claim 8, wherein the siRNA is Bevasiranib (SEQ. ID No.60 and SEQ. ID No.61).

10. The method of claim 6, wherein the therapeutic agent is an antisense oligonucleotide (ASO) (e.g., an 18-21 nucleotide long single-stranded oligonucleotide).

11. The method of claim 10, wherein the ASO comprises a nucleotide sequence selected from the group consisting of SEQ. ID Nos.1-59, and any combination thereof.

12. The method of claim 11, wherein the ASO is a nucleotide sequence selected from the group consisting of SEQ. ID Nos.3, 6, 8, 10, 34, 38, 47, 51, and 56.

13. The method of claim 12, wherein the ASO is SEQ. ID No.10 or 38.

14. The method of claim 3, wherein the RNA aptamer binds VEGF.

15. The method of claim 14, wherein the RNA aptamer is Pegaptanib.

16. The method of claim 1, wherein the therapeutic agent is a VEGF decoy receptor.

17. The method of claim 16, wherein the VEGF decoy receptor is Aflibercept or Conbercept.

18. The method of claim 1, wherein the therapeutic agent is an ankyrin repeat protein (DARPin).

19. The method of claim 18, wherein the DARPin is Abicipar pegol.

20. The method of claim 1, wherein the therapeutic agent is a stress resilience-enhancing drug (SRED).

21. The method of claim 20, wherein the SRED inhibits a cyclic nucleotide phosphodiesterase (PDE).

22. The method of claim 21, wherein the SRED is BAY 60-7550, rolipram, or BC 11-38. 8270628-02 3220-422529 23. The method of claim 1, wherein the subject has age-related macular degeneration (AMD), diabetic retinopathy (DR), or retinitis pigmentosa (RP).

24. The method of claim 23, wherein the AMD is wet.

25. The method of claim 1, wherein F is selected from the group consisting of a folate, a folate derivative, a folate analog, or a radical thereof that binds to a folate receptor.

26. The method of claim 25, wherein F is 5-methyltetrahydrofolate (5-MTHF) or an N5,N10- dimethylated derivative of tetrahydrofolic acid (DMTHF).

27. The method of claim 25, wherein F has or comprises the structure (or a radical thereof): O COOH OH O N .

28. The method of claim 25, wherein F has or comprises the structure (or a radical thereof): .

29. The method of claim 25, wherein F has or comprises the structure (or a radical thereof): .

30. The method of claim 25, wherein F has or comprises the structure (or a radical thereof): 8370628-02 3220-422529 .

31. The method of claim 25, wherein F has or comprises the structure (or a radical thereof): .

32. The method of claim 1, wherein L is or comprises a portion formed from a strain- promoted alkyne-azide cycloaddition (SPAAC) reaction (e.g., a fused dibenzocyclooctane-triazole).

33. The method of claim 32, wherein L comprises: .

34. The method of claim 1, wherein L comprises: ethylene, propylene, butylene, , ion35. The method of claim 1, wherein the conjugate is selected from the group consisting of: 8470628-02 3220-42252970628-02 3220-422529 (Folate-ASO-Cy5), or a pharmaceutically acceptable sat thereof.

36. A conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α (FRα), L is a linker, and A comprises an oligonucleotide (e.g., an interfering RNA (iRNA), a small interfering RNA (siRNA), an RNA aptamer, a microRNA, a ribozyme, a short hairpin RNA, or an antisense oligonucleotide (ASO).

37. The conjugate of claim 36, wherein A is an siRNA.

38. The conjugate of claim 37, wherein the siRNA comprises a nucleotide sequence selected from the group consisting of SEQ. ID Nos.60-71, and any combination thereof.

39. The conjugate of claim 38, wherein the siRNA is Bevasiranib (SEQ. ID No.60 and SEQ. ID No.61).

40. The conjugate of claim 36, wherein A is an ASO.

41. The conjugate of claim 40, wherein the ASO comprises a nucleotide sequence selected from the group consisting of SEQ. ID Nos.1-59, and any combination thereof.

42. The conjugate of claim 41, wherein the ASO is a nucleotide sequence selected from the group consisting of SEQ. ID Nos.3, 6, 8, 10, 34, 38, 47, 51, and 56.

43. The conjugate of claim 42, wherein the ASO is SEQ. ID No.10 or 38.

44. The conjugate of claim 36, wherein F is selected from the group consisting of a folate, a folate derivative, a folate analog, or a radical thereof that binds to a folate receptor (e.g., FRα).

45. The conjugate of claim 44, wherein F is of the formula (I): O COOH I),8670628-02 3220-422529 R1and R2, when present, are independently H or alkyl (e.g., methyl), R3is H or alkyl (e.g., methyl), and wherein each “ ” is independently a single or a double bond.

46. The conjugate of claim 36, wherein L is or comprises a portion formed from a strain- promoted alkyne-azide cycloaddition (SPAAC) reaction (e.g., a fused dibenzocyclooctane -triazole).

47. The conjugate of claim 46, wherein L comprises: .

48. The conjugate of claim 36, wherein L comprises: ethylene, propylene, butylene, , ion49. The conjugate of claim 1, wherein L does not comprise a disulfide, a maleimide, or an amino acid (e.g., cysteine or glutamic acid).

50. The conjugate of claim 36, wherein the conjugate is selected from the group consisting of: 8770628-02 3220-42252970628-02 3220-422529 (Folate-ASO-Cy5), or a pharmaceutically acceptable sat thereof.

51. A conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α (FRα), L is a linker, and A is Pegaptanib.

52. A conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α (FRα), L is a linker, and A is Aflibercept or Conbercept.

53. A conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α (FRα), L is a linker, and A is Abicipar pegol.

54. A conjugate of formula F-L-A, wherein F is a ligand that targets folate receptor α (FRα), L is a linker, and A is BAY 60-7550, rolipram, or BC 11-38.

55. A pharmaceutical composition comprising the conjugate of claim 36 and a pharmaceutically acceptable carrier. 89

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