RNA aptamer conjugates and uses thereof

Abstract

Pharmaceutical compositions and compounds comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide that is hybridized an RNA aptamer are useful in methods of treating cancer (such as leukemia) and methods of inhibiting DNA methyltransferase. In embodiments, the RNA aptamer binds to an intracellular target such as DNMT1, NF-kB, RUNX1, MYC, MYB, ETS, PAX5, MDM2, F0XM1, PU.l, STAT3, STATS. STAT6, FAD, ATP5B, or beta-catenin.

Description

Docket No. 048440-207001WO / TEC 24-031RNA APTAMER CONJUGATES AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to US Application No. 63 / 683,304 filed August 15, 2024. the disclosure of which is incorporated by reference herein in its entirety.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with government support under R01 CA284593 awarded by the National Institutes of Health. The government has certain rights in the invention.REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCH FILE

[0003] A Sequence Listing in an XML file having the title “048440-207001WO-Sequence- Listing-ST26,’‘ having 262,144 bytes, created on 22 July 2025 and modified on 7 August 2025, is incorporated by reference herein in its entirety.BACKGROUND

[0004] Leukemia may be classified into acute and chronic forms according to the progression rate thereof. The clinical conditions of leukemia are various according to disease type and the characters of the affected cells. When leukemia affects the myeloid cells, the disease is called myeloid leukemia. Chronic myeloid leukemia outbreaks as cells in the maturity period mutate. Acute myeloid leukemia (AML) is a kind of blood cancer characterized by the unlimited growth and suppression of differentiation of blasts in a specific stage of cell differentiation. AML shows various genetic mutations which are known to be closely related to the response to anticancer therapy as well as to the prognosis thereof. There is a need in the art for new and improved treatments of acute myeloid leukemia. The disclosure is directed to this, as w ell as other, important ends.BRIEF SUMMARY

[0005] Provided herein are compounds comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer. In embodiments, the RNA aptamer binds to an intracellular target. In embodiments, the RNA aptamer binds to an intracellular target selected from the group consisting of DNMT1, NF-kB, RUNX1, MYC, MYB, ETS, PAX5, MDM2, F0XM1, PU. l, STAT3, STAT5. STAT6, FAD, ATP5B, and beta-catenm.

[0006] Provided herein are methods of treating cancer in a patient in need thereof by administering to the patient an effective amount of a compound comprising a phosphorothioatedCpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer. In embodiments, the RNA aptamer binds to an intracellular target.

[0007] These and other embodiments and aspects of the disclosure are described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIGS. 1A-1I: DNMT1 inhibition and CpG / TLR9 stimulation synergize to stimulate CMM cell differentiation and leukemia regression in vivo. C57BL / 6 mice with established, disseminated CMM leukemia were treated IV using azacitidine (1 mg / kg), CpG Bl oligonucleotide (1 mg / kg), a combination thereof or PBS every7day for 6 times. Two days after the last treatment, mice were euthanized to analyze AML burden by measuring spleens weight (FIG. 1A) and size (FIG. IB), bone marrow appearance (FIG. 1C) and the percentages of proliferating GFP+ / c-Kit+leukemic cells in spleen and bone marrow (FIGS. ID- IE). The combined azacitidine / CpG Bl treatment induced expression of IRF8 in splenic leukemic cells as assessed using flow cytometry (FIG. IF) and Western blotting (FIG. 1G). The combination of DNMT1 inhibitor and TLR9 stimulation promoted (FIG. 1H) differentiation and maturation of CMM cells to antigen-presenting phenotype (CDI lb / MHC-II+ / CD86+) with (FIG. II) the increased recruitment of predominantly CD8 T cells with smaller percentages of regulatory T cells; means±SEM (ra=5).

[0009] FIG. 2: CpG oligonucleotides augment anti-leukemic effects of azacitidine against human AML cells. Human AML cells were treated for 48 h with different types of CpG ODNs (2.5 pM) in combination with azacitidine (0.1 pM) in vitro. Cell viability was determined using the Cell Counting Kit-8 (CCK-8) assay; shown are means±SEM (w=4).

[0010] FIGS. 3A-3B: the combination of azacitidine with CpG-A or CpG-C type ODNs enhances expression of differentiation markers on AML. Human AML cells MOLM-13 (FIG. 3A) or U937 (FIG. 3B) were treated in vitro for 48 hours with azacitidine (0.1 pM) alone, CpG ODNs (2.5 pM) or their combination. The surface levels of differentiation markers (CDl lb+, CD14+, CD70+) or antigen-presentation molecules (HLA-DR+) were assessed using flow cytometry. The treatment combinations were assessed using flow cytometry. Data are presented as mean±SEM (M=3); *P < 0.05, **P < 0.01 ***P < 0.001.

[0011] FIGS. 4A-4F: The design and stability7of CpG-DNMTl -aptamer conjugates. FIG. 4A: Schematic design of the CpG-DNMTl aptamer conjugate and its hypothetical processing in the presence of nucleases. FIG. 4B: DNMTlapt (unfolded) and CpGB1-DNA passenger oligonucleotide form a duplex CpGB1-DNMTlapt. FIG. 4C: Comparison of migration patterns for CpG-DNMTlapt conjugates utilizing different A-, Bl- and C ty pe of CpG sequences togenerate monomeric CpGBI-DNMTI apt. mono- / dimeric forms of CpGc-DNMTlapt and mono- / tetrameric CpGA-DNMTlapt. The DNMTlapt shown migrating in the unfolded (singlestranded) and folded (retarded gel migration band) forms with or without Cy3 fluorescent label. FIGS. 4E-4F: Serum stability of the chemically modified CpGB1-DNMTlapt (FIG. 4E) and DNMTlapt alone (FIG. 4E) as measured after incubation in 50% human serum at 37 °C for different times from 0 to 216 h. The quantification of the half-life of CpGB1-DNMTlapt complex compared to DNMTlapt alone (FIG. 4F). Samples were resolved on 15% PAGE. Show n are the representative results from one of four independent experiments. CpGA, CpGB1, and CpGccan alternatively be written as CpGA, CpGBl, and CpGC, respectively, or as CpG A, CpG Bl, and CpG C, respectively.

[0012] FIGS. 5A-5C: CpGB1-DNMTlapt conjugate shows improved uptake by target AML cells compared to DNMTlapt alone. FIG. 5A: Human AML cells were incubated for 1 h with fluorescently-labeled aptamer CpGB1-DNMTlaptCy3. The level of oligonucleotide uptake was assessed using flow' cytometry (grey = untreated control, red = CpGB1-DNMTlaptCy). FIG. 5B: MOLM-13 cells were incubated for 0.5 h with fluorescently-labeled aptamer CpGB1- DNMTlaptCy3or with an unconjugated DNMTlaptCy3at 100 nM concentration (top panel). The intracellular localization of oligonucleotides was examined using confocal microscopy. FIG. 5C: AML cells internalize CpGB1-DNMTlaptCy3using active endocytosis by scavenger receptor-mediated mechanism. MOLM-13 cells were pre-incubated for 4h at low temperature or for 2h in the presence of dextran sulfate (scavenger receptor inhibitor), amiloride (macropinocytosis inhibitor), unlabeled CpG or aptamer oligonucleotides or control chondroitin sulfate before adding an unconjugated DNMTlaptCy3or CpGB1-DNMTlaptCy3(100 nM) for 0.5 hour. The level of oligonucleotide uptake was measured using flow cytometry. Shown are results from one of three independent experiments.

[0013] FIGS. 6A-6D: CpG-DNMTlapt conjugate targets various AML cells reducing DNMT1 levels and inducing cytotoxicity. FIG. 6A: AML cells were incubated for 48h with CpGB1-DNMTlaptCy3in concentrations ranging from 0.5 to 10 pM. Cell viability' were determined using a colorimetric assay (Cell Counting Kit-8). FIGS. 6B-6C CpGB1-DNMTlapt reduces protein levels of DNMT1 in target AML cells. MOLM-13 (FIG. 6B) and U937 (FIG. 6C) cells were incubated for 48 h with 5 pM of CpGB1-DNMTlaptCy3, an unconjugated DNMTlaptCy3or azacitidine used as a benchmark DNMT1 inhibitor. Total DNMT1 protein levels were quantified by Western blotting with normalization to (3-actin; shown is the quantification of band intensities. FIG. 6D: DNMT1 activity in MA9.3ITD cells treated in vitro with CpGB1-DNMTlapt or azacitidine. DNMT1 activity was analyzed by EpiQuik™ DNAMethyltransferase assay. Shown are means±SEM.

[0014] FIG. 7: CpG Bl-DNMTlapt oligonucleotides synergize with venetoclax in inducing cytotoxic effects on human AML cells in vitro. Various human AML cells were incubated for 48 h with CpG Bl-DNMTlapt (lOpM), azacitidine (0.5pM), venetoclax (1 nM) or combinations thereof before assessing cell viability' using the colorimetric assay (CCK-8) (n=4).

[0015] FIGS. 8A-8F: Local injections of CpGB1-DNMTlapt conjugate effectively inhibits growth of two human AML xenotransplants in immunodeficient mice. Human MOLM-13 (FIGS. 8A-8C) and MA9.3-ITD (FIGS. 8D-8F) leukemia cells implanted subcutaneously in NSG mice and after 8-9 days injected intratumorally daily with 2.8 mg / kg CpGB1-DNMTlapt, 1.0 mg / kg unconjugated DNMTlapt or azacitidine as indicated by arrows (n=3-4 mice / group). FIGS. 8A, 8D: AML tumor growth kinetics. FIGS. 8B, 8E: tumor weight at the end of experiment. FIG. 8C: Protein levels of DNMT1, c-MYC and CEBPa as quantified by Western blotting. FIG. 8F: The expression of monocytic markers CD1 lb+, CD14+ and antigenpresentation molecules HLA-DR+ on AML cells as analyzed by flow cytometry. Data are presented as mean±SEM; *P < 0.05. **P < 0.01, ***P < 0.001. ****p < 0.0001 by one-way ANOVA with Bonferroni’s correction post hoc test.

[0016] FIGS. 9A-9G: CpGB1-DNMTlapt conjugate shows superior activity against MOLM- 13 xenotransplants in mice. Human NSG mice with established subcutaneous MOLM-13 leukemia (day 7 after engraftment) were injected IT daily using 2.8 mg / kg CpG(A’B1-C)-DNMT1 aptamer or equimolar amount (1.0 mg / kg) of unconjugated DNMT1 aptamer or azacitidine (1 mg / kg) intratumorally / IT as indicated by red arrows (n=5 mice / group). FIG. 9A: Tumor grow th inhibition by different treatments. FIG. 9B: images comparing tumor size at the experiment completion. FIG. 9C: comparison of tumor weights, FIG. 9D: intratumoral hemoglobin concentrations indicating tumor vascularization. FIG. 9E: DNMT1 activity’ measured using biochemical DNA methyltransferase assay (EpiQuik™). FIG. 9F: DNMT1 and yH2AX protein levels quantified by Western blotting. FIG. 9G: percentage of CDl lb+, HLA-DR+, CD70+, yH2AX expression on AML cells from different treatment groups as assessed using flow cytometry. Data are presented as mean±SEM; *P < 0.05, **P < 0.01, ***p < 0.001, ****p < 0.0001 by one-way ANOVA with Bonferroni’s post-test.

[0017] FIGS. 10A-10I: The different classes of CpG (A, Bl, C)-DNMTlapt conjugates lead to increased cy totoxicity' in human and mouse cancer cell lines in vitro. Human (SF-268, SF- 539, SNB-19, SF-295) or mouse (GL261) glioma cell lines and human epithelial cancers such as skin (A431), lung (A549), prostate (PC-3) or pancreatic (PANC-1) cancer cells were incubated for 48 h with three different classes of CpG-DNMT laptamers (CpG A-DNMTlapt, CpG Bl-DNMTlapt, CpG C-DNMTlapt), unconjugated DNMTlapt and CpG (A, Bl, C) ODNs at equimolar concentration (5pM). The viability of the cells was determined using the Cell Counting Kit-8 (CCK-8) assay (n=4). Shown are means±SEM; *P < 0.05, **P < 0.01, ***P < 0.001, ****p < 0.0001 by one-way ANOVA and Bonferroni’s post-hoc test.

[0018] FIGS. 11A-11F : CpG-DNMTl -aptamer conjugate shows cytotoxic, growth inhibitory and / or immunogenic effects on a variety of human MDS or AML cells. FIG. 11A: Reduced viability of MDS or AML cells after treatment with CpGB1-DNMTlapt compared to azacitidine as assessed using CCK-8 test. FIG. 11B: CpGB1-DNMTlapt but not azacitidine abrogates cell divisions in tested AML cells. FIG. 11C: The increased apoptotic cell death as verified using Annexin-V / Aqua dye staining and flow cytometry. FIGS. 11D-11E: CpGB1-DNMTlapt upregulates markers of immunogenic cell death such as extracellular ATP and surface calreticulin (CRT) (FIG. HD) as well as (FIG. HE) marker of antigen presentation marker (HLA-DR) in the treated MOLM-13 AML cells. FIG. HF: Inhibition of DNMT1 activity by CpGB1-DNMTlapt vs negative control CpGB1-R5mut conjugate (modified DNMT1 aptamer sequence with reduced activity) or azacitidine (benchmark). MOLM-13 cells were lysed after 6h treatment using the indicated oligonucleotides, DNMTlapt was immunoprecipitated from different samples using specific antibody and the activity was assessed using anti -5 -methyl cytosine antibody based ELISA-like assay.

[0019] FIGS. 12A-12C: CpGB1-DNMTlapt targets key compartments of human patient- derived AML blasts and eliminates leukemia stem cells. FIG. 12A: Compared to unformulated DNMTlapt, CpGB1-DNMTlapt conjugate shows improved internalization into all major compartments of AML; LPC - leukemia progenitor cells; LSC - leukemia stem cells. FIGS. 12B-12C: CpGB1-DNMTlapt alone (5 pM) or in combination with venetoclax, but not the negative control CpG-conjugate. reduces the percentage of LSC in four out of eight tested patients’ specimens. Both venetoclax and azacitidine alone failed to reduce AML-LSCs as assessed using flow cytometry7.

[0020] FIGS. 13A-13C: Intravenous administration of CpGB1-DNMTlapt inhibits progression of human AML xenotransplants in immunodeficient mice. Systemic administration of CpGB1- DNMTlapt (2.5 mg / kg / IV every other day) arrested progression of aggressive human M0LM14 AML (expressing luciferase) in immunodeficient mice. Progression of disseminated AML was monitored using whole body bioluminescent imaging (BLI), the representative images (FIG. 13A) and signal quantification (FIG. 13B). FIG. 13C: CpGB1-DNMTlapt alone, but not venetoclax alone or control oligonucleotides, extended animal survival («=5 / group).

[0021] FIGS. 14A-14H:. Intravenous administration of CpGB1-DNMTlapt results inregression of mouse AML in immunocompetent mice with the evidence of CD8 T cell activation and LSC elimination. FIG. 14A: Mice were engrafted with CMM (Cbjb / MYHl 1 M' pl) leukemia and treated after AML was established (1-5% of GFP+ / c-kit+ AML cell in blood). FIG. 14B: Systemic IV administration of oligonucleotides (2.8 mg / kg every other day) but not azacitidine (1 mg / kg) reduced circulating AML cells. FIG. 14C: CpGB1-DNMTlapt restores normal spleen size in treated mice; means±SD (7?=4-6 / group). FIGS. 14D-14E: Flow cytometric analysis demonstrated near complete elimination of AML / LSC (GFP+ / c-kit+) in spleens (FIG. 14D) and in bone marrow (FIG. 14E) of CpGB1-DNMTlapt treated mice. (F) CpGB1-DNMTlapt eliminates leukemia from the bone marrow while promoting infiltration by cytotoxic CD8+ and helper CD4+FoxP3- T-cells. FIG. 14G: CD8+ T-cell recruitment is associated with the pronounced effect of CpGB1-DNMTlapt on AML cell immunogenic cell death (CRT+) and differentiation to antigen-presenting phenotype (APC: MHC-II+ / CD86+). FIG. 14H: Bone marrow transplant performed after two-week treatment as described in Fig. 15A demonstrated lack of AML-LSCs in BM derived from CpGB1-DNMTlapt-treated donors.

[0022] FIGS. 15A-15B: CpGA-DNMTlapt inhibited tumor progression in the syngeneic GL261-luc glioblastoma C57BL / 6 model. CpGA-DNMTlapt alone (i.c., 0.25 mg / kg) and in combination with anti-PDl (i.p., 100 pg) improved surv ival of mice bearing intracranial GL261- luc glioma. Mice with established orthotopic gliomas were treated twice weekly over three weeks. FIG. 15A: GL261-luc glioma progression was monitored using bioluminescence imaging. FIG. 15B: Survival curves were obtained using Kaplan-Meier analysis (72=5—6 / group).

[0023] FIGS. 16A-16D: Lipid nanoparticle (LNP) encapsulated CpGB1-DNMTlapt oligonucleotide retains the cytotoxic and immunogenic activity on human AML cells. FIG. 16A: LNP formulated CpGB1-DNMTlapt conjugate alone (200 nM) and together with venetoclax (1 pM) shows the most potent cytotoxic effect on cultured human patient-derived AML blasts compared to LNP-formulated DNMTlapt or azacitidine (1 pM). Representative results (top row) and bar graphs (bottom) from the assessment of cell death using Annexin- V / Aqua staining and flow cytometry; means±SEM (n=4). FIG. 16B: LNP formulated CpGB1- DNMTlapt conjugate alone (200 nM) and together with venetoclax (IpM) is the most effective in the elimination of patient-derived AML-LSC (CD38-CD34+). Representative results (top row) and bar graphs (bottom) from the assessment of cell death using flow cytometry; means±SEM (n=4). FIG. 16C: LNP-formulated CpGB1-DNMTlapt combined with venetoclax reduces the percentage of human megakaryocytic CMK leukemia more effectively than LNP- DNMTlapt or azacitidine. Representative results (top row) and bar graphs (bottom) from flowcytometric analysis; means±SEM («=4). FIG. 16D: LNP-formulated CpGB1-DNMTlapt triggers expression of differentiation and immune activation markers such as MHC class II complexes (HLA-DR) on cultured CML cells. The LNP used in the experiments are described in Kang et al, Methods Mol Biol, 2691 :337-350 (2023), the disclosure of which is incorporated by reference herein in its entirety7. More particularly the lipid nanoparticle comprised dilinoleyl- methyl-4-dimethylaminobutyrate (MC3), hydrogenated soy phosphatidylcholine (HSPC), cholesterol, and l,2-dimyristoyl-rac-glycero-3-methoxy -poly ethylene glycol (DMG-PEG). wherein the polyethylene glycol has a molecular weight of about 2,000 Daltons in a molar ratio of 50: 10:38.5: 1.5.DETAILED DESCRIPTION

[0024] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. See, e.g., Singleton et al., Dictionary of Microbiology and Molecular Biology, 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., Molecular Cloning, A Laboratory7Manual, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this disclosure. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0025] The term “aptamer'’ as provided herein refers to oligonucleotides (e.g. short oligonucleotides or deoxyribonucleotides), that bind (e.g. with high affinity7and specificity) to proteins, peptides, and small molecules. Aptamers typically7have defined secondary or tertiary7structures owing to their propensity7to form complementary7base pairs and, thus, are often able to fold into diverse and intricate molecular structures. The three-dimensional structures are essential for aptamer binding affinity and specificity7, and specific three-dimensional interactions drive the formation of aptamer-target complexes. Aptamers can be selected in vitro from very large libraries of randomized sequences by the process of systemic evolution of ligands by exponential enrichment (SELEX as described in Ellington AD, Szostak JW (1990). In vitro selection of RNA molecules that bind specific ligands. Nature 346:818-822; Tuerk C, Gold L (1990) Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249:505-510) or by developing SOMAmers (slow off-rate modified aptamers) (Gold L et al. (2010) Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS ONE 5(12):el5004). Applying the SELEX and the SOMAmer technology includes for instance adding functional groups that mimic amino acid side chains to expand the aptamer's chemical diversity7. As a result, high affinity aptamers foralmost any protein target are enriched and identified. Aptamers exhibit many desirable properties for targeted drug delivery, such as ease of selection and synthesis, high binding affinity and specificity, flexible structure, low immunogenicity, and versatile synthetic accessibility. Exemplary aptamers are shown in Table A below .

[0026] Table A

[0027] Table Al: Chemical Modifications shown in Table A

[0028] The term “CpG oligodeoxynucleotide” or CpG ODN” refers to a 5’ C nucleotide connected to a 3 ' G nucleotide through a phosphodiester intemucleotide linkage or a phosphodiester derivative intemucleotide linkage. In embodiments, a CpG ODN includes a phosphodiester intemucleotide linkage. In embodiments, a CpG ODN includes a phosphodiesterderivative intemucleotide linkage. In embodiments, at least 20% of the internucleotide linkages in a CpG ODN are phosphodiester intemucleotide linkages or phosphodiester derivative intemucleotide linkages. In embodiments, at least 50% of the intemucleotide linkages in a CpG ODN are phosphodiester intemucleotide linkages or phosphodiester derivative intemucleotide linkages. In embodiments, at least 60% of the intemucleotide linkages in a CpG ODN are phosphodiester intemucleotide linkages or phosphodiester derivative intemucleotide linkages. In embodiments, at least 70% of the intemucleotide linkages in a CpG ODN are phosphodiester intemucleotide linkages or phosphodi ester derivative intemucleotide linkages. In embodiments, at least 80% of the intemucleotide linkages in a CpG ODN are phosphodiester intemucleotide linkages or phosphodi ester derivative intemucleotide linkages. In embodiments, at least 90% of the intemucleotide linkages in a CpG ODN are phosphodiester intemucleotide linkages or phosphodiester derivative intemucleotide linkages. In embodiments, 100% of the intemucleotide linkages in a CpG ODN are phosphodiester intemucleotide linkages or phosphodiester derivative intemucleotide linkages.

[0029] The term “Class A CpG ODN” or “A-class CpG ODN'’ or “D-type CpG ODN” or “Class A CpG DNA sequence” refers to a CpG motif including oligodeoxynucleotide including one or more of poly-G sequence at the 5’, 3’, or both ends; an internal palindrome sequence including CpG motif; or one or more phosphodiester derivatives linking deoxynucleotides. In embodiments, a Class A CpG ODN includes poly-G sequence at the 5', 3’, or both ends; an internal palindrome sequence including CpG motif; and one or more phosphodiester derivatives linking deoxynucleotides. In embodiments, the phosphodiester derivative is phosphorothioate Examples of Class A CpG ODNs include ODN D19, ODN 1585, ODN 2216, and ODN 2336, the sequences of which are known in the art.

[0030] The term “Class B CpG ODN” or “B-class CpG ODN” or “K-type CpG ODN” or “Class B CpG DNA sequence” refers to a CpG motif including oligodeoxynucleotide including one or more of a 6mer motif including a CpG motif; phosphodiester derivatives linking all deoxynucleotides. In embodiments, a Class B CpG ODN includes one or more copies of a 6mer motif including a CpG motif and phosphodiester derivatives linking all deoxynucleotides. In embodiments, the phosphodiester derivative is phosphorothioate. In embodiments, a Class B CpG ODN includes one 6mer motif including a CpG motif. In embodiments, a Class B CpG ODN includes two copies of a 6mer motif including a CpG motif. In embodiments, a Class B CpG ODN includes three copies of a 6mer motif including a CpG motif. In embodiments, a Class B CpG ODN includes four copies of a 6mer motif including a CpG motif. Examples of Class B CpG ODNs include ODN 1668, ODN 1826, ODN 2006, ODN 2007, ODN BW006, andODN D-SL01, the sequences of which are known in the art.

[0031] The term “Class C CpG ODN” or “C-class CpG ODN” “ or “C-type CpG DNA sequence” refers to an oligodeoxynucleotide including a palindrome sequence including a CpG motif and phosphodi ester derivatives (phosphorothioate) linking all deoxynucleotides. Examples of Class C CpG ODNs include ODN 2395, ODN M362, and ODN D-SL03, the sequences of which are known in the art.

[0032] Exemplary CpG ODN for use in the compounds and methods described herein are set forth in Table B below.

[0033] Table B

[0034] In Table A, underline refers to a phosphorothioated nucleotide (phosphorothioated intemucleotide linkage).

[0035] The term “linked” or “conjugated” when referring to two moieties (e.g., a phosphorothioated CpG ODN linked to a DNA oligonucleotide) means the two moieties arebonded, wherein the bond or bonds connecting the two moieties are covalent or non-covalent. In embodiments, the two moieties are covalently bonded to each other (e.g. directly or through a linking group). Exemplary linking groups include a covalent bond, a nucleic acid sequence (i.e., an RNA sequence or a DNA sequence), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or combinations of two or more thereof.

[0036] The term “BCL-2” or “B-cell lymphoma 2” as referred to herein includes any of the recombinant or naturally-occurring forms of B-cell lymphoma 2 (BCL-2) or variants or homologs thereof that maintain BCL-2 protein activity (e.g. within at least 50%, 80%, 90%, 95%. 96%. 97%. 98%. 99% or 100% activity compared to BCL-2 protein). In embodiments, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity’ across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring BCL-2 protein. In embodiments, the BCL-2 protein is substantially identical to the protein identified by the UniProt reference number Q92934 or a variant or homolog having substantial identity thereto. In embodiments, the BCL-2 protein is substantially identical to the protein identified by the UniProt reference number Q07817 or a variant or homolog having substantial identity thereto. In embodiments, the BCL-2 protein is substantially identical to the protein identified by the UniProt reference number A0A0S2Z3D2 or a variant or homolog having substantial identity thereto. In embodiments, the BCL-2 protein is substantially identical to the protein identified by the UniProt reference number Pl 0415 or a variant or homolog having substantial identity thereto.

[0037] The term “BCL-2 inhibitor’ or “B-cell lymphoma 2 inhibitor” refers to a compound that inhibits BCL-2. Exemplary BCL-2 inhibitors include oblimersen, navitoclax, venetoclax, obatoclax, sonrotoclax, lisaftoclax, ABT-737 (CAS No. 852808-04-9), S55746 (CAS No. 1448584-12-0), TW-37 (CAS No. 877877-35-5), gossypol, and the like. The skilled artisan will recognize that the BCL-2 inhibitors can optionally be in the form of a pharmaceutically acceptable salt.

[0038] The term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a proteininhibitor interaction means negatively affecting (e.g. decreasing) the activity’ or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In aspects inhibition means negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In aspectsinhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).

[0039] The terms "inhibitor." ‘‘repressor” or “antagonist” or "down regulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In embodiments, expression or activity is low er than the expression or activity in the absence of the antagonist.

[0040] “Nucleic acid” refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof; or nucleosides (e.g., deoxyribonucleosides or ribonucleosides). In embodiments, “nucleic acid” does not include nucleosides. The terms “polynucleotide,” “oligonucleotide,” “oligo” or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term “nucleoside” refers, in the usual and customary sense, to a glycosylamine including a nucleobase and a five-carbon sugar (ribose or deoxyribose). Non limiting examples, of nucleosides include, cytidine, uridine, adenosine, guanosine, thymidine and inosine. The term “nucleotide” refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e.. a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof. Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA. Examples of nucleic acid, e.g. polynucleotides, contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof. The term “duplex” in the context of polynucleotides refers, in the usual and customary7sense, to double strandedness. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides. Optionally, the branched nucleic acidsare repetitively branched to form higher ordered structures such as dendrimers and the like.

[0041] Nucleic acids, including e.g.. nucleic acids with a phosphorothioate backbone, can include one or more reactive moieties. As used herein, the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions. By way of example, the nucleic acid can include an amino acid reactive moiety that reacts with an amio acid on a protein or polypeptide through a covalent, non-covalent or other interaction.

[0042] The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non- naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphodiester derivatives including, e.g., phosphorami date, phosphorodiamidate, phosphorothioate (also known as phosphorothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, Oligonucleotides and Analogues: A Practical Approach, Oxford University Press) as well as modifications to the nucleotide bases such as, 2’0-methyl, 5 ’fluoro, 2 ’-deoxy-2' fluoro, 2’-deoxy, a universal base nucleotide, a 5-C methyl nucleotide, an inverted deoxybasic residue incorporation, 5-methyl cytidine, or pseudouridine: and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones: non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art). Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In embodiments, the intemucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.

[0043] “Unmodified nucleotide” refers to a nucleotide that is not modified from its natural state. An unmodified nucleotide does not contain any modifications to the base, does not contain any modifications to the sugar, and does not contain any modifications to the phosphate. In embodiments of the methods described herein, the DNA oligonucleotide only comprisesunmodified nucleotides.

[0044] “Modified nucleotide" refers to a nucleotide that is modified from its natural state. The modification to the nucleotide can be to the base, the sugar, the phosphate, or two or more thereof. Nucleotides can be modified, for example, to include 2’-O-aminopropyl group, a 2’-O- ethyl group, a 2’-fluoro group, a 2’-O-methyl group, 2’-deoxy-2’fluoro group, a 2’-O- methoxyethyl group, a 2’-O-allyl group. a 2’-O-propyl group, a 2’-O-pentyl group, or a constrained nucleotide.

[0045] A “spacer modification” refers to a moiety that does not include a nucleobase. Exemplary spacer modifications include an abasic spacer, a spacer phosphoramidite, abasic phosphoramidite, hexadecane phosphoramidite, octadecane phosphoramidite, a C6 disulfide phosphoramidite, and the like. In embodiments, the spacer phosphoramidite is a C3 spacer phosphoramidite, a C6 spacer phosphoramidite, or a C12 spacer phosphoramidite.

[0046] A “C3 spacer phosphoramidite” is a spacer modification represented by the structure:

[0047] “Abasic spacer” or “dspacer” is a r.2’-dideoxyribose without a nucleobase attached.

[0048] A polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (uracil (U) for thymine (T) when the polynucleotide is RNA). Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology7searching. Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and / or modified nucleotides.

[0049] “Conservatively modified variants” applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, “conservatively modified variants” refers to those nucleic acids that encode identical or essentially identical amino acid sequences. Because of the degeneracy of the genetic code, a number of nucleic acid sequences will encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are “silent variations,” which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide alsodescribes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence.

[0050] The term “complement,” as used herein, refers to a nucleotide (e.g.. RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanosine is cytosine. Thus, a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence. The nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. Where the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence. Examples of complementary' sequences include coding and anon-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. A further example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence. The complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other, may have a specified percentage of nucleotides that are the same (i.e., about 60% identity', preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity' over a specified region).

[0051] The term “gene” means the segment of DNA involved in producing a protein; it includes regions preceding and follow ing the coding region (leader and trailer) as well as intervening sequences (introns) betw een individual coding segments (exons). The leader, the trailer as well as the introns include regulatory elements that are necessary during the transcription and the translation of a gene. Further, a “protein gene product” is a protein expressed from a particular gene.

[0052] The word “expression’" or “expressed’" as used herein in reference to a gene means the transcriptional and / or translational product of that gene. The level of expression of a DNA molecule in a cell may be determined on the basis of either the amount of corresponding mRNA that is present within the cell or the amount of protein encoded by that DNA produced by the cell. The level of expression of non-coding nucleic acid molecules (e.g., siRNA) may be detected by standard PCR or Northern blot methods well known in the art.

[0053] The phrase “specifically (or selectively) binds” to an antibody or “specifically (or selectively) immunoreactive with,” when referring to a protein or peptide, refers to a binding reaction that is determinative of the presence of the protein, often in a heterogeneous population of proteins and other biologies. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein at least two times the background and more typically more than 10 to 100 times background. Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies can be selected to obtain only a subset of antibodies that are specifically immunoreactive with the selected antigen and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein.

[0054] The terms “isolate” or “isolated” when applied to a nucleic acid, virus, or protein, denotes that the nucleic acid, virus, or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0055] “Percentage of sequence identity ” is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield thepercentage of sequence identity.

[0056] The terms "identical’7or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity’ over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms or by manual alignment and visual inspection (e.g., ncbi.nlm.nih.gov / BLAST / or the like). Such sequences are then said to be “substantially identical.” This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.

[0057] The term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about means a range extending to + / - 5% of the specified value. In embodiments, about means a range extending to + / - 1 of the specified value. In embodiments, about includes the specified value.

[0058] “Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In embodiments, the control is used as a standard of comparison in evaluating experimental effects. In embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples). One of skill in the art will understand which standard controls are most appropriate in a given situation and be able to analyze data based on comparisons to standard control values. Standard controls are also valuable for determining the significance (e.g. statistical significance) of data. For example, if values for a given parameter are widely variant in standard controls, variation in test samples will not be considered as significant.

[0059] Where substituent groups are specified by their conventional chemical formulae,written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g.. -CH2O- is equivalent to -OCH2-.

[0060] The term '‘alkyl,’’ by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched non-cyclic carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl. n-octyl. and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl. 2-propenyl, crotyl. 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyL 3-(l,4-pentadienyl), ethynyl, 3-propynyl, 3- butynyl, and higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).

[0061] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene.” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0062] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable non-cyclic straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -(CH2)2-O-CH3, -(CH2)2-NH-CH3, -(CH2)3-OH, -CH2-NH2, -CH2-NO2, -(CH2)2-N(CH3)-CH3, -S(O)-CH3,-CH2-S-CH2-CH3, -(CH2)2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH-N-OCH ,. -O-CH3, -CH=CH-N(CH3)-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CEl2-NH-OCH3and -CH2-O-SI(CH3)3.

[0063] The term “heteroalkylene,” by itself or as part of another substituent, means, unlessotherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2-, -O-CH2-CH2-NH-CH2-, -O-(CH2)3-O-PO3-, -O-(CH2)-O-PO3-, -O-(CH2)2-O-PO3-, -O-(CH2)4-O-PO3-, and the like. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alky lene and heteroalkyd ene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(0)2R'- and -R'C(0)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R", -OR', -SR', and / or -SO2R'. Where ‘‘heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity7. Thus, the term “heteroalkyl” should not be interpreted as excluding specific heteroalkyl groups, such as -NR'R" or the like.

[0064] The terms “cycloalkyd” and “heterocycloalkyl.” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic non-aromatic versions of “alkyl” and “heteroalkyl,” respectively, wherein the carbons making up the ring or rings do not necessarily need to be bonded to a hydrogen due to all carbon valencies participating in bonds with nonhydrogen atoms. Additionally, for heterocycloalkyd, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyd include, but are not limited to, l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,4-morpholinyl. 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkydene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyd and heterocycloalkyd, respectively.

[0065] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(Ci-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyd, 3-bromopropyl, and the like.

[0066] Tlie term “acyl” means, unless otherwise stated. -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0067] The term '‘aryl’’ means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently (e.g., biphenyl). A fused ring ary l refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to and groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. Thus, the term “heteroaryl” includes fused ring heteroar l groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6.5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroary 1 ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of ary l and heteroary l groups include pheny l,1 -naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl. 4-imidazolyl, pyrazinyl, 2-oxazolyL 4-oxazolyl. 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2 -fury 1, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl,2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinoly 1. and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Non-limiting examples of heteroary l groups include pyridinyl, pyrimidinyl. thiophenyl, thienyl, furanyl, indolyl. benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl, pyrrolopyridinyl, indazolyL quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl. oxadiazolyl. pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyL pyrrolopyrimidinyl,benzotriazolyl, benzoxazolyl, or quinolyl. The examples above may be substituted or unsubstituted and divalent radicals of each heteroaryl example above are non-limiting examples of heteroarylene.

[0068] A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring helerocycloalkyl-aryl. fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein.

[0069] The term “oxo” means an oxygen that is double bonded to a carbon atom.

[0070] The term “alkylsulfonyl,” as used herein, means a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' may have a specified number of carbons (e.g., “C1-C4 alkylsulfonyl”).

[0071] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0072] Substituents for the alkyl and heteroalky l radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =0, =NR', =N-0R', -NR'R", -SR', -halogen, -SiR'R' R'", -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(0)NR"R", -NR"C(O)2R', -NR-C(NR'R"R'")=NR"", -NR-C(NR'R")=NR"', -S(O)R'. -S(O)2R'. -S(O)2NR'R", -NRSO2R', -NR'NR"R'", -ONR'R", -NR'C=(O)NR"NR"'R"", -CN, -NO2, in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R, R', R", R'", and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroary 1, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", and R"" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-. 5-. 6-, or 7- membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0073] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R", -SR', -halogen, -SiR'R' R'". -OC(O)R'. -C(O)R', -CO2R'. -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R", -NR"C(O)2R', -NR-C(NR'R"R'")=NR"", -NR-C(NR'R")=NR"', -S(O)R’, -S(O)2R’, -S(O)2NR’R", -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C=(O)NR"NR"’R"", -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(C i-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R"', and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", and R"" groups when more than one of these groups is present.

[0074] Two or more substituents may optionally be joined to form ary l, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In embodiments, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ringforming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In embodiments, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In embodiments, the ring-forming substituents are attached to non- adjacent members of the base structure.

[0075] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-. wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the ary l or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the ary l or heteroaryl ring mayoptionally be replaced with a substituent of the formula -(CRR')s-X'-(C"R"R"')d-, where s and d are independently integers of from 0 to 3, and X' is -O-. -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R", and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaiyl.

[0076] As used herein, the terms “heteroatom” or “ring heteroatom" are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0077] A “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2C1. -SO3H. -SO4H. -SO2NH2, -NHNH2, -ONH2. -NHC=(O)NHNH2, -NHC=(O) NH2, -NHSO2H, -NHC= (O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, -NHSO2CH3, -N3, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: (i) oxo. halogen, -CF3, -CN, -OH, -NH2, -COOH, -NO2,-CONH2, -SH, -SO2CI, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O) NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCHF2, -N3, -NHSO2CH3, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted ary l, unsubstituted heteroaryl, and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: (a) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CI, -SO3H, -SO4H, -SO2NH2, -N3, -NHNH2. -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -OCHF2, -NHC(O)-OH, -NHOH, -OCF3, -NHSO2CH3. unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2. -NO2, -SH, -SO2CI, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -OCF3, -OCHF2, -NHC(O)-OH, -NHOH, -N3, -NHSO2CH3, unsubstituted alkyd, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0078] In embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0079] In aspects of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In aspects of the compounds herein, each substituted or unsubstituted alky lene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted Ce-Cio arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0080] In embodiments, each substituted or unsubstituted alkyd is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalky 1, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio ary l, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-Cs alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkydene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted Ce-Cio arylene, and / or each substituted orunsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In embodiments, the compound is a chemical species set forth in the Examples section below.

[0081] Compounds

[0082] Provided herein are compounds comprising a phosphorothioated CpG oligodeoxynucleotide (ODN) linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer.

[0083] In embodiments, the RNA aptamer binds to an intracellular target. In embodiments, the intracellular target is DNMT1, NF-kB, RUNX1, MYC, MYB, ETS, PAX5, MDM2, F0XM1, PU. 1, STAT3, STAT5, STAT6, FAD, ATP5B, or beta-catenin. In embodiments, the RNA aptamer binds to DNMT (DNA(cytosine-5)-methyltransferase). In embodiments, the RNA aptamer binds to DNMT1 (DNA(cytosine-5)-methyltransferase 1). In embodiments, the RNA aptamer binds to NF-kB. In embodiments, the RNA aptamer binds to RUNX1. In embodiments, the RNA aptamer binds to MYC. In embodiments, the RNA aptamer binds to MYB. In embodiments, the RNA aptamer binds to ETS. In embodiments, the RNA aptamer binds to PAX5. In embodiments, the RNA aptamer binds to MDM2. In embodiments, the RNA aptamer binds to F0XM1. In embodiments, the RNA aptamer binds to PU. l. In embodiments, the RNA aptamer binds to STAT3. In embodiments, the RNA aptamer binds to STAT5. In embodiments, the RNA aptamer binds to STAT6. In embodiments, the RNA aptamer binds to FAD. In embodiments, the RNA aptamer binds to ATP5B. In embodiments, the RNA aptamer binds to beta-catenin.

[0084] In embodiments, the RNA aptamer that binds to DNMT1 has SEQ ID NO: 1. In embodiments, the RNA aptamer has at least 80% sequence identity to SEQ ID NO: 1. In embodiments, the RNA aptamer has at least 85% sequence identity to SEQ ID NO: 1. In embodiments, the RNA aptamer has at least 90% sequence identity to SEQ ID NO: 1. In embodiments, the RNA aptamer has at least 95% sequence identity to SEQ ID NO: 1 . In embodiments, the RNA aptamer has at least 96% sequence identity to SEQ ID NO: 1. In embodiments, the RNA aptamer has at least 97% sequence identity to SEQ ID NO: 1. In embodiments, the RNA aptamer has at least 98% sequence identity to SEQ ID NO: 1. In embodiments, the RNA aptamer has at least 99% sequence identity to SEQ ID NO: 1 . In embodiments, the RNA aptamer has SEQ ID NO: 1.

[0085] In embodiments, the RNA aptamer has at least 80% sequence identity to SEQ ID NO:2. In embodiments, the RNA aptamer has at least 85% sequence identity to SEQ ID NO:2. In embodiments, the RNA aptamer has at least 90% sequence identity to SEQ ID NO:2. In embodiments, the RNA aptamer has at least 95% sequence identity to SEQ ID NO: 2. Inembodiments, the RNA aptamer has at least 96% sequence identity to SEQ ID NO:2. In embodiments, the RNA aptamer has at least 97% sequence identity to SEQ ID NO:2. In embodiments, the RNA aptamer has at least 98% sequence identity to SEQ ID NO: 2. In embodiments, the RNA aptamer has at least 99% sequence identity to SEQ ID NO: 2. In embodiments, the RNA aptamer has SEQ ID NO: 2.

[0086] In embodiments, the RNA aptamer that binds to DNMT1 has SEQ ID NO: 33. In embodiments, the RNA aptamer has at least 80% sequence identity to SEQ ID NO: 33. In embodiments, the RNA aptamer has at least 85% sequence identity to SEQ ID NO: 33. In embodiments, the RNA aptamer has at least 90% sequence identity to SEQ ID NO: 33. In embodiments, the RNA aptamer has at least 95% sequence identity to SEQ ID NO: 33. In embodiments, the RNA aptamer has at least 96% sequence identity to SEQ ID NO: 33. In embodiments, the RNA aptamer has at least 97% sequence identity to SEQ ID NO: 33. In embodiments, the RNA aptamer has at least 98% sequence identity to SEQ ID NO: 33. In embodiments, the RNA aptamer has at least 99% sequence identity to SEQ ID NO: 33. In embodiments, the RNA aptamer has SEQ ID NO:33.

[0087] In embodiments, the RNA aptamer that binds to DNMT1 has SEQ ID NO:34. In embodiments, the RNA aptamer has at least 80% sequence identity to SEQ ID NO: 34. In embodiments, the RNA aptamer has at least 85% sequence identity to SEQ ID NO: 34. In embodiments, the RNA aptamer has at least 90% sequence identity to SEQ ID NO: 34. In embodiments, the RNA aptamer has at least 95% sequence identity to SEQ ID NO: 34. In embodiments, the RNA aptamer has at least 96% sequence identity to SEQ ID NO: 34. In embodiments, the RNA aptamer has at least 97% sequence identity to SEQ ID NO: 34. In embodiments, the RNA aptamer has at least 98% sequence identity to SEQ ID NO: 34. In embodiments, the RNA aptamer has at least 99% sequence identity to SEQ ID NO: 34. In embodiments, the RNA aptamer has SEQ ID NO: 34.

[0088] In embodiments, the RNA aptamer binds to MDM2, beta-catenin, FAD, ATP5B, or nucleolin.

[0089] In embodiments, the RNA aptamer binds to MDM2. In embodiments, the RNA aptamer has at least 80% sequence identity to SEQ ID NO:26. In embodiments, the RNA aptamer has at least 85% sequence identity to SEQ ID NO:26. In embodiments, the RNA aptamer has at least 90% sequence identity to SEQ ID NO:26. In embodiments, the RNA aptamer has at least 95% sequence identity to SEQ ID NO:26. In embodiments, the RNA aptamer has at least 96% sequence identity to SEQ ID NO:26. In embodiments, the RNA aptamer has at least 97% sequence identity to SEQ ID NO:26. In embodiments, the RNAaptamer has at least 98% sequence identity to SEQ ID NO:26. In embodiments, the RNA aptamer has at least 99% sequence identity to SEQ ID NO:26. In embodiments, the RNA aptamer has SEQ ID NO: 26.

[0090] In embodiments, the RNA aptamer binds to beta-catenin. In embodiments, the RNA aptamer has at least 80% sequence identity' to SEQ ID NO:27. In embodiments, the RNA aptamer has at least 85% sequence identity’ to SEQ ID NO:27. In embodiments, the RNA aptamer has at least 90% sequence identity to SEQ ID NO:27. In embodiments, the RNA aptamer has at least 95% sequence identity to SEQ ID NO:27. In embodiments, the RNA aptamer has at least 96% sequence identity' to SEQ ID NO:27. In embodiments, the RNA aptamer has at least 97% sequence identity' to SEQ ID NO:27. In embodiments, the RNA aptamer has at least 98% sequence identity to SEQ ID NO:27. In embodiments, the RNA aptamer has at least 99% sequence identity to SEQ ID NO:27. In embodiments, the RNA aptamer has SEQ ID NO: 27.

[0091] In embodiments, the RNA aptamer binds to nucleolin. In embodiments, the RNA aptamer has at least 80% sequence identity to SEQ ID NO:28. In embodiments, the RNA aptamer has at least 85% sequence identity to SEQ ID NO:28. In embodiments, the RNA aptamer has at least 90% sequence identity to SEQ ID NO:28. In embodiments, the RNA aptamer has at least 95% sequence identity' to SEQ ID NO:28. In embodiments, the RNA aptamer has at least 96% sequence identity’ to SEQ ID NO:28. In embodiments, the RNA aptamer has at least 97% sequence identity to SEQ ID NO:28. In embodiments, the RNA aptamer has at least 98% sequence identity to SEQ ID NO:28. In embodiments, the RNA aptamer has at least 99% sequence identity' to SEQ ID NO:28. In embodiments, the RNA aptamer has SEQ ID NO: 28.

[0092] In embodiments, the RNA aptamer binds to FAD. In embodiments, the RNA aptamer has at least 80% sequence identity to SEQ ID NO: 29. In embodiments, the RNA aptamer has at least 85% sequence identity to SEQ ID NO:29. In embodiments, the RNA aptamer has at least 90% sequence identity to SEQ ID NO:29. In embodiments, the RNA aptamer has at least 95% sequence identity to SEQ ID NO:29. In embodiments, the RNA aptamer has at least 96% sequence identity to SEQ ID NO:29. In embodiments, the RNA aptamer has at least 97% sequence identity to SEQ ID NO:29. In embodiments, the RNA aptamer has at least 98% sequence identity to SEQ ID NO:29. In embodiments, the RNA aptamer has at least 99% sequence identity to SEQ ID NO:29. In embodiments, the RNA aptamer has SEQ ID NO:29.

[0093] In embodiments, the RNA aptamer binds to ATP5B. In embodiments, the RNA aptamer has at least 80% sequence identity to SEQ ID NO:30. In embodiments, the RNAaptamer has at least 85% sequence identity to SEQ ID NO:30. In embodiments, the RNA aptamer has at least 90% sequence identity to SEQ ID NO:30. In embodiments, the RNA aptamer has at least 95% sequence identity to SEQ ID NO:30. In embodiments, the RNA aptamer has at least 96% sequence identity to SEQ ID NO:30. In embodiments, the RNA aptamer has at least 97% sequence identity' to SEQ ID NO:30. In embodiments, the RNA aptamer has at least 98% sequence identity’ to SEQ ID NO:30. In embodiments, the RNA aptamer has at least 99% sequence identity to SEQ ID NO:30. In embodiments, the RNA aptamer has SEQ ID NO: 30.

[0094] In embodiments, the DNA oligonucleotide is any DNA oligonucleotide that has a nucleic acid sequence that is capable of hybridizing to the RNA aptamer.

[0095] In embodiments, the DNA oligonucleotide comprises unmodified nucleotides. In embodiments, the DNA oligonucleotide comprises unmodified nucleotides that only contain phosphodiester bonds. In embodiments, the DNA oligonucleotide comprises unmodified nucleotides and does not comprise any modified nucleotides. In embodiments, the DNA oligonucleotide does not contain any nucleotides having a modified base, does not contain any nucleotides having a modified sugar, and does not contain any nucleotides having a modified phosphate. In embodiments, the DNA oligonucleotide: (i) does not contain any nucleotides having a modified phosphate, and (ii) contains a nucleotide having a modified base and / or a modified sugar. In embodiments, the DNA oligonucleotide: (i) does not contain any nucleotides having a modified phosphate, (ii) does not contain any nucleotides having a modified base, and (iii) contains a nucleotide having a modified sugar. In embodiments, the DNA oligonucleotide: (i) does not contain any nucleotides having a modified phosphate, (ii) contains a nucleotide having a modified base, and (iii) does not contain any nucleotides having a modified sugar. In embodiments, the DNA oligonucleotide: (i) does not contain any nucleotides having a modified phosphate, (ii) contains a nucleotide having a modified base, and (iii) contains a nucleotide having a modified sugar. As defined herein, “a” refers to one or more.

[0096] In embodiments, the DNA oligonucleotide hybridized to the RNA aptamer comprises a nucleic acid overhang. In embodiments, the DNA oligonucleotide contains the same number of nucleotides as the RNA aptamer + / - 20 nucleotides. In embodiments, the DNA oligonucleotide contains the same number of nucleotides as the RNA aptamer + / - 10 nucleotides. In embodiments, the DNA oligonucleotide contains the same number of nucleotides as the RNA aptamer + / - 5 nucleotides. In embodiments, the DNA oligonucleotide contains the same number of nucleotides as the RNA aptamer + / - 4 nucleotides. In embodiments, the DNA oligonucleotide contains the same number of nucleotides as the RNA aptamer + / - 3 nucleotides. Inembodiments, the DNA oligonucleotide contains the same number of nucleotides as the RNA aptamer + / - 2 nucleotides. In embodiments, the DNA oligonucleotide contains the same number of nucleotides as the RNA aptamer + / - 1 nucleotides. In embodiments, the DNA oligonucleotide contains the same number of nucleotides as the RNA aptamer + / - about 1 nucleotide to about 10 nucleotides. In embodiments, the DNA oligonucleotide contains the same number of nucleotides as the RNA aptamer + / - about 1 nucleotide to about 5 nucleotides. In embodiments, the DNA oligonucleotide contains the same number of nucleotides as the RNA aptamer.

[0097] In embodiments, the DNA oligonucleotide that is hybridized to an RNA aptamer is a DNA oligonucleotide having 80% sequence identity to 100% sequence identity' to SEQ ID NO:24. In embodiments, the DNA oligonucleotide has 80% sequence identity' to 100% sequence identity to SEQ ID NO: 24 and is hybridized to an RNA aptamer having from 80% sequence identity' to 100% sequence identity' to SEQ ID NO: 1. In embodiments, the DNA oligonucleotide has 85% sequence identity to 100% sequence identity' to SEQ ID NO:24 and is hybridized to an RNA aptamer having from 85% sequence identity to 100% sequence identity to SEQ ID NO: 1. In embodiments, the DNA oligonucleotide has 90% sequence identity’ to 100% sequence identity’ to SEQ ID NO:24 and is hybridized to an RNA aptamer having from 90% sequence identity to 100% sequence identity to SEQ ID NO: 1. In embodiments, the DNA oligonucleotide has 95% sequence identity to 100% sequence identity to SEQ ID NO:24 and is hybridized to an RNA aptamer having from 95% sequence identity to 100% sequence identity to SEQ ID NO: 1. In embodiments, the DNA oligonucleotide has 96% sequence identity to 100% sequence identity to SEQ ID NO:24 and is hybridized to an RNA aptamer having from 96% sequence identity to 100% sequence identity to SEQ ID NO: 1. In embodiments, the DNA oligonucleotide has 97% sequence identity to 100% sequence identity to SEQ ID NO:24 and is hybridized to an RNA aptamer having from 97% sequence identity to 100% sequence identity to SEQ ID NO: 1. In embodiments, the DNA oligonucleotide has 98% sequence identity to 100% sequence identity to SEQ ID NO:24 and is hybridized to an RNA aptamer having from 98% sequence identity to 100% sequence identity to SEQ ID NO: 1. In embodiments, the DNA oligonucleotide has 99% sequence identity to 100% sequence identity to SEQ ID NO:24 and is hybridized to an RNA aptamer having from 99% sequence identity to 100% sequence identity to SEQ ID NO: 1. In embodiments, the DNA oligonucleotide has SEQ ID NO:24 and is hybridized to an RNA aptamer having SEQ ID NO: 1. In embodiments, SEQ ID NO: 1 further comprises a detectable label. In embodiments. SEQ ID NO: 1 further comprises a detectable label and is represented by SEQ ID NO:2.

[0098] In embodiments, the DNA oligonucleotide has at least 80% sequence identity to SEQID NO:24. In embodiments, the DNA oligonucleotide has at least 85% sequence identity to SEQ ID NO:24. In embodiments, the DNA oligonucleotide has at least 90% sequence identity to SEQ ID NO:24. In embodiments, the DNA oligonucleotide has at least 95% sequence identity to SEQ ID NO:24. In embodiments, the DNA oligonucleotide has at least 96% sequence identity to SEQ ID NO:24. In embodiments, the DNA oligonucleotide has at least 97% sequence identity to SEQ ID NO:24. In embodiments, the DNA oligonucleotide has at least 98% sequence identity to SEQ ID NO:24. In embodiments, the DNA oligonucleotide has at least 99% sequence identity to SEQ ID NO:24. In embodiments, the DNA oligonucleotide has SEQ ID NO:24.

[0099] In embodiments, the DNA oligonucleotide further comprises a nucleotide having a modification. In embodiments, the DNA oligonucleotide further comprises a nucleotide having a modification to the base or sugar. In embodiments, the DNA oligonucleotide comprises a nucleotide having a modification selected from the group consisting of 2’-O-aminopropyl group, a 2’-O-ethyl group, a 2’-fluoro group, a 2’-O-methyl group, 2 ’-deoxy -2 ’fluoro group, a 2’-O- methoxyethyl group, a 2’-O-allyl group, a 2’-O-propyl group, a 2’-O-pentyl group, and a constrained nucleotide. In embodiments, the DNA oligonucleotide further comprises a nucleotide having a 2’0-methyl group. In embodiments, the DNA oligonucleotide further comprises a nucleotide having a 2’ fluoro group. In embodiments, the DNA oligonucleotide further comprises a nucleotide having a 2 ’-deoxy -2 'fluoro group.

[0100] In embodiments, the DNA oligonucleotide further comprises a spacer modification. In embodiments, the spacer modification is an abasic spacer, a spacer phosphoramidite. abasic phosphoramidite, hexadecane phosphoramidite, octadecane phosphoramidite, a C6 disulfide phosphoramidite, or a combination of two or more thereof. In embodiments, the spacer phosphoramidite is a C3 spacer phosphoramidite, a C6 spacer phosphoramidite, or a C 12 spacer phosphoramidite. In embodiments, the DNA oligonucleotide further comprises an abasic spacer modification. In embodiments, the DNA oligonucleotide further comprises a C3 spacer phosphoramidite.

[0101] The compounds described herein comprise a phosphorothioated CpG oligodeoxynucleotide (ODN). In embodiments, the CpG ODN is a CpG-A ODN, a CpG-B ODN, a CpG-C ODN, or a combination of two or more thereof. In embodiments, the CpG ODN is a CpG-A ODN. In embodiments, the CpG ODN is a CpG-B ODN. In embodiments, the CpG ODN is a CpG-C ODN. In embodiments, the CpG ODN is CpG ODN 1585, CpG ODN 2216, CpG ODN 2336, CpG ODN 1668, CpG ODN 1826, CpG ODN 2006, CpG ODN 2007, CpG ODN BW006, CpG ODN D-SL01, CpG ODN 2395, CpG ODN M362. CpG ODN D-SL03. CpG ODN DI 9, or a combination of two or more thereof. In embodiments, the CpG ODN isCpG ODN 1585. In embodiments, the CpG ODN is CpG ODN 2216. In embodiments, the CpG ODN is CpG ODN 2336. In embodiments, the CpG ODN is CpG ODN 1668. In embodiments, the CpG ODN is CpG ODN 1826. In embodiments, the CpG ODN is CpG ODN 2006. In embodiments, the CpG ODN is CpG ODN 2007. In embodiments, the CpG ODN is CpG ODN BW006. In embodiments, the CpG ODN is CpG ODN D-SL01. In embodiments, the CpG ODN is CpG ODN 2395. In embodiments, the CpG ODN is CpG ODN CpG ODN M362. In embodiments, the CpG ODN is CpG ODN D-SL03. In embodiments, the CpG ODN is CpG ODN DI 9.

[0102] In embodiments, the phosphorothioated CpG ODN comprises a nucleic acid having at least 80% sequence identity to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7. SEQ ID NO: 8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11. SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO:21, SEQ ID NO: 22, or SEQ ID NO: 23. In embodiments, the phosphorothioated CpG ODN comprises a nucleic acid having at least 85% sequence identity to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO:14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises a nucleic acid having at least 90% sequence identity to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises a nucleic acid having at least 95% sequence identity to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO:11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18. SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21. SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises a nucleic acid having at least 96% sequence identity to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO:11, SEQ ID NO: 12, SEQ ID NO: 13. SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO 16, SEQ ID NO: 17, SEQ ID NO: 18. SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21. SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises a nucleic acid having at least 97%sequence identity to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID N0:9, SEQ ID NO: 10. SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO:15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises a nucleic acid having at least 98% sequence identity to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10. SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises a nucleic acid having at least 99% sequence identity to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23.

[0103] In embodiments, the phosphorothioated CpG oligodeoxynucleotide (ODN) comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 3. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:4. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:5. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 6. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:7. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:8. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:9. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 10. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 11. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 12. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 13. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 14. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 15. In embodiments, the phosphorothioated CpG ODN compnses SEQ ID NO: 16. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 17. In embodiments, thephosphorothioated CpG ODN comprises SEQ ID NO: 18. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 19. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:20. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:21. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:22. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:23.

[0104] The phosphorothioated CpG ODN is linked to the DNA oligonucleotide by any linking group known in the art. In embodiments, the linking group comprises a bond, a nucleic acid sequence, a DNA sequence, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or a combination of two or more thereof. In embodiments, the linking group comprises a bond, a nucleic acid sequence, unsubstituted alkylene, unsubstituted heteroalkylene, or a combination of two or more thereof. In embodiments, the linking group is a covalent bond. In embodiments, the linking group is a nucleic acid sequence. In embodiments, the linking group is a DNA sequence. In embodiments, the linking group comprises a nucleic acid sequence and a substituted or unsubstituted alkylene. In embodiments, the linking group comprises a nucleic acid sequence and an unsubstituted alkylene. In embodiments, the linking group comprises a nucleic acid sequence and a substituted or unsubstituted heteroalkylene. In embodiments, the linking group comprises a nucleic acid sequence and an unsubstituted heteroalkylene. In embodiments, the linking group comprises a substituted or unsubstituted heteroalkylene. In embodiments, the linking group comprises a substituted heteroalkylene.

[0105] In embodiments, the linking group comprises a substituted heteroalkylene. In embodiments, the linking group comprises a substituted 6 to 60 membered heteroalkylene. In embodiments, the linking group comprises a substituted 6 to 54 membered heteroalkylene. In embodiments, the linking group comprises a substituted 12 to 48 membered heteroalk lene. In embodiments, the linking group comprises a substituted 18 to 42 membered heteroalky lene. In embodiments, the linking group comprises a substituted 24 to 36 membered heteroalkylene. In embodiments, the linking group comprises a substituted 30 membered heteroalkylene. In embodiments, the heteroalkylene comprises an oxygen atom, a phosphorous atom, or a combination thereof. In embodiments, the substituents on the substituted heteroalkylene comprise oxo, -OH, -O', or a combination of two or more thereof. In embodiments, the linking group comprises a substituted 18 to 42 membered heteroalkylene; wherein the heteroalkylene comprises an oxygen atom, a phosphorous atom, or a combination thereof; and wherein thesubstituents are independently selected from the group consisting of oxo, -OH, and -O'.

[0106] In embodiments, the linking group comprises any one of the following structures:wherein zl, z2, z3 and z4 are independently integers from 0 to 20; and each X is independently - OH or -O'. In embodiments, zl is an integer from 0 to 5. In embodiments, zl is an integer from 2 to 4. In embodiments, z2 is an integer from 0 to 5. In embodiments. z2 is an integer from 2 to 4. In embodiments, z3 is an integer from 0 to 5. In embodiments, zl is an integer from 2 to 4. Inembodiments, z4 is an integer from 3 to 7. In embodiments. z4 is an integer from 4 to 6. In embodiments, each X is -OH.

[0107] In embodiments, the linking group comprises the structure:wherein n is an integer from 1 to 10. In embodiments, n is an integer from 2 to 8. In embodiments, n is an integer from 3 to 7. In embodiments, n is an integer from 4 to 6. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10.

[0108] Provided herein is a compound comprising a phosphorothioated CpG ODN linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer; wherein the RNA aptamer comprises SEQ ID NO: 1; the DNA oligonucleotide comprises SEQ ID NO:24; and the phosphorothioated CpG ODN comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5. SEQ ID NO:6. SEQ ID NO:7. SEQ ID NO:8. SEQ ID NO:9. SEQ ID NO: 10, SEQ ID NO: 1 1, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO:17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:3. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:4. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:5. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 6. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:7. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:8. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:9. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 10. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 11. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 12. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 13. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 14. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 15. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 16. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 17. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 18. In embodiments, thephosphorothioated CpG ODN comprises SEQ ID NO: 19. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:20. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:21. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:22. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 23.

[0109] Provided herein is a compound comprising a phosphorothioated CpG ODN linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer; wherein the RNA aptamer comprises SEQ ID NO:33; the DNA oligonucleotide comprises SEQ ID NO:24; and the phosphorothioated CpG ODN comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5. SEQ ID NO:6. SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11. SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14. SEQ ID NO: 15, SEQ ID NO: 16. SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO 22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:3. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:4. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:5. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 6. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:7. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:8. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:9. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 10. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 11. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 12. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 13. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 14. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 15. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 16. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 17. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 18. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 19. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:20. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:21. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:22. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:23.

[0110] Provided herein is a compound comprising a phosphorothioated CpG ODN linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer;wherein the RNA aptamer comprises SEQ ID NO:34; the DNA oligonucleotide comprises SEQ ID NO:24; and the phosphorothioated CpG ODN comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO 22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:3. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:4. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:5. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 6. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:7. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:8. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:9. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 10. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 11. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 12. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 13. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 14. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 15. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 16. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 17. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 18. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 19. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:20. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:21. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:22. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:23.[OHl] Provided herein is a compound comprising a phosphorothioated CpG ODN linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer; wherein the RNA aptamer comprises SEQ ID NO:26; the DNA oligonucleotide is capable of hybridizing to SEQ ID NO:26; and the phosphorothioated CpG ODN comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15. SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO 18, SEQ ID NO: 19, SEQ ID NO:20. SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 3. In embodiments, the phosphorothioated CpG ODN comprisesSEQ ID N0:4. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:5. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:6. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:7. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 8. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:9. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 10. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 11. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 12. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 13. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 14. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 15. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 16. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 17. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 18. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 19. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:20. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:21. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:22. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 23.

[0112] Provided herein is a compound comprising a phosphorothioated CpG ODN linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer; wherein the RNA aptamer comprises SEQ ID NO:27; the DNA oligonucleotide is capable of hybridizing to SEQ ID NO:27; and the phosphorothioated CpG ODN comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11. SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14. SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 3. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:4. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:5. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:6. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:7. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 8. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:9. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 10. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 1 1. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 12. In embodiments, thephosphorothioated CpG ODN comprises SEQ ID NO: 13. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 14. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 15. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 16. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 17. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 18. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 19. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:20. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:21. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:22. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:23.

[0113] Provided herein is a compound comprising a phosphorothioated CpG ODN linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer; wherein the RNA aptamer comprises SEQ ID NO:28; the DNA oligonucleotide is capable of hybridizing to SEQ ID NO:28; and the phosphorothioated CpG ODN comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 3. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:4. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:5. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:6. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:7. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 8. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:9. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 10. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 11. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 12. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 13. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 14. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 15. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 16. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 17. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 18. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 19. In embodiments, thephosphorothioated CpG ODN comprises SEQ ID NO:20. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:21. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:22. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:23.

[0114] Provided herein is a compound comprising a phosphorothioated CpG ODN linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer; wherein the RNA aptamer comprises SEQ ID NO:29; the DNA oligonucleotide is capable of hybridizing to SEQ ID NO:29; and the phosphorothioated CpG ODN comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11. SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15. SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18. SEQ ID NO: 19, SEQ ID NO:20. SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 3. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:4. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:5. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:6. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:7. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 8. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:9. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 10. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 11. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 12. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 13. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 14. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 15. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 16. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 17. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 18. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 19. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:20. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:21. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:22. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 23.

[0115] Provided herein is a compound comprising a phosphorothioated CpG ODN linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer; wherein the RNA aptamer comprises SEQ ID NO:30; the DNA oligonucleotide is capable ofhybridizing to SEQ ID NO:30; and the phosphorothioated CpG ODN comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO:11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 3. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NON. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:5. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:6. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:7. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 8. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:9. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 10. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 1 1. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 12. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 13. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 14. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 15. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 16. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 17. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 18. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO: 19. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:20. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:21. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:22. In embodiments, the phosphorothioated CpG ODN comprises SEQ ID NO:23.

[0116] Provided herein is phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide comprising SEQ ID NO:25, SEQ ID NO:31, or SEQ ID NO:32. In embodiments, the phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide comprises SEQ ID NO:25. In embodiments, the phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide comprises SEQ ID NO:31. In embodiments, the phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide comprises SEQ ID NO:32.

[0117] Provided herein is phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide comprising SEQ ID NO:25. SEQ ID NO:31, or SEQ ID NO:32 linked to an RNA aptamer, wherein the DNA oligonucleotide is hybridized to an RNA aptamer, wherein theRNA aptamer binds to an intracellular target selected from the group consisting of DNMT1, NF- kB. RUNX1. MYC, MYB, ETS, PAX5. MDM2, F0XM1, PU.l, STAT3, STAT5, STAT6, FAD, ATP5B, and beta-catenin is MDM2, beta-catenin, FAD, ATP5B, or nucleolin. In embodiments, the phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide comprises SEQ ID NO:25, SEQ ID NO:31, or SEQ ID NO:32 linked to an RNA aptamer, wherein the DNA oligonucleotide is hybridized to an RNA aptamer, wherein the RNA aptamer is MDM2. beta-catenin. FAD, ATP5B. or nucleolin. In embodiments, the phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide comprises SEQ ID NO:25, SEQ ID NO:31, or SEQ ID NO:32 linked to an RNA aptamer, wherein the DNA oligonucleotide is hybridized to an RNA aptamer, wherein the RNA aptamer has at least 95% sequence identity to SEQ ID NO: 1, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, or SEQ ID NO:30.

[0118] Detectable Moiety

[0119] In embodiments, the compound further comprises a detectable moiety . In embodiments, the phosphorothioated CpG ODN, the DNA oligonucleotide, the RNA aptamer or any combination thereof comprise a detectable moiety. In embodiments, the phosphorothioated CpG ODN comprises a detectable moiety. In embodiments, the DNA oligonucleotide comprises a detectable moiety. In embodiments, the RNA aptamer comprises a detectable moiety.

[0120] A compound comprising a detectable moiety is one that is bound, either covalently, through a linker or a chemical bond, or noncovalently, through ionic, van der Waals. electrostatic, or hydrogen bonds to a detectable moiety such that the presence of the nucleic acid may be detected by detecting the presence of the detectable moiety bound to the nucleic acid. Alternatively, a method using high affinity interactions may achieve the same results where one of a pair of binding partners binds to the other, e.g., detectable moiety. In embodiments of the compounds described herein, the phosphorothioate nucleic acid or phosphorothioate polymer backbone includes a detectable agent, as disclosed herein and known in the art.

[0121] A “detectable agent” or “detectable moiety” is a compound or composition detectable by appropriate means such as spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. A detectable moiety is a monovalent detectable agent or a detectable agent bound (e.g. covalently and directly or via a linking group) with another compound, e.g., a nucleic acid. Exemplary7detectable agents / moieties for use in the present disclosure include an antibody ligand, a peptide, a nucleic acid, radioisotopes, paramagnetic metal ions, fluorophore (e.g. fluorescent dyes), electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, a biotin-avidin complex, abiotin-streptavidin complex, digoxigenin, magnetic beads (e.g., DYNABEADS® by ThermoFisher, encompassing functionalized magnetic beads such as DYNABEADS® M-270 amine by ThermoFisher), paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide nanoparticles, ultrasmall superparamagnetic iron oxide nanoparticle aggregates, superparamagnetic iron oxide nanoparticles, superparamagnetic iron oxide nanoparticle aggregates, monocrystalline iron oxide nanoparticles, monocrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing gadolinium chelate molecules, gadolinium, radionuclides (e g. carbon-11, nitrogen-13, oxygen-15, fluorine- 18, rubidium-82), fluorodeoxyglucose (e.g. fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g. including microbubble shells including albumin, galactose, lipid, and / or polymers; microbubble gas core including air, heavy gases, perfluorcarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g. iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate. ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide.

[0122] Pharmaceutical Compositions

[0123] In embodiments, the disclosure provides pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable excipient. “Pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a patient and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCL normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose. polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0124] A “effective amount” is an amount sufficient for a compound to accomplish a statedpurpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease). An example of an “effective amount’7is an amount sufficient to contribute to the treatment of a disease which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity' or frequency of the symptoms or elimination of the symptoms. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see. e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy. 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). For any compound described herein, therapeutically effective amount can be initially- determined from cell culture assays. Target concentrations will be those concentrations of active compound that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art. As is known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring the effectiveness of the compounds or compositions described herein, and adjusting the dosage upwards or downw ards. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0125] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0126] The term “administering” means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow -release device, e.g., amini-osmotic pump, to a patient. Administration is by any route, including parenteral and transmucosal (e.g.. buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intra-tumoral, intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. In embodiments, the compounds or pharmaceutical compositions described herein are parenterally administered to a patient. In embodiments, the compounds or pharmaceutical compositions described herein are administered intratumorally to a patient. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. In embodiments, the administering does not include administration of any active agent other than the recited active agent.

[0127] Methods of Treatment

[0128] In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein). In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of a pharmaceutical composition comprising a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein) and a pharmaceutically acceptable excipient.

[0129] In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effect ve amount of: (i) a BCL-2 inhibitor, and (ii) a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein). In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of: (i) a pharmaceutical composition comprising a BCL-2 inhibitor and a pharmaceutically acceptable excipient, and (ii) a pharmaceutical composition comprising a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein) and a pharmaceutically acceptable excipient. In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of a pharmaceutical composition comprising: (a) a BCL-2 inhibitor and (b)a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein). In embodiments, the BCL-2 inhibitor is oblimersen, navitoclax, venetoclax, obatoclax, sonrotoclax, lisaftoclax, ABT-737, S55746, TW-37, or gossypol. In embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient

[0130] In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of: (i) an anti-cancer agent, and (ii) a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein). In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of: (i) a pharmaceutical composition comprising an anti-cancer agent and a pharmaceutically acceptable excipient and (ii) a pharmaceutical composition comprising a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein) and a pharmaceutically acceptable excipient. In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of a pharmaceutical composition comprising: (a) an anti-cancer agent and (b) a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein). In embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. In embodiments, the anti-cancer agent is an immune checkpoint inhibitor, a chemotherapeutic agent, or a combination thereof. In embodiments, the anti-cancer agent is a chemotherapeutic agent. In embodiments, the chemotherapeutic agent is an antimetabolite. In embodiments, the antimetabolite is azacitidine, 5-fluorouracil, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine. pemetrexed, pentostatin, pralatrexate, or thioguanine. In embodiments, the antimetabohte is azacitidine. In embodiments, the anti-cancer agent is a BCL-2 inhibitor.

[0131] In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of: (i) a chemotherapeutic agent, (ii) a BCL-2 inhibitor, and (iii) a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide ishybridized to an RNA aptamer (including embodiments thereof as disclosed herein). In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of: (i) a pharmaceutical composition comprising an BCL-2 inhibitor and a pharmaceutically acceptable excipient, (ii) a pharmaceutical composition comprising a chemotherapeutic agent and a pharmaceutically acceptable excipient, and (iii) a pharmaceutical composition comprising a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein) and a pharmaceutically acceptable excipient. In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of a pharmaceutical composition comprising: (a) a chemotherapeutic agent, (b) a BCL-2 inhibitor, and (c) a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein). In embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of (i) a pharmaceutical composition comprising a chemotherapeutic agent and a pharmaceutically acceptable excipient and (ii) a pharmaceutical composition comprising: (a) a BCL-2 inhibitor, and (b) a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein). In embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of (i) a pharmaceutical composition comprising a BCL-2 inhibitor and a pharmaceutically acceptable excipient and (ii) a pharmaceutical composition comprising: (a) a chemotherapeutic agent and (b) a compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein). In embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. In embodiments, the disclosure provides methods of treating cancer in a patient in need thereof by adminsitering to the patient an effective amount of (i) a pharmaceutical composition comprising: (a) a BCL-2 inhibitor and (b) a chemotherapeutic agent and (ii) a pharmaceutical composition comprising a compound compnsing a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein theDNA oligonucleotide is hybridized to an RNA aptamer (including embodiments thereof as disclosed herein) and a pharmaceutically acceptable excipient. In embodiments, the BCL-2 inhibitor is oblimersen, navitoclax, venetoclax, obatoclax, sonrotoclax, lisaftoclax, ABT-737, S55746, or TW-37. In embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

[0132] In embodiments of the methods described herein, the anti-cancer agent is a BCL-2 inhibitor, an antimetabolite, or a combination thereof.

[0133] In embodiments, the anti-cancer agent is a BCL-2 inhibitor. In embodiments, the anticancer agent is an antimetabolite. In embodiments, the anti-cancer agent is a BCL-2 inhibitor and an antimetabolite. In embodiments, the BCL-2 inhibitor is oblimersen, navitoclax, venetoclax. obatoclax, sonrotoclax, lisaftoclax, ABT-737. S55746, or TW-37. In embodiments, the BCL-2 inhibitor is oblimersen, navitoclax, venetoclax, obatoclax, sonrotoclax, lisaftoclax, ABT-737, S55746, TW-37, or gossypol. In embodiments, the BCL-2 inhibitor is oblimersen. In embodiments, the BCL-2 inhibitor is navitoclax. In embodiments, the BCL-2 inhibitor is venetoclax. In embodiments, the BCL-2 inhibitor is obatoclax. In embodiments, the BCL-2 inhibitor is sonrotoclax. In embodiments, the BCL-2 inhibitor is lisaftoclax. In embodiments, the BCL-2 inhibitor is ABT-737. In embodiments, the BCL-2 inhibitor is S55746. In embodiments, the BCL-2 inhibitor is TW-37. In embodiments, the BCL-2 inhibitor is gossypol.

[0134] In embodiments of the methods described herein, the anti-cancer agent is an antimetabolite. In embodiments, the antimetabolite is azacitidine. 5 -fluorouracil, capecitabine. cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin, pralatrexate, or thioguanine. In embodiments, the antimetabolite is azacitidine. In embodiments, the antimetabolite is 5- fluorouracil. In embodiments, the antimetabolite is capecitabine. In embodiments, the antimetabolite is cladribine. In embodiments, the antimetabolite is clofarabine. In embodiments, the anti metabolite is cytarabine. In embodiments, the antimetabolite is decitabine. In embodiments, the antimetabolite is floxuridine. In embodiments, the antimetabolite is fludarabine. In embodiments, the antimetabolite is gemcitabine. In embodiments, the antimetabolite is hydroxyurea. In embodiments, the antimetabolite is methotrexate. In embodiments, the antimetabolite is nelarabine. In embodiments, the antimetabolite is pemetrexed. In embodiments, the antimetabolite pentostatin. In embodiments, the antimetabolite is pralatrexate. In embodiments, the antimetabolite is thioguanine.

[0135] In embodiments of the methods described herein, the anti-cancer agent is a tyrosine kinase inhibitor (TKI). In embodiments, the TKI is imatinib, erlotinib, gefitinib, dasatinib,sunitinib, sorafenib, nilotinib, lapatinib, ponatinib, axitinib, bosutinib, asciminib, cabozantinib, or pazopanib. In embodiments of the methods described herein, the anti-cancer agent comprises a BCL-2 inhibitor and a TKI. In embodiments of the methods described herein, the anti-cancer agent comprises a BCL-2 inhibitor, a TKI, and an antimetabolite. In embodiments of the methods described herein, the anti-cancer agent comprises a TKI and an immune checkpoint inhibitor.

[0136] In embodiments of the methods described herein, the anti-cancer agent is an immune checkpoint inhibitor. In embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, or a combination of two or more thereof. In embodiments, the PD-L1 inhibitor is atezolizumab. avelumab, durvalumab, envafolimab, cosibelimab, AUNP12, CA-170, or BMS-986189. In embodiments, the PD-L1 inhibitor is atezolizumab, avelumab, durvalumab, envafolimab, cosibelimab, AUNP12, CA-170, or BMS-986189. In embodiments, the PD-L1 inhibitor is atezolizumab, avelumab, durvalumab, envafolimab, or cosibelimab. In embodiments, the PD-L1 inhibitor is atezolizumab. In embodiments, the PD-L1 inhibitor is avelumab. In embodiments, the PD-L1 inhibitor is durvalumab. In embodiments, the PD-L1 inhibitor is envafolimab. In embodiments, the PD-L1 inhibitor is cosibelimab. In embodiments, the PD-L1 inhibitor is AUNP12. In embodiments, the PD-L1 inhibitor is CA-170. In embodiments, the PD-L1 inhibitor is BMS-986189.

[0137] In embodiments of the methods described herein, the cancer is leukemia, myelodysplastic syndrome, brain cancer, prostate cancer, pancreatic cancer, lung cancer, or epidermoid squamous carcinoma. In embodiments, the cancer is leukemia, brain cancer, prostate cancer, pancreatic cancer, lung cancer, or epidermoid squamous carcinoma. In embodiments, the cancer is brain cancer. In embodiments, the brain cancer is glioma. In embodiments, the brain cancer is glioblastoma. In embodiments, the cancer is prostate cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is lung cancer. In embodiments, the cancer is non-small cell lung cancer. In embodiments, the cancer is epidermoid squamous carcinoma.

[0138] In embodiments, the cancer is leukemia. In embodiments, the leukemia is myeloid leukemia or myelomonocytic leukemia. In embodiments, the leukemia is myeloid leukemia. In embodiments, the leukemia is myelomonocytic leukemia. In embodiments, the leukemia is acute myeloid leukemia, chronic myeloid leukemia, acute myelomonocytic leukemia, or chronic myelomonocytic leukemia In embodiments, the cancer is acute myeloid leukemia. In embodiments, the cancer is chronic myeloid leukemia. In embodiments, the cancer is acute myelomonocytic leukemia. In embodiments, the cancer is chronic myelomonocytic leukemia.

[0139] In embodiments, the cancer is myelodysplastic syndrome (MDS). There are several types of MDS, and they are classified based on the number of abnormal cells in the blood and bone marrow. Types of myelodysplastic syndrome include refractory anemia, refractory cytopenia with multilineage dysplasia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia and ringed sideroblasts, refractory anemia with excess blasts, MDS unclassified, and MDS associated with isolated del (5q).

[0140] The term '‘cancer’ refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemias, lymphomas, carcinomas and sarcomas.Exemplary7cancers that can be treated with the compounds and pharmaceutical compositions described herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, cancer of the head, Hodgkin's disease, and Non-Hodgkin's lymphomas. Other cancers that may be treated with the compounds and pharmaceutical compositions described herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus. Additional examples of cancers that may be treated with the compounds and pharmaceutical compositions described herein include, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma, ovarian cancer, rhabdomyosarcoma, primary' thrombocytosis, primary' macroglobulinemia, primary7brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary7tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary' thyroid cancer, medullary7thyroid carcinoma, melanoma, colorectal cancer, papillary7thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0141] The term ‘‘leukemia” refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0142] The terms "treating" or "treatment" refers to any indicia of clinical success in therapy or amelioration of a disease (e.g., cancer), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the disease more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination. The term “treating” does not include preventing.

[0143] “Patient” or “patient in need thereof’ refers to a living organism suffering from or prone to a disease n that can be treated by administration of a compound or pharmaceutical composition herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, cats, monkeys, goat, sheep, cows, and other non-mammalian animals. In embodiments, a patient is human.

[0144] Cancer model organism, as used herein, is an organism exhibiting a phenotype indicative of cancer, or the activity’ of cancer causing elements, within the organism. The term cancer is defined above. A wide variety of organisms may serve as cancer model organisms, and include for example, cancer cells and mammalian organisms such as rodents (e.g. mouse or rat) and primates (such as humans). Cancer cell lines are widely understood by those skilled in the art as cells exhibiting phenotypes or genotypes similar to in vivo cancers. Cancer cell lines as used herein includes cell lines from animals (e.g. mice) and from humans.

[0145] The term “immune checkpoint inhibitor” refers to a compound (e.g., an antibody) thatis capable of binding to an inhibitor}' receptor or capable of interfering with the interaction between an inhibitory receptor and its ligand, wherein the inhibitory receptor is essential to balance co-stimulatory receptor activity and limit T-cell activation. Thus, immune checkpoint inhibitors target immune system checkpoints such as the PD-1 pathway.

[0146] In embodiments of the methods of treating cancer as described herein, the methods further comprise administering to the patient an effective amount of an anti-cancer agent. “Anticancer agent” is used in accordance with its plain ordinary meaning and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the grow th or proliferation of cells. Exemplar ' anti-cancer agents include antibodies, small molecules, large molecules, and combinations thereof. In embodiments, an anti-cancer agent is a chemotherapeutic. In embodiments, an anti-cancer agent is an agent identified herein having utility in methods of treating cancer. In embodiments, an anti-cancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA. for treating cancer. Examples of anti-cancer agents include, but are not limited to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, CI-1040, PD035901, selumetimb, trametimb, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa. nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan). ethylenimine and methylmelamines (e.g.. hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin), triazenes (decarbazine)), anti-metabolites (e.g., 5- azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (e.g.. methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc ), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine. etoposide (VP16), etoposide phosphate, teniposide. etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds or platinum containing agents (e.g. cisplatin, oxaliplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e g., L-asparaginase), inhibitors of mitogen-activated proteinkinase signaling (e g. U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossypol, genasense, polyphenol E, chlorofusin, all trans-retinoic acid, bryostatin. tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'- deoxy cytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib, geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002. bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352. 20-epi-L 25 dihydroxy vitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azalyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors; castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis- porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cr ptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifl uridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; fdgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B: mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides: onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenyl acetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A: placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; pl atinum-tri amine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; ras inhibitors; ras-GAPinhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes: RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl: safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin: sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stemcell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene: totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitor}' factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone: zeniplatin; zilascorb; zinostatin stimalamer, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine: estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretimde; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabinehydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin II, or rlL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl ; interferon alfa-n3; interferon beta-la; interferon gamma- lb; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phases and / or modulate the formation or stability- of microtubules, (e.g.. paclitaxel), compounds comprising the taxane skeleton, erbulozole. dolastatin 10, mivobulin isethionate, vincristine, NSC-639829, discodermolide, ABT-751, altorhyrtins (e.g., altorhyrtin A and altorhyrtin C), spongistatins (e.g., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), demadotin hydrochloride, epothilones (e.g. epothilone A, epothilone B, epothilone C (i.e. desoxyepothilone A or dEpoA), epothilone D (i.e. KOS-862, dEpoB, and desoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B, 21 -hydroxy epothilone D (i.e., desoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin PE, soblidotin, vincristine sulfate, cryptophycin 52. vitilevuamide, tubulysin A, canadensol, centaureidin, oncocidin Al, fijianolide B. laulimalide, narcosine, nascapine. hermasterlin. vanadocene acetylacetonate. monsatrol, Inanocine, eleutherobins (such as desmethyleleutherobin, desaetyleleutherobin,Isoeleutherobin A, and Z-Eleutherobin), caribaeoside, caribaeolin, halichondrin B, diazonamide A, taccalonolide A, diozostatin, (-)-phenylahistin, myoseverin B, resverastatin phosphate sodium, steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., di ethly stilbestrol, ethinyl estradiol), antiestrogen (e.g.. tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone). antiandrogen (e.g.. flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin), levamisole, interleukin-2, alphainterferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody- calicheamicin conjugate. anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e g., anti-CD20 monoclonal antibody conjugated toinIn,90Y, or1?1I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin. irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib. erlotinib, gefitinib. EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutic (e.g. gefitinib, erlotinib, cetuximab, lapatinib, panitumumab, vandetanib, afatinib, canertinib, neratimb, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib, desmethyl erlotinib, AZD8931, AEE788, pelitinib, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626). sorafenib, imatmib, sunitinib, dasatinib, hormonal therapies, or the like.

[0147] Lipid Nanoparticles

[0148] The compounds described herein (and embodiments thereof) can be encapsulated in lipid nanoparticles (i.e., lipid nanoparticles comprising a compound described herein (and embodiments thereol) The lipid nanoparticles comprising a compound described herein can be administered to a patient in any of the methods described herein, including embodiments thereof. The lipid nanoparticle is any lipid nanoparticle known in the art. In embodiments, the lipid nanoparticle is a lipid nanoparticle described in WO 2023 / 205628, the disclosure of which is incorporated by reference herein in its entirety.

[0149] Provided herein are lipid nanoparticles comprising a cationic lipid (e.g., a dilinoleic cationic lipid), a phospholipid, a sterol, and a polyethylene glycol-lipid conjugate (PEG-lipid conjugate). In embodiments, the cationic lipid is DOTAP, DODAC, DODMA, DSDMA, DOTMA, DDAB, DC-Chol. DMRIE, DOSPA, DOGS. CLinDMA. CpLinDMA. DMOBA, DOcarbDAP, DOAP, C12-200, or a mixture of two or more thereof,. In embodiments, thecationic lipid is a dilinoleic cationic lipid. In embodiments, the dilinoleic cationic lipid is MC3, an MC3 derivative, DLinDMA, DLin-K-C2-DMA, DLin-K-C3-DMA, DLin-K-C4-DMA. DLin-K6-DMA, DLin-K-MPZ, DLin-K-DMA, DLin-C-DAP, DLin-DAC, DLin-MA, DLinDAP, DLm-S-DMA, DLm-2-DMAP, DLin-TMA, DLin-TAP, DLin-MPZ, DLinAP, DLin- EG-DMA, DLincarbDAP, or a mixture of two or more thereof. In embodiments, the dilinoleic cationic lipid is MC3. In embodiments, the phospholipid is DSPC, DPPC, DOPE, POPC, POPE. POPG. DPPE, DMPE. DSPE, MMPE, DMPE, DEPE, SOPE. EPC. HSPC. or a mixture of two or more thereof. In embodiments, the phospholipid is DSPC, DPPC, DOPE, POPC, POPE, POPG, DPPE, DMPE, DSPE, MMPE, DMPE, DEPE, SOPE, EPC, HSPC, DPPG, or a mixture of two or more thereof. In embodiments, the phospholipid is HSPC. In embodiments, the phospholipid is DPPG. In embodiments, the sterol is cholesterol, cholestanol, cholestanone, cholestenone, coprostanol, cholesteryl-2'-hydroxyethyl ether, cholesteryl-4’-hydro.xybutyl ether, or a mixture of two or more thereof. In embodiments, the sterol is cholesterol, cholestanol, cholestanone, cholestenone, coprostanol, cholesteryl-2'-hydroxyethyl ether, cholesteryl-4'- hydroxybutyl ether, cholesteryl hemisuccinate, or a mixture of two or more thereof. In embodiments, the sterol is cholesterol. In embodiments, the sterol is cholesteryl hemisuccinate. In embodiments, the sterol is cholesterol, cholestery l hemi succinate, or a mixture thereof. In embodiments, the sterol is cholesterol and cholesteryl hemisuccinate (i.e., a mixture of cholesterol and cholesteryl hemisuccinate). In embodiments, the PEG-lipid conjugate is a polyethylene glycol having a molecular weight from about 1.000 Daltons to about 6.000 Daltons conjugated to a C12-C22 fatty acid lipid. In embodiments, the PEG-lipid conjugate is DMG-PEG, DPPE-PEG, DPG-PEG, DSG-PEG, DSPE-PEG, or a mixture of two or more thereof. In embodiments, the PEG-lipid conjugate is DMG-PEG In embodiments, the PEG-lipid conjugate is DMG-PEG, DPPE-PEG, DPG-PEG, DSG-PEG, DSPE-PEG, or a mixture of two or more thereof, wherein the PEG in each compound has a molecular weight of about 2,000 Daltons. In embodiments, the PEG-lipid conjugate is DMG-PEG2000 (i.e., wherein PEG2000 refers to PEG having a molecular weight of about 2,000 Daltons). In embodiments, the cationic lipid is MC3, the phospholipid is DSPC, the sterol is cholesterol, and the PEG-lipid conjugate is DMG- PEG2000. In embodiments, the cationic lipid is MC3, the phospholipid is DPPG, the sterol is cholesterol, and the PEG-lipid conjugate is DMG-PEG2000. In embodiments, the cationic lipid is MC3, the phospholipid is DSPC, the sterol is cholesterol and cholesteryl hemisuccinate, and the PEG-lipid conjugate is DMG-PEG2000. In embodiments, the lipid nanoparticles are a plurality of lipid nanoparticles.

[0150] Provided herein are lipid nanoparticles comprising: (i) about 40 mole% to about 60mole% of a cationic lipid; (ii) about 5 mole% to about 15 mole% of a phospholipid; (iii) about 25 mole% to about 50 mole% of a sterol; and (iv) about 0.1 mole% to about 4 mole% of a PEG- lipid conjugate. In embodiments, the lipid nanoparticles comprise: (i) about 45 mole% to about 55 mole% of a cationic lipid; (ii) about 5 mole% to about 15 mole% of a phospholipid; (iii) about 33 mole% to about 44 mole% of a sterol; and (iv) about 0. 1 mole% to about 3 mole% of a PEG-lipid conjugate. In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of a cationic lipid; (ii) about 8 mole% to about 12 mole% of a phospholipid; (iii) about 36 mole% to about 42 mole% of a sterol; and (iv) about 0.1 mole% to about 2 mole% of a PEG-lipid conjugate. In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of a cationic lipid; (ii) about 8 mole% to about 12 mole% of a phospholipid;(iii) about 36 mole% to about 40 mole% of a sterol; and (iv) about 1 mole% to about 2 mole% of a PEG-lipid conjugate. In embodiments, the lipid nanoparticles comprise: (i) about 50 mole% of a cationic lipid; (ii) about 10 mole% of a phospholipid; (iii) about 38.5 mole% of a sterol; and(iv) about 1.5 mole% of a PEG-lipid conjugate. In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of a cationic lipid; (ii) about 8 mole% to about 12 mole% of a phospholipid; (iii) about 38 mole% to about 42 mole% of a sterol; and (iv) about 0. 1 mole% to about 1 mole% of a PEG-lipid conjugate. In embodiments, the lipid nanoparticles comprise: (i) about 50 mole% of a cationic lipid; (ii) about 10 mole% of a phospholipid; (iii) about 39.5 mole% of a sterol; and (iv) about 0.5 mole% of a PEG-lipid conjugate.

[0151] Provided herein are lipid nanoparticles comprising: (i) about 40 mole% to about 60 mole% of a dilinoleic cationic lipid; (ii) about 5 mole% to about 15 mole% of a phospholipid; (iii) about 25 mole% to about 50 mole% of a sterol; and (iv) about 0.1 mole% to about 4 mole% of a PEG-lipid conjugate. In embodiments, the lipid nanoparticles comprise: (i) about 45 mole% to about 55 mole% of a dilinoleic cationic lipid; (ii) about 5 mole% to about 15 mole% of a phospholipid; (iii) about 33 mole% to about 44 mole% of a sterol; and (iv) about 0. 1 mole% to about 3 mole% of a PEG-lipid conjugate. In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of a dilinoleic cationic lipid; (ii) about 8 mole% to about 12 mole% of a phospholipid; (iii) about 36 mole% to about 42 mole% of a sterol; and (iv) about 0. 1 mole% to about 2 mole% of a PEG-lipid conjugate. In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of a dilinoleic cationic lipid; (ii) about 8 mole% to about 12 mole% of a phospholipid; (iii) about 36 mole% to about 40 mole% of a sterol; and (iv) about 1 mole% to about 2 mole% of a PEG-lipid conjugate. In embodiments, the lipid nanoparticles comprise: (i) about 50 mole% of a dilinoleic cationic lipid; (ii) about 10 mole% of a phospholipid; (iii) about 38.5 mole% of a sterol; and (iv) about 1.5 mole% of aPEG-lipid conjugate. In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of a dilinoleic cationic lipid; (ii) about 8 mole% to about 12 mole% of a phospholipid; (iii) about 38 mole% to about 42 mole% of a sterol; and (iv) about 0.1 mole% to about 1 mole% of a PEG-lipid conjugate. In embodiments, the lipid nanoparticles comprise: (i) about 50 mole% of a dilinoleic cationic lipid; (ii) about 10 mole% of a phospholipid; (iii) about 39.5 mole% of a sterol; and (iv) about 0.5 mole% of a PEG-lipid conjugate.

[0152] In embodiments of the lipid nanoparticles described herein, the cationic lipid is any cationic lipid known in the art. In embodiments, the cationic lipid is DOTAP, DODAC, DODMA, DSDMA, DOTMA, DDAB, DC-Chol, DMRIE, DOSPA, DOGS, CLinDMA, CpLinDMA, DMOBA, DOcarbDAP, DOAP, Cl 2-200, or a mixture of two or more thereof. In embodiments, the cationic lipid is DOTAP. In embodiments, the cationic lipid is DODAC. In embodiments, the cationic lipid is DODMA. In embodiments, the cationic lipid is DSDMA. In embodiments, the cationic lipid is DOTMA. In embodiments, the cationic lipid is DDAB. In embodiments, the cationic lipid is DC-Chol. In embodiments, the cationic lipid is DMRIE. In embodiments, the cationic lipid is DOSPA. In embodiments, the cationic lipid is DOGS. In embodiments, the cationic lipid is CLinDMA. In embodiments, the cationic lipid is CpLinDMA. In embodiments, the cationic lipid is DMOBA. In embodiments, the cationic lipid is DOcarbDAP. In embodiments, the cationic lipid is DOAP. In embodiments, the cationic lipid is Cl 2-200. In embodiments, the cationic lipid is a dilinoleic cationic lipid. In embodiments, the cationic lipid is not a dilinoleic cationic lipid.

[0153] In embodiments of the lipid nanoparticles described herein, the dilinoleic cationic lipid is any known in the art. In embodiments, the dilinoleic cationic lipid is MC3, an MC3 derivative, DLinDMA. DLin-KC2-DMA, DLin-KC3-DMA, DLin-KC4-DMA, DLin-K6-DMA, DLin-K-MPZ, DLin-K-DMA. DLin-C-DAP, DLin-DAC. DLin-MA. DLinDAP. DLin-S-DMA. DLin-2-DMAP, DLin-TMA, DLin-TAP, DLin-MPZ, DLinAP, DLin-EG-DMA, DLincarbDAP, or a mixture of two or more thereof. In embodiments, the dilinoleic cationic lipid is MC3, DLinDMA, DLin-KC2-DMA, DLin-KC3-DMA, DLin-KC4-DMA, DLin-K6-DMA. DLin-K- MPZ, DLin-K-DMA, DLin-C-DAP. DLin-DAC, DLin-MA, DLinDAP, DLin-S-DMA, DLin-2- DMAP, DLin-TMA, DLin-TAP, DLin-MPZ, DLinAP, DLin-EG-DMA, DLincarbDAP, or a mixture of two or more thereof. In embodiments, the dilinoleic cationic lipid is MC3. In embodiments, the dilinoleic cationic lipid is Dlin-KC2-DMA. In embodiments, the dilinoleic cationic lipid is DLinDMA. In embodiments, the dilinoleic cationic lipid is DLin-KC3-DMA. In embodiments, the dilinoleic cationic lipid is DLin-KC4-DMA. In embodiments, the dilinoleic cationic lipid is DLin-K6-DMA. In embodiments, the dilinoleic cationic lipid is DLin-K-MPZ.In embodiments, the dilinoleic cationic lipid is DLin-K-DMA. In embodiments, the dilinoleic cationic lipid is DLin-C-DAP. In embodiments, the dilinoleic cationic lipid is DLin-DAC. In embodiments, the dilinoleic cationic lipid is DLin-MA. In embodiments, the dilinoleic cationic lipid is DLinDAP. In embodiments, the dilinoleic cationic lipid is DLin-S-DMA. In embodiments, the dilinoleic cationic lipid is DLin-2-DMAP. In embodiments, the dilinoleic cationic lipid is Dlin-TMA. In embodiments, the dilinoleic cationic lipid is Dlin-TAP. In embodiments, the dilinoleic cationic lipid is DLin-MPZ. In embodiments, the dilinoleic cationic lipid is DLinAP. In embodiments, the dilinoleic cationic lipid is DLin-EG-DMA. In embodiments, the dilinoleic cationic lipid is DLincarbDAP.

[0154] In embodiments of the lipid nanoparticles described herein, the phospholipid is any phospholipid known in the art. In embodiments, the phospholipid is DSPC. DPPC. DOPE. POPC, POPE, POPG, DPPE, DMPE, DSPE, MMPE, DMPE, DEPE, SOPE, EPC, HSPC, or a mixture of two or more thereof. In embodiments, the phospholipid is DSPC, DPPC, DOPE, POPC, POPE, POPG, DPPE, DMPE, DSPE, MMPE, DMPE, DEPE, SOPE, EPC, HSPC, DPPG. or a mixture of two or more thereof. In embodiments, the phospholipid is DSPC. In embodiments, the phospholipid is DPPC. In embodiments, the phospholipid is DOPE. In embodiments, the phospholipid is POPC. In embodiments, the phospholipid is POPE. In embodiments, the phospholipid is POPG. In embodiments, the phospholipid is DPPE. In embodiments, the phospholipid is DMPE. In embodiments, the phospholipid is DSPE. In embodiments, the phospholipid is MMPE. In embodiments, the phospholipid is DMPE. In embodiments, the phospholipid is DEPE. In embodiments, the phospholipid is SOPE. In embodiments, the phospholipid is EPC. In embodiments, the phospholipid is HSPC. In embodiments, the phospholipid is DPPG.

[0155] In embodiments of the lipid nanoparticles described herein, the sterol is any sterol known in the art. In embodiments, the sterol is cholesterol, cholestanol, cholestanone, cholestenone, coprostanol, cholesteryl-2'-hydroxyethyl ether, cholesteryl-4'-hydroxybutyl ether, or a mixture of two or more thereof. In embodiments, the sterol is cholesterol, cholestanol, cholestanone, cholestenone, coprostanol, cholesteryl-2'-hydroxyethyl ether, cholesteryl-4'- hydroxybutyl ether, cholesteryl hemisuccinate, or a mixture of two or more thereof. In embodiments, the sterol is a mixture of two compounds selected from the group consisting of cholesterol, cholestanol, cholestanone, cholestenone, coprostanol, cholesteryl-2'-hydroxyethyl ether. cholesteryl-4'-hydroxybutyl ether, and cholesteryl hemisuccinate. In embodiments, the sterol is cholesterol. In embodiments, the sterol is cholestanol. In embodiments, the sterol is cholestanone. In embodiments, the sterol is cholestenone. In embodiments, the sterol iscoprostanol. In embodiments, the sterol is cholesteryl-2'-hydroxy ethyl ether. In embodiments, the sterol is cholesteryl-4'-hydroxybutyl ether. In embodiments, the sterol is cholesteryl hemisuccinate. In embodiments, the sterol is cholesterol, cholesteryl hemisuccinate, or a mixture thereof. In embodiments, the sterol is cholesterol and cholesteryl hemisuccinate (i.e., a mixture of cholesterol and cholesteryl hemisuccinate).

[0156] In embodiments of the lipid nanoparticles described herein, the PEG-lipid conjugate is a polyethylene glycol having a molecular weight from about 1,000 Daltons to about 6.000 Daltons conjugated to a C12-C22 fatty acid lipid. In embodiments, the PEG-lipid conjugate is a polyethylene glycol having a molecular weight from about 1,000 Daltons to about 6,000 Daltons conjugated to a C12-C20 fatty acid lipid. In embodiments, the PEG-lipid conjugate is a polyethylene glycol having a molecular weight from about 1,000 Daltons to about 6.000 Daltons conjugated to a C12-C18 fatty acid lipid. In embodiments, the PEG-lipid conjugate is a polyethylene glycol having a molecular weight from about 1,000 Daltons to about 5,000 Daltons conjugated to a C12-C22 fatty acid lipid. In embodiments, the PEG-lipid conjugate is a polyethylene glycol having a molecular weight from about 1,000 Daltons to about 4,000 Daltons conjugated to a C12-C20 fatty acid lipid. In embodiments, the PEG-lipid conjugate is a polyethylene glycol having a molecular weight from about 1,500 Daltons to about 4,000 Daltons conjugated to a C12-C18 fatty acid lipid. In embodiments, the PEG-lipid conjugate is a polyethylene glycol having a molecular weight from about 1,500 Daltons to about 3,000 Daltons conjugated to a C12-C18 fatty acid lipid. In embodiments, the PEG-lipid conjugate is a polyethylene glycol having a molecular weight from about 1,500 Daltons to about 2,500 Daltons conjugated to a C 12 fatty acid lipid. In embodiments, the fatty7acid lipid is saturated. In embodiments, the fatty acid lipid is unsaturated. In embodiments, the fatty acid lipid comprises one, two. or three -CH=CH- groups. In embodiments, the fatty acid lipid comprises one - CH=CH- group. In embodiments, the fatty acid lipid comprises two -CH=CH- groups. In embodiments, the PEG-lipid conjugate is DMG-PEG, DPPE-PEG, DPG-PEG, DSG-PEG, DSPE-PEG, or a mixture of two or more thereof. In embodiments, the PEG-lipid conjugate is DMG-PEG. In embodiments, the PEG-lipid conjugate is DPPE-PEG. In embodiments, the PEG- lipid conjugate is DPG-PEG. In embodiments, the PEG-lipid conjugate is DSG-PEG. In embodiments, the PEG-lipid conjugate is DSPE-PEG. In embodiments, the PEG-lipid conjugate is DMG-PEG2000, DPPE-PEG2000, DPG-PEG2000, DSG-PEG2000, DSPE-PEG2000, or a mixture of two or more thereof, wherein PEG2000 refers to PEG having a molecular weight of about 2,000 Daltons. In embodiments, the PEG-lipid conjugate is DMG-PEG2000. In embodiments, the PEG-lipid conjugate is DPPE-PEG2000. In embodiments, the PEG-lipidconjugate is DPG-PEG2000. In embodiments, the PEG-lipid conjugate is DSG-PEG2000. In embodiments, the PEG-lipid conjugate is DSPE-PEG2000.

[0157] Provided herein are lipid nanoparticles comprising: (i) about 40 mole% to about 60 mole% of MC3; (ii) about 5 mole% to about 15 mole% of HSPC; (iii) about 25 mole% to about 50 mole% of cholesterol; and (iv) about 0.1 mole% to about 4 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 45 mole% to about 55 mole% of MC3; (ii) about 5 mole% to about 15 mole% of HSPC; (iii) about 33 mole% to about 44 mole% of cholesterol; and (iv) about 0.1 mole% to about 3 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of MC3; (ii) about 8 mole% to about 12 mole% of HSPC; (iii) about 36 mole% to about 42 mole% of cholesterol; and (iv) about 0. 1 mole% to about 2 mole% of DMG-PEG2000.

[0158] In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of MC3; (ii) about 8 mole% to about 12 mole% of HSPC; (iii) about 36 mole% to about 40 mole% of cholesterol; and (iv) about 1 mole% to about 2 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 49 mole% to about 51 mole% of MC3; (ii) about 9 mole% to about 11 mole% of HSPC; (iii) about 37.5 mole% to about 39.5 mole% of cholesterol; and (iv) about 1 mole% to about 2 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 50 mole% of MC3; (ii) about 10 mole% of HSPC; (iii) about 38.5 mole% of cholesterol; and (iv) about 1.5 mole% of DMG-PEG2000.

[0159] In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of MC3; (ii) about 8 mole% to about 12 mole% of HSPC; (iii) about 38 mole% to about 42 mole% of cholesterol; and (iv) about 0.1 mole% to about 1 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 49 mole% to about 51 mole% of MC3;(ii) about 9 mole% to about 11 mole% of HSPC; (iii) about 38.5 mole% to about 40.5 mole% of cholesterol; and (iv) about 0.2 mole% to about 1 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 50 mole% of MC3; (ii) about 10 mole% of HSPC;(iii) about 39.5 mole% of cholesterol; and (iv) about 0.5 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles are a plurality of lipid nanoparticles.

[0160] In embodiments, the lipid nanoparticles comprise: (i) about 40 mole% to about 60 mole% of MC3; (ii) about 5 mole% to about 15 mole% of DPPG; (iii) about 25 mole% to about 50 mole% of cholesterol; and (iv) about 0.1 mole% to about 4 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 45 mole% to about 55 mole% of MC3; (ii) about 5 mole% to about 15 mole% of DPPG; (iii) about 33 mole% to about 44 mole% of cholesterol; and (iv) about 0.1 mole% to about 3 mole% of DMG-PEG2000. In embodiments,the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of MC3; (ii) about 8 mole% to about 12 mole% of DPPG; (iii) about 36 mole% to about 42 mole% of cholesterol; and (iv) about 0.1 mole% to about 2 mole% of DMG-PEG2000.

[0161] In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of MC3; (ii) about 8 mole% to about 12 mole% of DPPG; (iii) about 36 mole% to about 40 mole% of cholesterol; and (iv) about 1 mole% to about 2 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 49 mole% to about 51 mole% of MC3; (ii) about 9 mole% to about 11 mole% of DPPG; (iii) about 37.5 mole% to about 39.5 mole% of cholesterol; and (iv) about 1 mole% to about 2 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 50 mole% of MC3; (ii) about 10 mole% of DPPG; (iii) about 38.5 mole% of cholesterol; and (iv) about 1.5 mole% of DMG-PEG2000.

[0162] In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of MC3; (ii) about 8 mole% to about 12 mole% of DPPG; (iii) about 38 mole% to about 42 mole% of cholesterol; and (iv) about 0.1 mole% to about 1 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 49 mole% to about 51 mole% of MC3;(ii) about 9 mole% to about 11 mole% of DPPG; (iii) about 38.5 mole% to about 40.5 mole% of cholesterol; and (iv) about 0.2 mole% to about 1 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 50 mole% of MC3; (ii) about 10 mole% of DPPG;(iii) about 39.5 mole% of cholesterol; and (iv) about 0.5 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles are a plurality of lipid nanoparticles.

[0163] In embodiments, the lipid nanoparticles comprise: (i) about 40 mole% to about 60 mole% of MC3; (ii) about 5 mole% to about 15 mole% of HSPC; (iii) about 25 mole% to about 50 mole% of a mixture of cholesterol and cholesteryl hemisuccinate; and (iv) about 0. 1 mole% to about 4 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 45 mole% to about 55 mole% of MC3; (ii) about 5 mole% to about 15 mole% of HSPC; (iii) about 33 mole% to about 44 mole% of a mixture of cholesterol and cholesteryl hemisuccinate; and (iv) about 0. 1 mole% to about 3 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of MC3; (ii) about 8 mole% to about 12 mole% of HSPC; (iii) about 36 mole% to about 42 mole% of a mixture of cholesterol and cholesteryl hemisuccinate; and (iv) about 0.1 mole% to about 2 mole% of DMG-PEG2000. In embodiments, the molar ratio of cholesterol to cholesteryl hemisuccinate is from about 3: 1 to about 1:3. In embodiments, the molar ratio of cholesterol to cholesteryl hemisuccinate is from about 2: 1 to about 1 :2.

[0164] In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52mole% of MC3; (ii) about 8 mole% to about 12 mole% of HSPC; (iii) about 36 mole% to about 40 mole% of a mixture of cholesterol and cholesteryl hemisuccinate; and (iv) about 1 mole% to about 2 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 49 mole% to about 51 mole% of MC3; (ii) about 9 mole% to about 11 mole% of HSPC; (iii) about 37.5 mole% to about 39.5 mole% of a mixture of cholesterol and cholestery l hemisuccinate; and (iv) about 1 mole% to about 2 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles compnse: (i) about 50 mole% of MC3; (ii) about 10 mole% of HSPC; (iii) about 38.5 mole% of a mixture of cholesterol and cholesteryl hemisuccinate; and (iv) about1.5 mole% of DMG-PEG2000. In embodiments, the molar ratio of cholesterol to cholesteryl hemisuccinate is from about 3 : 1 to about 1 : 3. In embodiments, the molar ratio of cholesterol to cholesteryl hemisuccinate is from about 2: 1 to about 1 :2. In embodiments, the lipid nanoparticles comprise: (i) about 50 mole% of MC3; (ii) about 10 mole% of HSPC; (iiia) about18.5 mole% of cholesterol; (iiib) about 20 mole% of cholesteryl hemisuccinate; and (iv) about1.5 mole% of DMG-PEG2000.

[0165] In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of MC3; (ii) about 8 mole% to about 12 mole% of HSPC; (iii) about 38 mole% to about 42 mole% of a mixture of cholesterol and cholesteryl hemisuccinate; and (iv) about 0. 1 mole% to about 1 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 49 mole% to about 51 mole% of MC3; (ii) about 9 mole% to about 11 mole% of HSPC; (iii) about 38.5 mole% to about 40.5 mole% of a mixture of cholesterol and cholesteryl hemisuccinate; and (iv) about 0.2 mole% to about 1 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 50 mole% of MC3; (ii) about 10 mole% of HSPC; (iii) about 39.5 mole% of a mixture of cholesterol and cholesteryl hemisuccinate; and (iv) about 0.5 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles are a plurality of lipid nanoparticles. In embodiments, the molar ratio of cholesterol to cholesteryl hemisuccinate is from about 3: 1 to about 1 :3. In embodiments, the molar ratio of cholesterol to cholestery l hemisuccinate is from about 2:1 to about 1:2.

[0166] In embodiments, the lipid nanoparticles comprise: (i) about 40 mole% to about 60 mole% of MC3; (ii) about 5 mole% to about 15 mole% of HSPC; (iii) about 12 mole% to about 25 mole% of cholesterol; (iv) about 12 mole% to about 25 mole% of cholesteryl hemisuccinate; and (v) about 0.1 mole% to about 4 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 48 mole% to about 52 mole% of MC3; (ii) about 8 mole% to about 12 mole% of HSPC; (iii) about 16.5 mole% to about 20.5 mole% of cholesterol, (iv) about 18 mol% to about 22 mol% of cholesteryl hemisuccinate; and (v) about 0.1 mole% to about 1mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 49 mole% to about 51 mole% of MC3; (ii) about 9 mole% to about 11 mole% of HSPC; (iii) about 17.5 mole% to about 19.5 mole% of cholesterol, (iv) about 19 mol% to about 21 mol% of cholesteryl hemisuccinate; and (v) about 0.2 mole% to about 1 mole% of DMG-PEG2000. In embodiments, the lipid nanoparticles comprise: (i) about 50 mole% of MC3; (ii) about 10 mole% of HSPC; (iiia) about 18.5 mole% of cholesterol; (iiib) about 20 mole% of cholesteryl hemisuccinate; and (iv) about 1.5 mole% of DMG-PEG2000.

[0167] The lipid nanoparticles (or plurality of lipid nanoparticles) described herein typically have an average size (e.g., mean diameter) from about 10 nm to about 200 nm, from about 20 nm to about 190 nm, from about 30 nm to about 175 nm, from about 40 nm to about 160 nm, from about 50 nm to about 150 nm, or from about 60 nm to about 140 nm. In embodiments, the average size is about 40 nm to about 120 nm. In embodiments, the average size is about 60 nm to about 100 nm.

[0168] The term “lipid conjugate’' refers to a conjugated lipid that inhibits aggregation of lipid particles. Such lipid conjugates include PEG-lipid conjugates such as, e.g., PEG coupled to dialkyloxypropyls (e.g., DAA-PEG conjugates), PEG coupled to diacylglycerols (e.g., DAGPEG conjugates), PEG coupled to cholesterol, PEG coupled to phosphatidylethanolamines, PEG conjugated to ceramides, cationic PEG lipids, polyoxazoline (POZ)-lipid conjugates (e.g., POZ- DAA conjugates), polyamide oligomers (e.g., ATTA-lipid conjugates), and mixtures thereof. PEG or POZ can be conjugated directly to the lipid or may be linked to the lipid via a linker moiety. Any linker moiety suitable for coupling the PEG or the POZ to a lipid can be used including, e.g., non-ester containing linker moieties and ester-containing linker moieties. In embodiments, non-ester containing linker moieties, such as amides or carbamates, are used.

[0169] In embodiments, the term “polyethylene gly col-lipid conjugate” or “PEG-lipid conjugate” refers to a polyethylene glycol (PEG) having a molecular weight from about 500 Daltons to about 10,000 Daltons conjugated to a C 12-C22 fatty acid lipid. In embodiments, a PEG-lipid conjugate is polyethylene glycol having a molecular weight from about 1,000 Daltons to about 6,000 Daltons conjugated to a C12-C22 fatty acid lipid. In embodiments, a PEG-lipid conjugate is polyethylene glycol having a molecular weight from about 2,000 Daltons to about 5,000 Daltons conjugated to a C12-C20 fatty acid lipid. In embodiments, a PEG-lipid conjugate is polyethylene glycol having a molecular weight from about 2,000 Daltons to about 5,000 Daltons conjugated to a C12-C18 fatty acid lipid. In embodiments, a PEG-lipid conjugate is polyethylene glycol having a molecular weight from about 1.500 Daltons to about 2.500 Daltons conjugated to a C12-C18 fatty acid lipid. In embodiments, a PEG-lipid conjugate is polyethylene glycolhaving a molecular weight from about 2,000 Daltons conjugated to a C12-C18 fatty acid lipid. In embodiments, the PEG-lipid conjugate is N-palmitoyl-sphingosine-l-{succinyl[methoxy- (poly ethylene glycol)]} (Cl 6 PEG ceramide), l,2-dimyristoyl-rac-glycero-3-methoxy- poly ethylene glycol (DMG-PEG), l,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- [azido(polyethylene glycol) (DPPE-PEG), l,2-dipalmitoyl-rac-glycero-3-methylpolyoxy- ethylene (DPG-PEG), distearoyl-rac-glycerol(polyethylene glycol) (DSG-PEG), 1 ,2-distearoyl- sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol) (DSPE-PEG). In embodiments, the polyethylene glycol has an average molecular weight of about 2000 daltons (e g., DMG-PEG2000, DPPE-PEG2000, DPG-PEG2000, DSG-PEG2000, DSPE-PEG2000). In embodiments, DMG-PEG is a mixture of 1,2-DMG PEG2000 and 1,3-DMG PEG2000. In embodiments, DMG-PEG is a mixture of 1,2-DMG PEG2000 and 1,3-DMG PEG2000 in a ratio of about 99: 1 to about 90: 10. The polyethylene gly col-lipid conjugate can optionally be in the form of a pharmaceutically acceptable salt (e.g., ammonium salt).

[0170] The term “average molecular weight” refers to the average molecular weight of a polymer sample that is determined by a technique known in the art. such as gel permeation chromatography, light-scattering measurements and viscosity measurements. In embodiments, the average molecular weight is the number average molecular weight which is defined as the total weight of polymer divided by the total number of molecules.

[0171] “Phospholipids” are a class of lipids whose molecule has a hydrophilic “head” containing a phosphate group and two hydrophobic ”tails” derived from fatty acids, joined by an alcohol residue. Exemplary phospholipids include dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoyl-phosphatidylcholine (POPC). palmitoyloleoyl-phosphatidylethanolamine (POPE), palmitoyloleyol-phosphatidylglycerol (POPG), dipalmitoyl-phosphatidylethanolamine (DPPE), dimyristoyl-phosphatidylethanolamine (DMPE), distearoyl-phosphatidylethanolamine (DSPE), monomethyl-phosphatidylethanolamine (MMPE), dimethyl-phosphatidylethanolamine (DMPE), dielaidoyl-phosphatidylethanolamine (DEPE), stearoyloleoyl-phosphatidyl- ethanolamine (SOPE), egg phosphatidylcholine (EPC), hydrogenated soy phosphatidylcholine (HSPC), dipalmitoyl-phosphatidylglycerol (DPPG), and mixtures thereof. In embodiments, DSPC is l,2-distearoyl-sn-glycero-3-phosphocholine. In embodiments, DPPG is 1,2- dipalmitoyl-phosphatidyl-glycerol. In embodiments, DPPG is l,2-dihexadecanoyl-sn-glycero-3- phospho-(l'-sn-glycerol).

[0172] A “cationic lipid” is a positively charged lipid that has the ability to form aggregate complexes with anionic nucleic acids (such as DNA or RNA). Exemplary cationic lipids includeN,N-dioleyl-N.N-dimethylammonium chloride (DODAC), l,2-dioleyloxy-N,N-dimethyl- aminopropane (DODMA). l,2-distearyloxy-N,N-dimethylaminopropane (DSDMA). N-(l-(2,3- dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N,N-distearyl-N,N- dimethyl ammonium bromide (DDAB), l,2-dioleoyloxy-3-(trimethylammonium)propane (DOTAP), 3-(N-(N',N'-dimethylaminoethane)-carbamoyl)cholesterol (DC-Chol), N-(l,2- dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethyl ammonium bromide (DMRIE), 2,3- dioleyloxy-N-[2(spermine-carboxamido)ethyl]-N.N-dimethyl-l-propanaminium-trifluoroacetate (DOSPA), dioctadecylamidoglycyl spermine (DOGS), 3-dimethylamino-2-(cholest-5-en-3-beta- oxybutan-4-oxy)-l-(cis,cis-9,12-octadecadienoxy)-propane (CLinDMA), 2-[5'-(cholest-5-en-3- beta-oxy)-3'-oxapentoxy)-3-dimethy-l-(cis,cis-9',l-2'-octadecadienoxy)-propane (CpLinDMA), N,N-dimethy 1-3,4-dioley loxybenzylamine (DMOB A), 1 ,2-N.N'-dioleylcarbamyl-3-dimethyl- aminopropane (DOcarbDAP), 3-(N,N-dioleylamino)-l,2-propanedio (DOAP), and 1 ,1 ’-((2-(4- (2-((2-(bis(2-hydroxydodecyl)amino)ethyl) (Cl 2-200). In embodiments, the cationic lipid is a “dilinoleic cationic lipid"’ as defined herein. In embodiments, the term “cationic lipid” does not include a “dilinoleic cationic lipid.”

[0173] “Dilinoleic cationic lipid” refers to any cationic lipid containing two linoleic moieties (e.g., two Cis moieties optionally containing 1, 2, or 3 -CH=CH- groups). In embodiments, a dilinoleic cationic moiety' comprises tyvo -(CH2)8CH=CHCH2CH=CH(CH2)4CH3 moieties. Exemplary dilinoleic cationic lipids include MC3. MC3 derivatives, l,2-dilinoleyloxy-N,N- dimethylaminopropane (DLinDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[l,3]-dioxolane (DLin-KC2-DMA), 2,2-dilinoleyl-4-(3-dimethylaminopropyl)-[1 ,3]-dioxolane (DLin-K-3- DMA), 2, 2-dilinoleyl-4-(4-dimethylaminobutyl)-[l,3]-di oxolane (DLin-KC4-DMA), 2,2- dilinoleyl-5-dimethylaminomethyl-[l,3]-di oxane (DLin-K6-DMA), 2,2-dilinoleyl-4-N- methylpepiazino-[ 1 ,3] -di oxolane (DLin-K-MPZ). 2,2-dilinoley l-4-dimethylaminomethyl-[ 1.3]- dioxolane (DLin-K-DMA), l,2-dilinoleylcarbamoyloxy-3-dimethylaminopropane (DLin-C- DAP), l,2-dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), l,2-dilinoleyoxy-3- morpholinopropane (DLin-MA). l,2-dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2- dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), l-linoleoyl-2-linoleyloxy-3- dimethyl aminopropane (DLin-2-DMAP), l,2-dilinoleyloxy-3-trimethylaminopropane or a salt thereof (DLin-TMA), l,2-dilinoleoyl-3-trimethylaminopropane or a salt thereof (DLin-TAP), l,2-dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), 3-(N,N-dilinoleylamino)-I,2- propanediol (DLinAP), 3-(N,N-dioleylamino)-l,2-propanedio (DOAP), l,2-dilinoleyloxo-3-(2- N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), and 1.2-N,N'-dilinoleylcarbamyl-3- dimethylaminopropane (DLincarbDAP).

[0174] The term “MC3” or “Dlin-MC3-DMA” refer to dilinoleyl-methyl-4- dimethylaminobutyrate. In embodiments, ”MC3" refers to heptatriaconta-6,9,28.31-tetraen- 19-yl 4-(dimethylamino)butanoate. In embodiments, ‘ MC3” refers to (6Z,9Z,28Z,31Z)- heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butanoate. The term “MC3 derivative” refers to derivatives of MC3 such as those described in US Publication No. 2017 / 0151333.Exemplary MC3 derivatives include LenMC3, y-LenMC3, MC3 ether, MC4 ether. MC3MC, MC2C. MC2MC, MC3 thioester, MC3 alkyne, MC3 amide, and other compounds described in US Publication No. 2017 / 0151333.

[0175] Embodiments 1 to 86.

[0176] Embodiment 1. A compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer.

[0177] Embodiment 2. The compound of Embodiment 1, wherein the RNA aptamer binds to an intracellular target selected from the group consisting of DNMT1, NF-kB. RUNX1, MYC, MYB, ETS, PAX5, MDM2, F0XM1, PU. l. STAT3, STAT5, STAT6, FAD, ATP5B, and beta- catenin.

[0178] Embodiment 3. The compound of Embodiment 1, wherein the RNA aptamer binds to an intracellular target, wherein the intracellular target is DNMT1.

[0179] Embodiment 4. The compound of Embodiment 1, wherein the RNA aptamer is MDM2, beta-catenin, FAD, ATP5B, or nucleolin.

[0180] Embodiment 5. The compound of Embodiment 1, wherein the RNA aptamer has at least 95% sequence identity to SEQ ID NO:1.

[0181] Embodiment 6. The compound of Embodiment 1, wherein the RNA aptamer has SEQ ID NOT.

[0182] Embodiment 7. The compound of Embodiment 1, wherein the RNA aptamer has at least 95% sequence identity to SEQ ID NO:26.

[0183] Embodiment 8. The compound of Embodiment 1, wherein the RNA aptamer has SEQ ID NO:26.

[0184] Embodiment 9. The compound of Embodiment 1, wherein the RNA aptamer has at least 95% sequence identity to SEQ ID NO:27.

[0185] Embodiment 10. The compound of Embodiment 1, wherein the RNA aptamer has SEQ ID NO:27.

[0186] Embodiment 11. The compound of Embodiment 1, wherein the RNA aptamer has at least 95% sequence identity to SEQ ID NO:28.

[0187] Embodiment 12. The compound of Embodiment 1, wherein the RNA aptamer has SEQ ID NO:28.

[0188] Embodiment 13. The compound of Embodiment 1, wherein the RNA aptamer has at least 95% sequence identity to SEQ ID NO:29.

[0189] Embodiment 14. The compound of Embodiment 1, wherein the RNA aptamer has SEQ ID NO:29.

[0190] Embodiment 15. The compound of Embodiment 1, wherein the RNA aptamer has at least 95% sequence identity to SEQ ID NO:30.

[0191] Embodiment 16. The compound of Embodiment 1, wherein the RNA aptamer has SEQ ID NOTO.

[0192] Embodiment 17. The compound of any one of Embodiments 1 to 16, wherein the aptamer is released into a cell.

[0193] Embodiment 18. The compound of any one of Embodiments 1 to 17, wherein the phosphorothioated CpG oligodeoxynucleotide is a Class A CpG oligodeoxynucleotide.

[0194] Embodiment 19. The compound of any one of Embodiments 1 to 17, wherein the phosphorothioated CpG oligodeoxynucleotide is a Class B CpG oligodeoxynucleotide.

[0195] Embodiment 20. The compound of any one of Embodiments 1 to 17, wherein the phosphorothioated CpG oligodeoxynucleotide is a Class C CpG oligodeoxynucleotide.

[0196] Embodiment 21. The compound of any one of Embodiments 1 to 17, wherein the phosphorothioated CpG oligodeoxynucleotide has at least 95% sequence identity to SEQ ID NOT, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NOT, SEQ ID NOTO, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NOTO, or SEQ ID NOTE

[0197] Embodiment 22. The compound of any one of Embodiments 1 to 17, wherein the phosphorothioated CpG oligodeoxynucleotide has SEQ ID NOT, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NOT, SEQ ID NOT, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13. SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16. SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NOTO, or SEQ ID NOTE

[0198] Embodiment 23. The compound of Embodiment 21 or 22, wherein the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NOT.

[0199] Embodiment 24. The compound of Embodiment 21 or 22. wherein the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:4.

[0200] Embodiment 25. The compound of Embodiment 21 or 22, wherein thephosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:5.

[0201] Embodiment 26. The compound of Embodiment 21 or 22. wherein the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:6.

[0202] Embodiment 27. The compound of Embodiment 1, wherein: (a) the RNA aptamer comprises SEQ ID NO: 1; (b) the DNA oligonucleotide comprises SEQ ID NO:22; and (c) the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NOT, SEQ ID NO:9, SEQ ID NOTO. SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NOTE

[0203] Embodiment 28. The compound of Embodiment 1, wherein: (a) the RNA aptamer comprises SEQ ID NO:26: and (b) the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NOT, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NOT, SEQ ID NOT, SEQ ID NOT, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19. SEQ ID NOTO, or SEQ ID NOTE

[0204] Embodiment 29. The compound of Embodiment 1, wherein: (a) the RNA aptamer comprises SEQ ID NO:27; and (b) the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NOT, SEQ ID NOT, SEQ ID NO:5, SEQ ID NOT, SEQ ID NOT, SEQ ID NOT, SEQ ID NOT, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14. SEQ ID NO: 15, SEQ ID NO:16, SEQ ID NO: 17. SEQ ID NO: 18, SEQ ID NO: 19. SEQ ID NOTO, or SEQ ID NOTE

[0205] Embodiment 30. The compound of Embodiment 1, wherein: (a) the RNA aptamer comprises SEQ ID NO:28; and (b) the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NOT, SEQ ID NOT, SEQ ID NO:5, SEQ ID NOT, SEQ ID NOT, SEQ ID NOT, SEQ ID NOT, SEQ ID NO: 10, SEQ ID NO: 11 , SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NOTO, or SEQ ID NOTE

[0206] Embodiment 31. The compound of Embodiment 1, wherein: (a) the RNA aptamer comprises SEQ ID NO:29; and (b) the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NOT, SEQ ID NOT, SEQ ID NO:5, SEQ ID NOT, SEQ ID NOT, SEQ ID NOT, SEQ ID NOT, SEQ ID NOTO, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14. SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19. SEQ ID NOTO, or SEQ ID NOTE

[0207] Embodiment 32. The compound of Embodiment 1, wherein: (a) the RNA aptamercomprises SEQ ID NO:30: and (b) the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NON, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO:15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

[0208] Embodiment 33. The compound of any one of Embodiments 27 to 32, wherein the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:3.

[0209] Embodiment 34. The compound of Embodiments 27 to 32, wherein the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NON.

[0210] Embodiment 35. The compound of Embodiments 27 to 32, wherein the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:5.

[0211] Embodiment 36. The compound of Embodiments 27 to 32, wherein the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:6.

[0212] Embodiment 37. The compound of any one of Embodiments 1 to 36, wherein the DNA oligonucleotide comprises unmodified nucleotides.

[0213] Embodiment 38. The compound of any one of Embodiments 1 to 36, wherein the DNA oligonucleotide consists of unmodified nucleotides.

[0214] Embodiment 39. The compound of any one of Embodiments 1 to 38, wherein the DNA oligonucleotide only comprises phosphodiester bonds.

[0215] Embodiment 40. The compound of any one of Embodiments I to 39, wherein the DNA oligonucleotide has a nucleic acid sequence capable of hybridizing to the RNA aptamer.

[0216] Embodiment 41. The compound of any one of Embodiments 1-27 and 38-40, wherein the DNA oligonucleotide has at least 95% sequence identity to SEQ ID NO:22.

[0217] Embodiment 42. The compound of Embodiment 41, wherein the DNA oligonucleotide has SEQ ID NO:22.

[0218] Embodiment 43. The compound of any one of Embodiments 1 to 42, wherein the 3’ end of the phosphorothioated CpG oligodeoxynucleotide is linked to the 5’ end of the DNA oligonucleotide.

[0219] Embodiment 44. The compound of any one of Embodiments 1 to 43, wherein the phosphorothioated CpG oligodeoxynucleotide is linked to the DNA oligonucleotide via a linking group.

[0220] Embodiment 45. The compound of Embodiment 44, wherein the linking group comprises a bond, a nucleic acid, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted orunsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or a combination of two or more thereof.

[0221] Embodiment 46. The compound of Embodiment 44, wherein the linking group comprises substituted or unsubstituted 6 to 60 membered heteroalkylene.

[0222] Embodiment 47. The compound of Embodiment 44, wherein the linking group comprises substituted heteroalkylene of the formula:, wherein n is an integer from 1 to 10.

[0223] Embodiment 48. A pharmaceutical composition comprising the compound of any one of Embodiments 1 to 47 and a pharmaceutically acceptable excipient.

[0224] Embodiment 49. The pharmaceutical composition of Embodiment 48, further comprising a BCL-2 inhibitor.

[0225] Embodiment 50. The pharmaceutical composition of Embodiment 49, wherein the BCL-2 inhibitor is venetoclax, oblimersen, ABT-737, navitoclax, or sonrotoclax.

[0226] Embodiment 51. The pharmaceutical composition of Embodiment 49, wherein the BCL-2 inhibitor is venetoclax.

[0227] Embodiment 52. The pharmaceutical composition of any one of Embodiments 48 to 51 , further comprising a chemotherapeutic agent.

[0228] Embodiment 53. The pharmaceutical composition of Embodiment 52, wherein the chemotherapeutic agent is an antimetabolite.

[0229] Embodiment 54. The pharmaceutical composition of Embodiment 53, wherein the antimetabolite is azacitidine, 5-fluorouracil, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin, pralatrexate, or thioguanine.

[0230] Embodiment 55. The pharmaceutical composition of Embodiment 53, wherein the antimetabolite is azacitidine.

[0231] Embodiment 56. A method of delivering a compound into a cell in vivo, the method comprising administering the compound of any one of Embodiments 1 to 47 or the pharmaceutical composition of any one of Embodiments 48 to 55 to a patient, thereby delivering the compound into the cell in vivo.

[0232] Embodiment 57. A method of inhibiting DNA methyltransferase in vitro or in vivo, the method comprising contacting DNA methyltransferase in vivo or in vitro with the compound ofany one of Embodiments 1-3, 5, 6, 17-27, and 33-47 or the pharmaceutical composition of any one of Embodiments 48 to 55.

[0233] Embodiment 58. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of any one of Embodiments 1 to 47 or the pharmaceutical composition of any one of Embodiments 48 to 55, thereby treating cancer in the patient.

[0234] Embodiment 59. The method of Embodiment 58, wherein the cancer is leukemia.

[0235] Embodiment 60. The method of Embodiment 59, wherein the leukemia is acute myeloid leukemia.

[0236] Embodiment 61. The method of Embodiment 59, wherein the leukemia is chronic myelomonocytic leukemia.

[0237] Embodiment 62. The method of Embodiment 58, wherein the cancer is brain cancer.

[0238] Embodiment 63. The method of Embodiment 58, wherein the cancer is glioma.

[0239] Embodiment 64. The method of Embodiment 58, wherein the cancer is glioblastoma.

[0240] Embodiment 65. The method of Embodiment 58, wherein the cancer is prostate cancer.

[0241] Embodiment 66. The method of Embodiment 58, wherein the cancer is pancreatic cancer.

[0242] Embodiment 67. The method of Embodiment 58, wherein the cancer is lung cancer.

[0243] Embodiment 68. The method of Embodiment 58, wherein the cancer is epidermoid squamous carcinoma.

[0244] Embodiment 69. The method of any one of Embodiments 56 to 68, comprising administering the compound or the pharmaceutical composition by intravenous infusion.

[0245] Embodiment 70. The method of any one of Embodiments 56 to 68, comprising administering the compound or the pharmaceutical composition intratumorally.

[0246] Embodiment 71. The method of any one of Embodiments 56 to 70, further comprising administering to the patient an effective amount of a BCL-2 inhibitor.

[0247] Embodiment 72. The method of Embodiment 71, wherein the BCL-2 inhibitor is venetoclax. oblimersen, ABT-737, navitoclax, or sonrotoclax.

[0248] Embodiment 73. The method of Embodiment 71, wherein the BCL-2 inhibitor is venetoclax.

[0249] Embodiment 74. The method of any one of Embodiments 56 to 73, further comprising administering to the patient an effective amount of a chemotherapeutic agent.

[0250] Embodiment 75. The method of Embodiment 74, wherein the chemotherapeutic agent is an antimetabolite.

[0251] Embodiment 76. The method of Embodiment 75, wherein the antimetabolite is azacitidine, 5-fluorouracil. capecitabine. cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin, pralatrexate, or thioguanine.

[0252] Embodiment 77. The method of Embodiment 75, wherein the antimetabolite is azacitidine.

[0253] Embodiment 78. The method of Embodiment 58, wherein the cancer is a myelodysplastic syndrome.

[0254] Embodiment 79. The compound of Embodiment 1, wherein the RNA aptamer has at least 95% sequence identity to SEQ ID NO:33.

[0255] Embodiment 80. The compound of Embodiment 1, wherein the RNA aptamer has SEQ ID NO:33.

[0256] Embodiment 81. The compound of Embodiment 1, wherein the RNA aptamer has at least 95% sequence identity to SEQ ID NO:34.

[0257] Embodiment 82. The compound of Embodiment 1, wherein the RNA aptamer has SEQ ID NO:34.

[0258] Embodiment 83. The compound of Embodiment 1, wherein: (a) the RNA aptamer comprises SEQ ID NO:33; (b) the DNA oligonucleotide comprises SEQ ID NO:22; and (c) the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10. SEQ ID NO: 11, SEQ ID NO:12, SEQ ID NO: 13, SEQ ID NO 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO:17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

[0259] Embodiment 84. The compound of Embodiment 1, wherein: (a) the RNA aptamer comprises SEQ ID NO:34: (b) the DNA oligonucleotide comprises SEQ ID NO:22; and (c) the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NOTO, SEQ ID NO: 11, SEQ ID NO:12, SEQ ID NO: 13, SEQ ID NO 14, SEQ ID NO: 15, SEQ ID NO: 16. SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19. SEQ ID NO:20, or SEQ ID NO:21.

[0260] Embodiment 85. A lipid nanoparticle comprising the compound of any one of Embodiments 1-47 and 79-84.

[0261] Embodiment 86. A pharmaceutical composition comprising a lipid nanoparticle comprising the compound of any one of Embodiments 1-47 and 79-84.

[0262] Embodiments P I to P22

[0263] Embodiment PE A compound comprising a phosphorothioated CpGoligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer.

[0264] Embodiment P2. The compound of Embodiment Pl, wherein the RNA aptamer binds to an intracellular target selected from the group consisting of DNMT1, NF-kB, RUNX1, MYC, MYB, ETS, PAX5, MDM2, FOXM1, PU.l, STAT3, STAT5, STAT6, FAD, ATP5B, and beta- catenin.

[0265] Embodiment P3. The compound of Embodiment Pl, wherein the RNA aptamer is MDM2, beta-catenin, FAD, ATP5B, or nucleolin.

[0266] Embodiment P4. The compound of Embodiment Pl, wherein the RNA aptamer has at least 95% sequence identity to SEQ ID NO: 1, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30. SEQ ID NO:33, or SEQ ID NO:34.

[0267] Embodiment P5. The compound of any one of Embodiments Pl to P4, wherein the aptamer is released into a cell.

[0268] Embodiment P6. The compound of any one of Embodiments Pl to P5, wherein the phosphorothioated CpG oligodeoxynucleotide is a Class A CpG oligodeoxynucleotide, a Class B CpG oligodeoxynucleotide, or a Class C CpG oligodeoxynucleotide.

[0269] Embodiment P7. The compound of any one of Embodiments Pl to P5, wherein the phosphorothioated CpG oligodeoxynucleotide has at least 95% sequence identity to any one of SEQ ID NOS:3-23.

[0270] Embodiment P8. The compound of Embodiment Pl, wherein: (i) the RNA aptamer comprises SEQ ID NO: 1; the DNA oligonucleotide comprises SEQ ID NO: 24; and the phosphorothioated CpG oligodeoxynucleotide comprises any one of SEQ ID NOS:3-23; (ii) the RNA aptamer comprises SEQ ID NO:33; the DNA oligonucleotide comprises SEQ ID NO:24; and the phosphorothioated CpG oligodeoxynucleotide comprises any one of SEQ ID NOS:3-23; (iii) the RNA aptamer comprises SEQ ID NO:34; the DNA oligonucleotide comprises SEQ ID NO:24; and the phosphorothioated CpG oligodeoxynucleotide comprises any one of SEQ ID NOS:3-23; (iv) the RNA aptamer comprises SEQ ID NO:26; and the phosphorothioated CpG oligodeoxynucleotide comprises any one of SEQ ID NOS:3-23; (v) the RNA aptamer comprises SEQ ID NO:27; and the phosphorothioated CpG oligodeoxynucleotide comprises any one of SEQ ID NOS:3-23; (vi) the RNA aptamer comprises SEQ ID NO:28; and the phosphorothioated CpG oligodeoxynucleotide comprises any one of SEQ ID NOS: 3-23; (vii) the RNA aptamer comprises SEQ ID NO:29; and the phosphorothioated CpG oligodeoxynucleotide comprises any one of SEQ ID NOS:3-23; or (viii) the RNA aptamer comprises SEQ ID NO:30; and the phosphorothioated CpG oligodeoxynucleotide comprises any one of SEQ ID NOS:3-23.

[0271] Embodiment P9. The compound of any one of Embodiments Pl to P8, wherein the DNA oligonucleotide comprises unmodified nucleotides.

[0272] Embodiment PIO. The compound of any one of Embodiments Pl to P9, wherein the DNA oligonucleotide only comprises phosphodiester bonds.

[0273] Embodiment P 11. The compound of any one of Embodiments Pl to PIO, wherein the DNA oligonucleotide has a nucleic acid sequence capable of hybridizing to the RNA aptamer.

[0274] Embodiment P12. The compound of any one of Embodiments Pl to Pl 1. wherein the DNA oligonucleotide has at least 95% sequence identity to SEQ ID NO:24.

[0275] Embodiment Pl 3. The compound of any one of Embodiments Pl to Pl 2, wherein the 3’ end of the phosphorothioated CpG oligodeoxynucleotide is linked to the 5’ end of the DNA oligonucleotide.

[0276] Embodiment P14. The compound of any one of Embodiments Pl to P13, wherein the phosphorothioated CpG oligodeoxynucleotide is linked to the DNA oligonucleotide via a linking group.

[0277] Embodiment P15. The compound of any one of Embodiments Pl to P5, wherein the phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide comprises SEQ ID NO:25, SEQ ID NO:31, or SEQ ID NO:32.

[0278] Embodiment Pl 6. A lipid nanoparticle comprising the compound of any one of Embodiments Pl to P 15.

[0279] Embodiment P l 7. A pharmaceutical composition comprising the compound of any one of Embodiments Pl to P15 and a pharmaceutically acceptable excipient; or the lipid nanoparticle of Embodiment P 15.

[0280] Embodiment Pl 8. A method of delivering a compound into a cell in vivo, the method comprising administering the compound of any one of Embodiments Pl to P15, the lipid nanoparticle of Embodiment Pl 6, or the pharmaceutical composition of Embodiment Pl 7 to a patient, thereby delivering the compound into the cell in vivo.

[0281] Embodiment Pl 9. A method of inhibiting DNA methyltransferase in vitro or in vivo, the method comprising contacting DNA methyltransferase in vivo or in vitro with the compound of any one of Embodiments Pl to Pl 5, the lipid nanoparticle of Embodiment Pl 6, or the pharmaceutical composition of Embodiment Pl 7, thereby inhibiting DNA methyltransferase.

[0282] Embodiment P20. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of any one of Embodiments P l to P15. the lipid nanoparticle of Embodiment P16, or the pharmaceutical composition of Embodiment Pl 7, thereby treating cancer in the patient.

[0283] Embodiment P21. The method of Embodiment P20, wherein the cancer is leukemia, brain cancer, prostate cancer, pancreatic cancer, lung cancer, epidermoid squamous carcinoma, or a myelodysplastic syndrome.

[0284] Embodiment P22. The method of Embodiment P21 or P21, further comprising administering to the patient an effective amount of a BCL-2 inhibitor, an antimetabolite, or a combination thereof.

[0285] Embodiment P23. The method of Embodiment P21 or P22, further comprising administering to the patient an effective amount of a a tyrosine kinase inhitor.EXAMPLES

[0286] AML cells resist differentiation stimuli despite high expression of innate immune receptors, such as Toll-like Receptor 9 (TLR9). We previously demonstrated that targeting STAT3 using TLR9-targeted decoy oligodeoxynucleotide (CpG-STAT3dODN) results in increased immunogenicity of human and mouse AML cells (Hossain et al. Blood 2014; Zhang et al. Blood 2016). In our recent study (Wang et al,L‘Bi-functional CpG-STAT3 decoy oligonucleotide triggers multilineage differentiation of acute myeloid leukemia in mice." Molecular Therapy: Nucleic Acid (July 16, 2024), we elucidated molecular mechanisms of CpG-STAT3dODN-driven differentiation of inv(16) AML, Cbfb / Myhl 1 / Mpl (CMM). We found that CpG-STAT3dODN induced epigenetic reprogramming and multi-lineage differentiation of AML cells into monocytes / macrophages, erythroblastic and B cell-lineages.

[0287] Correspondingly, we found that CpG-STAT3dODN downregulated STAT3-controlled methylation regulators, such as DNMT1, thereby inducing expression of transcription factors regulating myeloid cell differentiation such as IRF8. In fact, the combination of DNMT1 inhibition using azacitidine with TLR9 stimulation mimicked CpG-STAT3dODN effects resulting in regression of AML cells including c-kit+ leukemia stem cells (LSC) in mice (FIG. 1).

[0288] These effects correlated with the upregulation of IRF8 and antigen presenting molecules on AML cells, together with increased infiltration of CD8 T cells into leukemiabearing spleen. We further verified that CpG oligonucleotides, especially type A and C, augmented anti-leukemic effect of azacitidine on a panel of human AML cells including CD34+ KGla and FLT3ITD+ MV4-11 leukemia (FIG. 2). In addition, azacitidine combined with CpG- A or CpG-C enhanced the expression of myeloid differentiation markers, such as CD1 lb, CD14, CD70 or HLA-DR, on human AML cells (FIG. 3).

[0289] Based on these initial findings, we designed a bi-functional oligonucleotide combiningan RNA aptamer inhibiting DNMT1 with CpG ODN for TLR9-mediated delivery' and immunostimulation of AML cells (FIG. 4A). The CpG-DNMTlapt conjugate allowed for the delivery of DNMT1 RNA aptamer using a complementary passenger DNA strand directly conjugated on 5’ end to 3’ end of CpG ODN (FIG. 4A-4C and Table 1). The unmodified passenger DNA strand would be degraded after cellular uptake to allow for release and folding of the aptamer into an active form.

[0290] The chemically modified DNMT1 aptamer alone was confirmed to be nuclease resistant (Tl / 2 about 216 h), while the conjugate would undergo processing to release the aptamer with half-life of about 26 h. Thus, the conjugate would remain intact during systemic delivery' to target cancer cells typically requiring 1-2 h (e.g. using slow intravenous infusion). The CpGB1-DNMTlapt conjugate was effectively internalized into various human AML cells (FIG. 5A) in contrast to the unconjugated DNMT1 aptamer which showed minimal uptake (FIG. 5B). The mechanism of CpGB1-DNMTlapt uptake relied on the active endocytosis mediated by scavenger receptors (SRs) (FIG. 5C). CpGB1-DNMTlapt reduced viability of target AML cells (FIG. 6A) with the evidence of reduction of DNMT1 protein levels (FIGS. 6B-6C) or DNMT1 activity' (FIG. 6D).

[0291] While CpGB1-DNMTlapt showed anti-leukemic activity as a single agent, it also synergized with venetoclax (a BCL-2 inhibitor), a clinically relevant inhibitor of anti-apoptotic signaling in AML cells. As shown in FIG. 7, the combination of CpGB1-DNMTlapt with venetoclax resulted in enhanced cytotoxic effects on various AML cells including FLT3ITD+ MA9.3ITD leukemia in vitro. Next, we verified the antileukemic activity of CpGB1-DNMTlapt in two xenotransplanted AML models - MOLM-13 and MA9.3ITD - in immunodeficient NSG mice (FIG. 8). Local intratumoral injections of CpGBI-DNMTlapt were superior in inhibiting growth of MOLM-13 leukemia to the equimolar amount of the unconjugated DNMTlapt alone and comparable to the azacitidine used as a benchmark treatment. The anti-leukemic effects of CpGB1-DNMTlapt and azacitidine correlated with the reduced protein levels of DNMT1 and oncogenic c-MYC. while C / EBPa levels were increased indicating myeloid differentiation of AML cells. CpGB1-DNMTlapt had similar growth inhibitory effect on MA9.3ITD leukemia in NSG mice, although in this model we did observe significant activity of DNMTlapt alone that may result from the high intratumoral concentration of the aptamer. CpGB1-DNMTlapt resulted in the upregulation of several myeloid / monocyte differentiation markers such as CD1 lb, CD 14 or antigen-presenting HLA-DR molecules.

[0292] To compare the efficacy of three variants of CpG-DNMTlapt using A, B and C types of CpG ODN sequences, we repeated experiments using MOLM-13 AML model in NSG mice.CpGBI-DNMTI apt proved superior to type A and C conjugate variants resulting in the maximal growth inhibition (FIG. 9A), reduction of leukemia volume (FIG. 9B-9C) and vascularization (FIG. 9D). These effects correlated with the inhibition of DNMT1 activity (FIG. 9E) and protein levels (FIG. 9F) in vivo, with concomitant elevation of CD1 lb, CD70 and HLA-DR differentiation markers on AML cells (FIG. 9G).

[0293] The data indicate that CpG-DNMTlapt conjugates, e.g.. CpG^-DNMT 1 apt variant, will have broad activity against a variety’ of human cancer cells derived from solid tumors (FIG. 10). CpG-DNMTlapt significantly reduced viability of several human and mouse glioma cells as well as prostate, pancreatic, lung and skin cancer cells within 2 days of in vitro culture. Therefore, CpG-DNMTlapt strategy' will allow for epigenetic reprogramming and induction of cytotoxic or cytostatic effects in human cancers not limited to myeloid leukemia.

[0294] Table 1

[0295] It is understood that the examples described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and scope of this application and claims. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application are expressly incorporated by reference herein in their entirety and for all purposes.

Claims

CLAIMSWhat is claimed is:

1. A compound comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide, wherein the DNA oligonucleotide is hybridized to an RNA aptamer.

2. The compound of claim 1, wherein the RNA aptamer binds to an intracellular target selected from the group consisting of DNMT1, NF-kB, RUNX1, MYC, MYB, ETS. PAX5, MDM2, F0XM1, PU. l, STAT3. STAT5, STAT6, FAD, ATP5B. and beta-catenin.

3. The compound of claim 1, wherein the RNA aptamer is MDM2, beta-catenin, FAD, ATP5B, or nucleolin.

4. The compound of claim 1, wherein the RNA aptamer has at least 95% sequence identity to SEQ ID NO: 1, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, or SEQ ID NO:30.

5. The compound of claim 1, wherein the aptamer is released into a cell.

6. The compound of claim 1, wherein the phosphorothioated CpG oligodeoxynucleotide is a Class A CpG oligodeoxynucleotide, a Class B CpG oligodeoxynucleotide, or a Class C CpG oligodeoxynucleotide.

7. The compound of claim 1, wherein the phosphorothioated CpG oligodeoxynucleotide has at least 95% sequence identity to SEQ ID NO: 3, SEQ ID NO:4, SEQ ID NO:

5. SEQ ID NO:

6. SEQ ID NOY. SEQ ID NO:

8. SEQ ID NO:

9. SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO:17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO: 23.

8. The compound of claim 1, wherein:(i) the RNA aptamer comprises SEQ ID NO: 1; the DNA oligonucleotide comprises SEQ ID NO:24; and the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NOY, SEQ ID NO: 8, SEQ ID NOY, SEQ ID NOTO, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO:

14. SEQ ID NO:15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:

21. SEQ ID NO:22, or SEQ ID NO:23;(ii) the RNA aptamer comprises SEQ ID NO:33; the DNA oligonucleotide comprisesSEQ ID NO:24; and the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NON, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO: 8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 1 1, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO 22, or SEQ ID NO:23;(iii) the RNA aptamer comprises SEQ ID NO:34; the DNA oligonucleotide comprises SEQ ID NO:24: and the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NON, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO: 8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO:

14. SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO:

17. SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, or SEQ ID NO:23;(iv) the RNA aptamer comprises SEQ ID NO:26; and the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NON, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:

21. SEQ ID NO:22, or SEQ ID NO:23;(v) the RNA aptamer comprises SEQ ID NO:27; and the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NON, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO:

14. SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO:

17. SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23;(vi) the RNA aptamer comprises SEQ ID NO:28; and the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NON, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NON, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23;(vii) the RNA aptamer comprises SEQ ID NO:29; and the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NON, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NON, SEQ ID NO: 10,SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO:

14. SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO:

17. SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23; or(viii) the RNA aptamer comprises SEQ ID NO:30; and the phosphorothioated CpG oligodeoxynucleotide comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO:

12. SEQ ID NO: 13, SEQ ID NO:

14. SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23.

9. The compound of claim 1, wherein the DNA oligonucleotide comprises unmodified nucleotides.

10. The compound of claim 1, wherein the DNA oligonucleotide only comprises phosphodiester bonds.

11. The compound of claim 1, wherein the DNA oligonucleotide has a nucleic acid sequence capable of hybridizing to the RNA aptamer.

12. The compound of claim 1, wherein the DNA oligonucleotide has at least 95% sequence identity to SEQ ID NO:24.

13. The compound of claim 1, wherein the 3’ end of the phosphorothioated CpG oligodeoxy nucleotide is linked to the 5’ end of the DNA oligonucleotide.

14. The compound of claim 1, wherein the phosphorothioated CpG oligodeoxynucleotide is linked to the DNA oligonucleotide via a linking group.

15. The compound of claim 1, wherein the phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide comprises SEQ ID NO: 25, SEQ ID NO:31, or SEQ ID NO:32.

16. A lipid nanoparticle comprising the compound of claim 1.

17. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

18. A method of delivering a compound into a cell in vivo, the method comprising administering the compound of claim 1 to a patient, thereby delivering the compound into the cell in vivo.

19. A method of inhibiting DNA methyltransferase in vitro or in vivo, the methodcomprising contacting DNA methyltransferase in vivo or in vitro with the compound of claim 1, thereby inhibiting DNA methyltransferase.

20. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of claim 1. thereby treating cancer in the patient.

21. The method of claim 20, wherein the cancer is leukemia, brain cancer, prostate cancer, pancreatic cancer, lung cancer, epidermoid squamous carcinoma, or a myelodysplastic syndrome.

22. The method of claim 20, further comprising administering to the patient an effective amount of a BCL-2 inhibitor, an antimetabolite, or a combination thereof.

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