Micronutrient-stabilizing materials

Abstract

Provided herein are metal-organic frameworks, and compositions, food products, beverages, nutritional supplements and kits thereof, as well as associated methods and uses. The metal-organic frameworks provided herein are biocompatible and are useful for delivery of guest molecules for the treatment and / or prevention of various diseases and conditions.

Description

MICRONUTRIENT-STABILIZING MATERIALSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. provisional application number 63 / 672,657, filed July 17, 2024, which is incorporated by reference herein in its entirety.BACKGROUND

[0002] Micronutrients, encompassing indispensable vitamins and minerals, are integral to maintaining human health (7). Their absence precipitates severe and potentially lifethreatening conditions. Iron deficiency (2), for instance, correlates with compromised immune functionality, reduced work capacity, and heightened susceptibility to maternal and infant mortality, emerging as a primary determinant of developmental impairments in children. Globally, the prevalence of iron deficiency anemia is staggering, affecting approximately two billion individuals, with 42% of children under the age of 5 and 40% of pregnant women worldwide grappling with anemia (3). In parallel, iodine deficiency disorders afflict a substantial population, impacting the lives of 2 billion people globally (4). These statistics underscore the importance of addressing micronutrient deficiencies for public health initiatives and interventions.

[0003] The World Health Organization (WHO) advocates for dietary diversification, micronutrient supplementation (5), and food fortification as strategic measures against micronutrient deficiencies. Among these, food fortification emerges as the most cost- effective and efficient approach, especially in marginalized regions where broader application of the former strategies proves challenging. For example, the fortification of salt with iodine represents a significant success, playing a critical role in reducing the prevalence of iodine deficiency diseases worldwide. This achievement is attributed to the global dietary staple status of salt, facilitating widespread success in over 120 countries, including rural and marginalized communities. The demonstrated efficacy of iodized salt has prompted recommendations for its use as a vehicle for iron fortification initially proposed in 1960s (6), aiming to address iron deficiency. Nonetheless, this approach has faced persistent technical and logistical challenges. The direct addition of iron compounds is complicated by their high reactivity and poor palatability. Additionally, the interaction between iron and iodine compounds (oxidation of iron (II) and iodide, and reduction of iodate) poses further challenges, reducing iron's bioavailability and causing iodine to sublimate, thereby necessitating a solution for their stable coexistence in double-fortified salt (DFS). Inaddition, the valence of iron salts plays an important role in the efficacy of DFS applications (7-9). Iron in its ferrous form exhibits superior bioavailability. Nevertheless, preserving ferrous iron is a formidable challenge as ferrous iron salts are prone to oxidation, converting into ferric salts which exhibit diminished bioavailability. In response to these challenges, a DFS formulation utilizing encapsulation technology has been developed that entails the agglomeration of ferrous fumarate with hydroxypropyl methylcellulose, subsequently coated with titanium dioxide to conceal the red hue of ferrous fumarate. However, the coating material makes up 55% of the final product, bringing potential additional cost and stability concerns, especially when stored at high-humidity environments (5,51 ). These issues underscore the need for ongoing research and development to refine DFS technology, ensuring its efficacy and stability in nutrient absorption after consumption for widespread application.

[0004] More broadly, there is a need for technologies to improve stability and delivery of micronutrients and various other agents.SUMMARY OF THE INVENTION

[0005] In one aspect, provided herein are metal-organic frameworks, comprising: a plurality of biocompatible metal cores comprising iron, calcium, magnesium, selenium, zinc, or a combination thereof; and a plurality of biocompatible organic ligands, each comprising at least two alkoxide or carboxylate moieties; wherein: each metal core is linked to at least one other metal core by at least one organic ligand.

[0006] In another aspect, provided herein are metal-organic frameworks, comprising: a plurality of biocompatible metal cores; a plurality of biocompatible organic ligands; and a metal-polyphenolic network (MPN) coating; wherein: each metal core is linked to at least one other metal core by at least one organic ligand, forming a particle; and the MPN coating is deposited on the surface of the particle.

[0007] In another aspect, provided herein are compositions comprising a metal-organic framework provided herein and an excipient.

[0008] In another aspect, provided herein are food products comprising a metal-organic framework provided herein and an excipient.

[0009] In another aspect, provided herein are beverages comprising a metal-organic framework provided herein and water.

[0010] In another aspect, provided herein are nutritional supplements comprising a metalorganic framework provided herein and an excipient.

[0011] In another aspect, provided herein are kits comprising: a metal-organic framework, a composition, a food product, a beverage, or a nutritional supplement provided herein; and instructions for using the metal-organic framework, composition, food product, beverage, or nutritional supplement.

[0012] In another aspect, provided herein are methods of delivering an agent to a subject, comprising administering to the subject a metal-organic framework, a composition, a food product, a beverage, or a nutritional supplement provided herein.

[0013] In another aspect, provided herein are methods of treating or preventing a disease, disorder, or condition in a subject, comprising administering to the subject a metal-organic framework, a composition, a food product, a beverage, or a nutritional supplement provided herein.

[0014] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0001] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, provide non-limiting examples of the invention.

[0002] FIGs. 1A-1C The development of fortified supplement using large language model and artificial intelligence. (FIG. 1A) Large language model for data mining from literature. (FIG. IB) Artificial intelligence for prediction and high throughput screening. (FIG. 1C) NuMOF as fortified supplements (MOF and nutrients are not to scale relative to cells).

[0003] FIGs. 2A-2D Synthesis of Fe(II) NuMOFs and proposed mechanism of iron oxo oxidation cluster. (FIG. 2A) Illustration of synthesis of NuMOFs with different valences, including reduction of Fe(III) MOF to Fe(II) MOF such as by addition of vitamin C. (FIG. 2B) Reduction of Fe(III) NuMOF. (FIG. 2C) Proposed mechanism of iron oxo cluster oxidation from Fe(II) complex to Fe(III) MOE (FIG. 2D) The structures of NuMOFs as described herein, including NuMOF- 1 (fumaric acid as ligand), NuMOF-2 (aspartic acid as ligand), NuMOF-3 (mesaconic acid as ligand), NuMOF-4 (trans, trans-muconic acid as ligand), and NuMOF- 19 (2,3-dimethyl fumaric acid).

[0004] FIGs. 3A-3H Structural and morphological characterizations NuMOF- 1. (FIG. 3A) PXRD patterns of the experimental NuMOF- 1 and simulated NuMOF- 1. (FIG. 3B, FIG. 3C) HRTEM of NuMOF- 1 (Fe2+) with d-spacing and FFT image. (FIG. 3D, FIG. 3E) SEM and elemental mapping of NuMOF- 1 (Fe2+). (FIG. 3F) Fe 2p XPS spectra of NuMOF- 1 (Fe2+). (FIG. 3G) The XPS spectrum of NuMOF-l(Fe2+) and NuMOF- l(Fe3+). (FIG. 3H) The Brunauer-Emmett-Teller curve of NuMOF- 1.

[0005] FIGs. 4A-4H Post iodine adsorption characterizations of NuMOF- 1. (FIG. 4A) Gaseous iodine uptake capacities of NuMOF- 1 Fe(II) and NuMOF- 1 Fe(III) over time. (FIG. 4B) Fe 2p and (FIG. 4C) I 3d, XPS spectra of NuMOF- 1 (Fe2+) after iodine adsorption. (FIG. 4D) Raman mapping of I2@NUMOF-1 (Fe2+). (FIG. 4E) Raman spectra of NuMOF- 1 (Fe2+) after E loading. (FIG. 4F) Raman spectra of NuMOF- 1 (Fe2+) before (black) and after loading with KI (red), I2 (blue) and KIO3 (green). (FIG. 4G) FTIR spectra of NuMOF- 1 (Fe2+) before (black) and after loading with KI (red), I2 (blue) and KIO3 (green). (FIG. 4H) TGA of profile of NuMOF- 1 (Fe2+) before and after loading with KI, I2 and KIO3, and images of NuMOF-1 before and after loading with KI, I2, or KIO3.

[0006] FIGs. 5A-5I NuMOF-1 stabilized loaded iodine compounds under harsh treatment conditions. Iodine, iodide, and iodate compounds were effectively stabilized in NuMOF-1 platform when treated under (FIG. 5A) boiling water (100 °C), (FIG. 5B) oven heating (100 °C), and (FIG. 5C) light exposure (25 °C) for 2 hours. (FIG. 5D, FIG. 5E, FIG. 5F) When NuMOF-1 was placed in the aqueous solution of various polyphenol compounds, iron ions were effectively shielded from complex interaction with the polyphenol compounds (FIG. 5E), giving high recovery of soluble ions in the solution (FIG. 5D) and low color change (FIG. 5F). The color change of solutions in FIG. 5F were calculated by distance AE, shown in FIG. 5E. (FIG. 5G) shows percent recovery after placing I2@NUMOF- 1 (Fe2+) in a simulated high temperature and high humidity environment (75% rH at 40°C). (FIG. 5H) shows recovery of elemental iodine under normal storage conditions (75% rH at 25°C).(FIG. 51) shows a comparison of the stability of valence states within NuMOFs synthesized through varying methodologies, including synthesis in aqueous and dimethylformamide (DMF) solvents and reduction by ascorbic acid.

[0007] FIGs. 6A-6G In vitro release of iron and iodine from NuMOF-1. (FIG. 6A) pH- dependent iron releasing of NuMOF-1 (Fe2+). (FIG. 6B) Controlled release of iron from NuMOF-1 (Fe2+) when treated with room-temperature water (black triangles), boiling water (blue squares), or 37 °C SGF (red circles). (FIG. 6C) Controlled release of iodine from l2@ NuMOF-1 (Fe2+) when treated with room-temperature water (blue squares), boiling water (black triangles), or 37 °C SGF (red circles). (FIG. 6D) Schematics of cellular uptake of NuMOF-1 components by Caco-2 cells. (FIG. 6E) Cell uptake of iron from NuMOF-1 in caco-2 cell. (FIG. 6F) Confocal imaging of Caco-2 cells with absorption of SGF-treated NuMOF-1 (Fe2+) loaded with fluorescent cargo molecules. The cytoplasm, NuMOF-1 (arrows), and nucleus are shown. (FIG. 6G) SEM images of NuMOF-1 when treated with room-temperature water (2 hours), boiling water (2 hours), or 37 °C SGF (10 minutes).

[0008] FIGs. 7A-7C In vivo release and absorption of iodine. (FIG. 7A) Temporal imaging, (FIG. 7B) pharmacokinetics in gastrointestinal tract, and (FIG. 7C) biodistribution of mice after oral administration of free-form Na125! and Na125I-loaded NuMOF-1 at various time points up to 48 hours. Signal in FIGs. 7B-7C was quantified using temporal images shown in FIG. 7A.

[0009] FIG. 8 The workflow of Human-ChatGPT collaborative data mining.

[0010] FIG. 9 Inadequate response from ChatGPT due to unspecific querying. An example chatbox interaction between a user and ChatGPT demonstrating the necessity of prompt engineering. The user asks, "What is MOF?" to which ChatGPT responds with a general description of "Metal-Organic Frameworks" (MOFs) without specific context. The answer, though correct, highlights the importance of tailored prompts to generate more focused and applicable responses for specialized academic inquiries.

[0011] FIG. 10 Enhanced response from ChatGPT with contextual prompting. An example chatbox interaction demonstrating the improvement in ChatGPT’ s response when initiated with specific context in the field of chemistry and material science. The user defines ChatGPT as an Al assistant with expertise in these areas and inquires, "What is MOF?" ChatGPT provides a detailed and scientific explanation of MOFs, highlighting their structural characteristics and applications. Subsequent queries about MOF ligands and specific MOFs (MIL-88A) elicit accurate and detailed responses, while an inquiry about a non-existent MOF("MOF99999") showcases ChatGPT’s ability to correctly identify and address erroneous or fictional information.

[0012] FIG. 11 ChatGPT's proficiency in summarizing academic criteria. This figure illustrates an interaction where ChatGPT is provided with a document containing established criteria for classifying the water stability of MOFs. This review was chosen for its high citation and clear instructions for water stability classifications for MOFs. After reviewing the document, ChatGPT accurately summarizes the criteria into four categories: Thermodynamically Stable MOFs, MOFs with High Kinetic Stability, MOFs with Low Kinetic Stability, and Unstable MOFs. Each category is defined based on its stability characteristics under various moisture conditions. The summary highlights ChatGPT’s capability to assimilate and concisely relay complex scientific content, aiding in the classification and selection of MOFs for research and industrial applications.

[0013] FIG. 12 Criteria for MOF water stability classifications.

[0014] FIG. 13 ChatGPT’s capacity of data summarization and CSV file generation. This figure displays a summary table generated by ChatGPT after being tasked with extracting and classifying information about MOFs from a scholarly article. The Al was asked to identify MOFs mentioned in the paper, summarize characterization information related to their water stability, and classify each MOF into one of four tiers (Thermodynamically Stable, High Kinetic Stability, Low Kinetic Stability, Unstable). Additionally, ChatGPT was instructed to generate a CSV file from the table data, enhancing usability for further analysis. The result is a structured table categorizing three variants of MIL-88B MOFs by their water stability metrics, which exemplifies the capabilities of Al in data processing and documentation in a scientific context.

[0015] FIG. 14 Enhanced throughput capability of ChatGPT in processing multiple academic papers simultaneously. This figure demonstrates ChatGPT's advanced ability to handle multiple documents in a single query. The Al was tasked with identifying MOFs, summarizing characterization information related to water stability, classifying them into tiers, and generating a CSV file for each paper. Summaries and classifications for MOFs from three separate documents ("refl9.pdf", "ref20.pdf", and "ref21.pdf") are displayed in structured tables, showcasing the Al’s robust data processing capabilities in a scientific context. Each table includes the MOF names, characterization summaries, tier classifications, and corresponding CSV file generation, emphasizing ChatGPT’s capacity to efficiently process and document extensive data sets for academic research.

[0016] FIG. 15 Machine learning results. The pairwise correlation matrix of the top 6 molecular descriptors ranked by Gini importance, including PEOE_VSA3, BCUT2D_MRHI, PEOE_VSA9, MinAbsPartialCharge, MaxPartialCharge, and solubility (sol). The diagonal panels display the distribution of each feature, while the off-diagonal scatter plots illustrate relationships between different descriptor pairs.

[0017] FIGs. 16A-16B Machine learning results: feature importance and true versus predicted performance. (FIG. 16A) Feature importance indicated by the Gini importance of molecular descriptors used in the model, with PEOE_VSA3 and BCUT2D_MRHI showing the highest significance. (FIG. 16B) Confusion matrix illustrating the model’s predictive performance, with true labels compared to predicted labels for three classes.

[0018] FIG. 17 The PXRD patterns of reaction products for water stability screening to verify machine learning model.

[0019] FIGs. 18A-18C Pictures of NuMOF-1 solutions synthesized in water (FIG. 18A) and DMF (FIG. 18B) and (FIG. 18C) alkaline water.

[0020] FIGs. 19A-19B Experimentally determined and simulated PXRD patterns for the NuMOF-1 synthesized by hydrothermal method (FIG. 19A) or solvent thermal method (FIG. 19B), covering a 29 range between 5° and 30°.

[0021] FIGs. 20A-20B The FTIR spectrum of the NuMOF-1 synthesized by hydrothermal method (FIG. 20A) or solvent thermal method (FIG. 20B).

[0022] FIGs. 21A-21B SEM images of NuMOF- 1 synthesized by hydrothermal method (FIG. 21A) or solvent thermal method (FIG. 21B).

[0023] FIG. 22 XPS patterns of NuMOF- 1 synthesized by hydrothermal method. (Left graph) survey XPS and (Right graph) high energy XPS patterns of Fe2p.

[0024] FIG. 23 XPS patterns of NuMOF-1 synthesized by solvent thermal method (DMF). (Left graph) survey XPS and (Right graph) high energy XPS patterns of Fe2p.

[0025] FIG. 24 Photos of iron kits result for iron NuMOF-1 synthesized by hydrothermal method, iron NuMOF-1 powder and iron NuMOF-1 solutions.

[0026] FIG. 25 The XPS spectrum of NuMOF synthesized by alkaline water and high energy XPS.

[0027] FIGs. 26A-26B Images of NuMOF- l(Fe3+) (FIG. 26A) and NuMOF- l(Fe2+) (FIG. 26B) synthesized by alkaline water or reduced by ascorbic acid.

[0028] FIGs. 27A-27B The SEM images of NuMOF-1 (Fe3+) (FIG. 27A) and reduced by ascorbic acid (FIG. 27B).

[0029] FIG. 28 XPS pattern of NuMOF-1 (Fe3+) reduced by ascorbic acid.

[0030] FIGs. 29A-29B SEM images of NuMOF-2 synthesized by (FIG. 29A) hydrothermal method or (FIG. 29B) solvent thermal method.

[0031] FIGs. 30A-30B SEM images of NuMOF-3 synthesized by (FIG. 30A) hydrothermal method or (FIG. 30B) solvent thermal method.

[0032] FIGs. 31A-31B SEM images of NuMOF-4 synthesized by (FIG. 31A) hydrothermal method or (FIG. 31B) solvent thermal method.

[0033] FIG. 32 High-resolution transmission electron microscopy (HRTEM) images of NuMOF-1.

[0034] FIGs. 33A-33B (FIG. 33A) SEM elemental mapping image (scale bar 2 pm) and (FIG. 33B) elemental ratio of NuMOF-1.

[0035] FIG. 34 XPS survey of I2@NUMOF- 1.

[0036] FIG. 35 Image of Raman spectroscopy mapping of NuMOF-1 after I2 absorption test.

[0037] FIG. 36 XPS patterns and Fe 2P3 / 2 of NuMOF-3.

[0038] FIG. 37 XPS patterns of NuMOF-19.

[0039] FIG. 38 XPS patterns of NuMOF-4.

[0040] FIGs. 39A-39C The DFT calculation for the mechanism study. (FIG. 39A) The relative free energies of Fu-Fe(II), transition state of fumaric acid-iron complex with H2O (TS-Fu-Fe(II)+H2O), and (FIG. 39B). (FIG. 39C) The optimized structures of initial, transition, and final states.

[0041] FIG. 40 PXRD of NuMOF-1 (Fe3+) reduced by ascorbic acid.

[0042] FIG. 41 The experimentally determined and simulated PXRD patterns for the NuMOF-3 (Mesaconic acid) with solvent thermal method, covering a 29 range between 5° and 20°.

[0043] FIG. 42 The experimentally determined and simulated PXRD patterns for the NuMOF-19 (Dimethyl fumaric acid) with solvent thermal method, covering a 29 range between 5° and 30°.

[0044] FIGs. 43A-43F Biodistribution and gastrointestinal transit of CD-MOF and MPN- CD-MOF formulations. (FIG. 43A) In vivo fluorescence imaging of mice at different time points (0-24 hours) following administration of Control, MOF, or MPN formulations. Abdominal accumulation was most pronounced in the MOF and MPN / MOF groups at 2-4 hours. (FIG. 43B) Quantitative average radiant efficiency over time from abdominal ROI (region of interest). (FIG. 43C) Ex vivo imaging of major organs (Heart, Fiver, Spleen, Fung, Kidney, Intestine) at 24 hours post-administration. (FIG. 43D) Quantified radiant efficiency in isolated organs (n = 3), with highest signals in intestine for MOF andMPN / MOF groups. (FIG. 43E) Ex vivo imaging of fecal pellets collected at intervals postdosing with Control, NuMOF, or MPN / MOF. (FIG. 43F) Quantitative fecal fluorescence over 48 hours. MPN / MOF showed highest and longest retention.

[0045] FIGs. 44A-44B Ex vivo intestinal imaging of MOF and MPN formulations. (FIG. 44A) Representative images of dissected intestines from mice treated with Control, MOF, or MPN formulations at 2, 4, 8, 12, and 24 hours post-administration. (FIG. 44B) Quantitative radiant efficiency from intestinal tissues (n = 3), showing signal decay profiles.DEFINITIONS

[0046] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modem Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0047] Metal-organic frameworks provided herein can comprise organic ligands that comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the metal-organic frameworks described herein can comprise organic ligands in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0048] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0049] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non- superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (z.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0050] Unless otherwise provided, formulae and structures provided herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, metal-organic frameworks wherein hydrogen is replaced by deuterium or tritium,19F is replaced with18F, or12C is replaced by a13C- or14C-enriched carbon are within the scope of the disclosure.

[0051] The metal-organic frameworks provided herein can comprise isotopes. The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0052] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “Ci-6 alkyl” encompasses, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, CM, CI-3, Ci-2, C2-6, C2-5, C2M, C2-3, C3-6, C3-5, C34, C4-6, C -5, and C5-6alkyl.

[0053] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxy,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -ON(Rbb)2, -OC(=O)SRaa,-OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OSi(Raa)3, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X-, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, and -OP(=O)(N(Rbb))2, wherein X-, R^, Rbb, and Rccare as defined herein.

[0054] The term “alkoxide” refers to an alkyl-O-group, e.g. alkyl-O". In some embodiments, the oxygen atom of an alkoxide group is bonded to a metal atom.

[0055] The term “carboxyl” refers to the group -COOH or salts thereof. The term “substituted carboxyl” refers to a carboxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen. The term “carboxylate” refers to the group -COO". In some embodiments, the oxygen atom of a carboxylate group is bonded to a metal atom.

[0056] The term “framework” refers to a framework having a 2-D or 3-D structure comprised of repeating units. In some embodiments, each repeat unit comprises a metal and a linking moiety (e.g., an organic ligand).

[0057] The term “organic ligand” refers to a mono-dentate, bidentate or multidentate compound that binds a biocompatible metal or a plurality of biocompatible metals. In some embodiments, the organic ligand is a bidentate or multidentate compound that binds a biocompatible metal or a plurality of biocompatible metals. In some embodiments, an organic ligand coordinates two or more metals, creating a metal-organic framework having void regions or channels. In some embodiments, an organic ligand is a biocompatible. In some embodiments, an organic ligand is a non-toxic molecule. Examples of a linking ligand useful in the methods and compositions of the disclosure include fumaric acid, 2,3- dimethylfumaric acid, aspartic acid, mesaconic acid, muconic acid, succinic acid, citric acid, ascorbic acid, curcumin, thiomalic acid, adipic acid, tartronic acid, vitamin C, or a combination thereof.

[0058] The term “guest molecule” refers to any chemical species that resides within the void regions of a framework that is not considered integral to the structure of the framework. In some embodiments, guest molecules comprise molecules of the solvent that fill the void regions during the synthetic process, other molecules exchanged for the solvent, or a guest molecule introduced into the framework. In some embodiments, a guest molecule is an agent to be “carried” or “delivered” by the framework. In some embodiments, a guest molecule is a micronutrient, probiotic, natural extract, small molecule drug, protein, peptide, or nucleic acid. In some embodiments, a framework may comprise multiple guest molecules, which may be the same or different from one another.

[0059] The term “biocompatible” refers to a material that is compatible with a biological system such as a cell, cell culture, tissue, or organism. In some embodiments, a biocompatible material has low toxicity or is non-toxic. In some embodiments, a biocompatible material does not cause a significant adverse reaction in the recipient.

[0060] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0061] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not limited in any manner by the above exemplary listing of substituents.

[0062] The following definitions are more general terms used throughout the present application.

[0063] The terms “composition” and “formulation” are used interchangeably.

[0064] A “subject” to which administration is contemplated refers to a human (z.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0065] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0066] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0067] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0068] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. Incertain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0069] An “effective amount” of a compound or agent provided herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound or agent provided herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound or agent, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactically effective amount. In certain embodiments, an effective amount is the amount of a compound or agent provided herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound or agent provided herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0070] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0071] In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0072] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medicalpractitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0073] A “therapeutically effective amount” of a compound or agent described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound or agent means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering an agent to a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a micronutrient deficiency. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering an agent to a subject and treating a micronutrient deficiency.

[0074] A “prophylactically effective amount” of a compound or agent described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound or agent means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering an agent to a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a micronutrient deficiency. In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering an agent to a subject and preventing a micronutrient deficiency.

[0075] The term “genetic disease” refers to a disease caused by one or more abnormalities in the genome of a subject, such as a disease that is present from birth of the subject. Genetic diseases may be heritable and may be passed down from the parents’ genes. A genetic disease may also be caused by mutations or changes of the DNAs and / or RNAs of the subject. In such cases, the genetic disease will be heritable if it occurs in the germline. Exemplary genetic diseases include, but are not limited to, Aarskog-Scott syndrome, Aase syndrome, achondroplasia, acrodysostosis, addiction, adreno-leukodystrophy, albinism,ablepharon-macrostomia syndrome, alagille syndrome, alkaptonuria, alpha- 1 antitrypsin deficiency, Alport’s syndrome, Alzheimer’s disease, asthma, autoimmune polyglandular syndrome, androgen insensitivity syndrome, Angelman syndrome, ataxia, ataxia telangiectasia, atherosclerosis, attention deficit hyperactivity disorder (ADHD), autism, baldness, Batten disease, Beckwith-Wiedemann syndrome, Best disease, bipolar disorder, brachy dactyl), breast cancer, Burkitt lymphoma, chronic myeloid leukemia, Charcot-Marie- Tooth disease, Crohn’s disease, cleft lip, Cockayne syndrome, Coffin Lowry syndrome, colon cancer, congenital adrenal hyperplasia, Cornelia de Lange syndrome, Costello syndrome, Cowden syndrome, craniofrontonasal dysplasia, Crigler-Najjar syndrome, Creutzfeldt-Jakob disease, cystic fibrosis, deafness, depression, diabetes, diastrophic dysplasia, DiGeorge syndrome, Down’s syndrome, dyslexia, Duchenne muscular dystrophy, Dubowitz syndrome, ectodermal dysplasia Ellis-van Creveld syndrome, Ehlers-Danlos, epidermolysis bullosa, epilepsy, essential tremor, familial hypercholesterolemia, familial Mediterranean fever, fragile X syndrome, Friedreich’s ataxia, Gaucher disease, glaucoma, glucose galactose malabsorption, glutaricaciduria, gyrate atrophy, Goldberg Shprintzen syndrome (velocardiofacial syndrome), Gorlin syndrome, Hailey-Hailey disease, hemihypertrophy, hemochromatosis, hemophilia (e.g., hemophilias A and B), hereditary motor and sensory neuropathy (HMSN), hereditary non polyposis colorectal cancer (HNPCC), Huntington’s disease, immunodeficiency with hyper- IgM, juvenile onset diabetes, Klinefelter’s syndrome, Kabuki syndrome, Leigh’s disease, long QT syndrome, lung cancer, malignant melanoma, manic depression, Marfan syndrome, Menkes syndrome, miscarriage, mucopolysaccharide disease, multiple endocrine neoplasia, multiple sclerosis, muscular dystrophy, myotrophic lateral sclerosis, myotonic dystrophy, neurofibromatosis, Niemann-Pick disease, Noonan syndrome, obesity, ovarian cancer, pancreatic cancer, Parkinson’s disease, paroxysmal nocturnal hemoglobinuria, Pendred syndrome, peroneal muscular atrophy, phenylketonuria (PKU), polycystic kidney disease, Prader-Willi syndrome, primary biliary cirrhosis, prostate cancer, REAR syndrome, Refsum disease, retinitis pigmentosa, retinoblastoma, Rett syndrome, Sanfilippo syndrome, schizophrenia, severe combined immunodeficiency, sickle cell anemia, spina bifida, spinal muscular atrophy, spinocerebellar atrophy, sudden adult death syndrome, Tangier disease, Tay-Sachs disease, thrombocytopenia absent radius syndrome, Townes-Brocks syndrome, tuberous sclerosis, Turner syndrome, Usher syndrome, von Hippel-Lindau syndrome, Waardenburg syndrome, Weaver syndrome, Werner syndrome, Williams syndrome, Wilson’s disease, xeroderma piginentosum, and Zellweger syndrome.

[0076] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g.. collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (z.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0077] As used herein, the term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g.. VEGF). “Pathological angiogenesis” refers to abnormal (e.g.. excessive or insufficient) angiogenesis that amounts to and / or is associated with a disease.

[0078] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, andthese tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0079] The term “cancer” refers to a malignant neoplasm (Stedman ’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelio sarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B- cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cellHL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrinetumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA),melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0080] As used herein, the term “inflammatory disease” or “inflammation” refers to a disease caused by, resulting from, or resulting in inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0081] As used herein, an “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid, arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigusvulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme arthritis, Guillain-Barre syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0082] The term “liver disease” or “hepatic disease” refers to damage to or a disease of the liver. Non-limiting examples of liver disease include intrahepatic cholestasis (e.g., alagille syndrome, biliary liver cirrhosis), fatty liver (e.g., alcoholic fatty liver, Reye’s syndrome), hepatic vein thrombosis, hepatolenticular degeneration (z.e., Wilson's disease), hepatomegaly, liver abscess (e.g., amebic liver abscess), liver cirrhosis (e.g., alcoholic, biliary, and experimental liver cirrhosis), alcoholic liver diseases (e.g., fatty liver, hepatitis, cirrhosis), parasitic liver disease (e.g., hepatic echinococcosis, fascioliasis, amebic liver abscess), jaundice (e.g., hemolytic, hepatocellular, cholestatic jaundice), cholestasis, portal hypertension, liver enlargement, ascites, hepatitis (e.g., alcoholic hepatitis, animal hepatitis, chronic hepatitis (e.g., autoimmune, hepatitis B, hepatitis C, hepatitis D, drug inducedchronic hepatitis), toxic hepatitis, viral human hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E), granulomatous hepatitis, secondary biliary cirrhosis, hepatic encephalopathy, varices, primary biliary cirrhosis, primary sclerosing cholangitis, hepatocellular adenoma, hemangiomas, bile stones, liver failure (e.g., hepatic encephalopathy, acute liver failure), angiomyolipoma, calcified liver metastases, cystic liver metastases, fibrolamellar hepatocarcinoma, hepatic adenoma, hepatoma, hepatic cysts (e.g., Simple cysts, Polycystic liver disease, hepatobiliary cystadenoma, choledochal cyst), mesenchymal tumors (mesenchymal hamartoma, infantile hemangioendothelioma, hemangioma, peliosis hepatis, lipomas, inflammatory pseudotumor), epithelial tumors (e.g., bile duct hamartoma, bile duct adenoma), focal nodular hyperplasia, nodular regenerative hyperplasia, hepatoblastoma, hepatocellular carcinoma, cholangiocarcinoma, cystadenocarcinoma, tumors of blood vessels, angiosarcoma, Karposi's sarcoma, hemangioendothelioma, embryonal sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, carcinosarcoma, teratoma, carcinoid, squamous carcinoma, primary lymphoma, peliosis hepatis, erythrohepatic porphyria, hepatic porphyria (e.g., acute intermittent porphyria, porphyria cutanea tarda), and Zellweger syndrome.

[0083] The term “spleen disease” refers to a disease of the spleen. Example of spleen diseases include, but are not limited to, splenomegaly, spleen cancer, asplenia, spleen trauma, idiopathic purpura, Felty’s syndrome, Hodgkin’s disease, and immune-mediated destruction of the spleen.

[0084] The term “lung disease” or “pulmonary disease” refers to a disease of the lung. Examples of lung diseases include, but are not limited to, bronchiectasis, bronchitis, bronchopulmonary dysplasia, interstitial lung disease, occupational lung disease, emphysema, cystic fibrosis, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), asthma (e.g., intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma), chronic bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, interstitial lung disease, sarcoidosis, asbestosis, aspergilloma, aspergillosis, pneumonia (e.g., lobar pneumonia, multilobar pneumonia, bronchial pneumonia, interstitial pneumonia), pulmonary fibrosis, pulmonary tuberculosis, rheumatoid lung disease, pulmonary embolism, and lung cancer (e.g., non-small-cell lung carcinoma (e.g., adenocarcinoma, squamous-cell lung carcinoma, large-cell lung carcinoma), small-cell lung carcinoma).

[0085] As used herein, a “hematological disease” includes a disease which affects a hematopoietic cell or tissue. Hematological diseases include diseases associated withaberrant hematological content and / or function. Examples of hematological diseases include diseases resulting from bone marrow irradiation or chemotherapy treatments for cancer, diseases such as Pernicious Anemia, Hemorrhagic Anemia, Hemolytic Anemia, Aplastic Anemia, Sickle Cell Anemia, Sideroblastic Anemia, Anemia associated with chronic infections such as Malaria, Trypanosomiasis, HTV, Hepatitis virus or other viruses, Myelophthisic Anemias caused by marrow deficiencies, renal failure resulting from Anemia, Anemia, Polycethemia, Infectious Mononucleosis (EVI), Acute Non-Lymphocytic Leukemia (ANLL), Acute Myeloid Leukemia (AML), Acute Promyelocytic Leukemia (APL), Acute Myelomonocytic Leukemia (AMMoL), Polycethemia Vera, Lymphoma, Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia, Wilm’s Tumor, Ewing’s Sarcoma, Retinoblastoma, Hemophilia, disorders associated with an increased risk of Thrombosis, Herpes, Thalessemia, antibody-mediated disorders such as transfusion reactions and Erythroblastosis, mechanical trauma to red blood cells such as micro-angiopathic hemolytic anemias, Thrombotic Thrombocytopenic Purpura and disseminated intravascular coagulation, infections by parasites such as Plasmodium, chemical injuries from, e.g., lead poisoning, and Hypersplenism.

[0086] The term “neurological disease” refers to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system).Neurodegenerative diseases also refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including fronto-temporal dementia), and Huntington’s disease. Examples of neurological diseases include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuroophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illness, include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include Acquired Epileptiform Aphasia; Acute Disseminated Encephalomyelitis;Adrenoleukodystrophy; agenesis of the corpus callosum; Agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; Alternating hemiplegia; Alzheimer’s disease; Amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; Angiomatosis; Anoxia; aphasia; apraxia; Arachnoid Cysts; Arachnoiditis; Arnold-Chiari malformation;Arteriovenous malformation; Asperger syndrome; Ataxia Telangiectasia; Attention Deficit Hyperactivity Disorder; autism; autonomic dysfunction; Back Pain; Batten disease; Behcet’s disease; Bell’s palsy; Benign Essential Blepharospasm; Benign Focal; Amyotrophy; Benign Intracranial Hypertension; Binswanger’s disease; Blepharospasm; Bloch Sulzberger syndrome; Brachial plexus injury; Brain abscess; Brain injury; Brain tumors (including Glioblastoma multiforme); Spinal tumor; Brown-Sequard syndrome; Canavan disease; Carpal tunnel syndrome (CTS); Causalgia; Central pain syndrome; Central pontine myelinolysis; Cephalic disorder; Cerebral aneurysm; Cerebral arteriosclerosis; Cerebral atrophy; Cerebral gigantism; Cerebral palsy; Charcot-Marie-Tooth disease; Chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; Chorea; Chronic inflammatory demyelinating polyneuropathy (CIDP); Chronic pain; Chronic regional pain syndrome; Coffin Lowry syndrome; Coma, including Persistent Vegetative State; Congenital facial diplegia; Corticobasal degeneration; Cranial arteritis; Craniosynostosis; Creutzfeldt- Jakob disease; Cumulative trauma disorders; Cushing’s syndrome; Cytomegalic inclusion body disease (CIBD); Cytomegalovirus Infection; Dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumpke palsy; Dementia; Dermatomyositis; Diabetic neuropathy; Diffuse sclerosis; Dysautonomia; Dysgraphia;Dyslexia; Dystonias; Early infantile epileptic encephalopathy; Empty sella syndrome; Encephalitis; Encephaloceles; Encephalotrigeminal angiomatosis; Epilepsy; Erb’s palsy; Essential tremor; Fabry’s disease; Fahr’s syndrome; Fainting; Familial spastic paralysis; Febrile seizures; Fisher syndrome; Friedreich’s ataxia; Fronto-Temporal Dementia and other “Tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; Giant cell arteritis; Giant cell inclusion disease; Globoid cell Leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; Head injury; Headache; Hemifacial Spasm; Hereditary Spastic Paraplegia; Heredopathia atactica polyneuritiformis; Herpes zoster oticus; Herpes zoster; Hirayama syndrome; HIV- Associated Dementia and Neuropathy (see also Neurological manifestations of AIDS); Holoprosencephaly; Huntington’s disease and other poly glutamine repeat diseases; Hydranencephaly; Hydrocephalus; Hypercortisolism; Hypoxia; Immune-Mediated encephalomyelitis; Inclusion body myositis; Incontinentia pigmenti; Infantile; phytanic acid storage disease; Infantile Refsum disease; Infantile spasms; Inflammatory myopathy; Intracranial cyst; Intracranial hypertension; Joubert syndrome;Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg- Welander disease; Kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau- Kleffner syndrome; Lateral medullary (Wallenberg)syndrome; Learning disabilities; Leigh’s disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; Leukodystrophy; Lewy body dementia; Lissencephaly; Locked-In syndrome; Lou Gehrig’s disease (aka Motor Neuron Disease or Amyotrophic Lateral Sclerosis); Lumbar disc disease; Lyme disease-Neurological Sequelae; Machado-Joseph disease; Macrencephaly; Megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; Meningitis; Menkes disease; Metachromatic leukodystrophy; Microcephaly; Migraine; Miller Fisher syndrome; Mini-Strokes; Mitochondrial Myopathies; Mobius syndrome; Monomelic amyotrophy; Motor Neurone Disease; Moyamoya disease; Mucopolysaccharidoses; Multi-Infarct Dementia; Multifocal motor neuropathy; Multiple sclerosis and other demyelinating disorders; Multiple system atrophy with postural hypotension; Muscular dystrophy; Myasthenia gravis;Myelinoclastic diffuse sclerosis; Myoclonic encephalopathy of infants; Myoclonus; Myopathy; Myotonia congenital; Narcolepsy; Neurofibromatosis; Neuroleptic malignant syndrome; Neurological manifestations of AIDS; Neurological sequelae of lupus;Neuromyotonia; Neuronal ceroid lipofuscinosis; Neuronal migration disorders; Niemann- Pick disease; O’Sullivan-McLeod syndrome; Occipital Neuralgia; Occult Spinal Dysraphism Sequence; Ohtahara syndrome; Olivopontocerebellar Atrophy; Opsoclonus Myoclonus; Optic neuritis; Orthostatic Hypotension; Overuse syndrome; Paresthesia; Parkinson’s disease; Paramyotonia Congenita; Paraneoplastic diseases; Paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; Periodic Paralyses; Peripheral Neuropathy; Painful Neuropathy and Neuropathic Pain; Persistent Vegetative State; Pervasive developmental disorders; Photic sneeze reflex; Phytanic Acid Storage disease; Pick’s disease; Pinched Nerve; Pituitary Tumors; Polymyositis; Porencephaly; Post-Polio syndrome; Postherpetic Neuralgia (PHN); Postinfectious Encephalomyelitis; Postural Hypotension; Prader-Willi syndrome; Primary Lateral Sclerosis; Prion diseases; Progressive; Hemifacial Atrophy;Progressive multifocal leukoencephalopathy; Progressive Sclerosing Poliodystrophy;Progressive Supranuclear Palsy; Pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; Reflex Sympathetic Dystrophy syndrome; Refsum disease; Repetitive Motion Disorders; Repetitive Stress Injuries; Restless Legs syndrome; Retrovirus-Associated Myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; Schizencephaly; Septo-Optic Dysplasia; Shaken Baby syndrome; Shingles; Shy-Drager syndrome; Sjogren’s syndrome; Sleep Apnea; Soto’s syndrome; Spasticity; Spina bifida; Spinal cord injury; Spinal cord tumors; Spinal Muscular Atrophy; Stiff-Person syndrome; Stroke; Sturge-Weber syndrome; Subacute Sclerosing Panencephalitis; Subarachnoid Hemorrhage; Subcortical Arteriosclerotic Encephalopathy;Sydenham Chorea; Syncope; Syringomyelia; Tardive dyskinesia; Tay-Sachs disease; Temporal arteritis; Tethered Spinal Cord syndrome; Thomsen disease; Thoracic Outlet syndrome; Tic Douloureux; Todd’s Paralysis; Tourette syndrome; Transient ischemic attack; Transmissible Spongiform Encephalopathies; Transverse myelitis; Traumatic Brain injury; Tremor; Trigeminal Neuralgia; Tropical Spastic Paraparesis; Tuberous Sclerosis; Vascular Dementia (Multi-Infarct Dementia); Vasculitis including Temporal Arteritis; Von Hippel- Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig-Hoffman disease; West syndrome; Whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome.

[0087] A “painful condition” includes, but is not limited to, neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post-operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre -operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, bum pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre-term labor, pain associated with withdrawl symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter's arthritis), lumbosacral pain, musculoskeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, dental / maxillofacial pain, visceral pain and the like. One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g. nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more types of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.

[0088] The term “psychiatric disorder” refers to a disease of the mind and includes diseases and disorders listed in the Diagnostic and. Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV), published by the American Psychiatric Association, Washington D. C. (1994). Psychiatric disorders include, but are not limited to, anxiety disorders (e.g., acute stress disorder agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, andspecific phobia), childhood disorders, (e.g., attention-deficit / hyperactivity disorder, conduct disorder, and oppositional defiant disorder), eating disorders (e.g., anorexia nervosa and bulimia nervosa), mood disorders (e.g., depression, bipolar disorder, cyclothymic disorder, dysthymic disorder, and major depressive disorder), personality disorders (e.g., antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizoid personality disorder, and schizotypal personality disorder), psychotic disorders (e.g., brief psychotic disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, schizophrenia, and shared psychotic disorder), substance-related disorders (e.g., alcohol dependence, amphetamine dependence, cannabis dependence, cocaine dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, opioid dependence, phencyclidine dependence, and sedative dependence), adjustment disorder, autism, delirium, dementia, multi-infarct dementia, learning and memory disorders (e.g., amnesia and age- related memory loss), and Tourette’s disorder.

[0089] The term “metabolic disorder” refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Factors affecting metabolism include, and are not limited to, the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders include, but are not limited to, diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.

[0090] The term “musculoskeletal disease” or “MSD” refers to an injury and / or pain in a subject’s joints, ligaments, muscles, nerves, tendons, and structures that support limbs, neck, and back. In certain embodiments, an MSD is a degenerative disease. In certain embodiments, an MSD includes an inflammatory condition. Body parts of a subject that may be associated with MSDs include upper and lower back, neck, shoulders, and extremities (arms, legs, feet, and hands). In certain embodiments, an MSD is a bone disease, such as achondroplasia, acromegaly, bone callus, bone demineralization, bone fracture, bone marrow disease, bone marrow neoplasm, dyskeratosis congenita, leukemia (e.g., hairy cell leukemia, lymphocytic leukemia, myeloid leukemia, Philadelphia chromosome-positive leukemia,plasma cell leukemia, stem cell leukemia), systemic mastocytosis, myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, myeloid sarcoma, myeloproliferative disorders, multiple myeloma, polycythemia vera, pearson marrow-pancreas syndrome, bone neoplasm, bone marrow neoplasm, Ewing sarcoma, osteochondroma, osteoclastoma, osteosarcoma, brachydactyly, Camurati-Engelmann syndrome, Craniosynostosis, Crouzon craniofacial dysostosis, dwarfism, achondroplasia, bloom syndrome, Cockayne syndrome, Ellis-van Creveld syndrome, Seckel syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, Werner syndrome, hyperostosis, osteophyte, Klippel-Trenaunay-Weber syndrome, Marfan syndrome, McCune- Albright syndrome, osteitis, osteoarthritis, osteochondritis, osteochondrodysplasia, Kashin-Beck disease, Leri- Weill dyschondrosteosis, osteochondrosis, osteodystrophy, osteogenesis imperfecta, osteolysis, Gorham-Stout syndrome, osteomalacia, osteomyelitis, osteonecrosis, osteopenia, osteopetrosis, osteoporosis, osteosclerosis, otospondylomegaepiphyseal dysplasia, pachydermoperiostosis, Paget disease of bone, Polydactyly, Meckel syndrome, rickets, Rothmund- Thomson syndrome, Sotos syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, syndactyly, Apert syndrome, syndactyly type II, or Werner syndrome. In certain embodiments, an MSD is a cartilage disease, such as cartilage neoplasm, osteochondritis, osteochondrodysplasia, Kashin-Beck disease, or Leri-Weill dyschondrosteosis. In certain embodiments, an MSD is hernia, such as intervertebral disk hernia. In certain embodiments, an MSD is a joint disease, such as arthralgia, arthritis (e.g., gout (e.g., Kelley-Seegmiller syndrome, Lesch-Nyhan syndrome), Lyme disease, osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatic fever, rheumatoid arthritis, Eelty syndrome, synovitis, Blau syndrome, nail-patella syndrome, spondyloarthropathy, reactive arthritis, Stickler syndrome, synovial membrane disease, synovitis, or Blau syndrome. In certain embodiments, an MSD is Langer- Giedion syndrome. In certain embodiments, an MSD is a muscle disease, such as Barth syndrome, mitochondrial encephalomyopathy, MELAS syndrome, MERRE syndrome, MNGIE syndrome, mitochondrial myopathy, Kearns-Sayre syndrome, myalgia, fibromyalgia, polymyalgia rheumatica, myoma, myositis, dermatomyositis, neuromuscular disease, Kearns-Sayre syndrome, muscular dystrophy, myasthenia, congenital myasthenic syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis, myotonia, myotonia congenita, spinal muscular atrophy, tetany, ophthalmoplegia, or rhabdomyolysis. In certain embodiments, an MSD is Proteus syndrome. In certain embodiments, an MSD is a rheumatic diseases, such as arthritis (e.g., gout (e.g., Kelley-Seegmiller syndrome, Lesch-Nyhan lyme disease)), osteoarthritis, psoriatic arthritis,reactive arthritis, rheumatic fever, rheumatoid arthritis, Felty syndrome, synovitis, Blau syndrome, gout (e.g., Kelley-Seegmiller syndrome, Lesch-Nyhan syndrome), polymyalgia rheumatica, rheumatic fever, rheumatic heart disease, or Sjogren syndrome. In certain embodiments, an MSD is Schwartz- Jampel syndrome. In certain embodiments, an MSD is a skeleton disease, such as Leri-Weill dyschondrosteosis, skeleton malformations, Melnick- Needles syndrome, pachydermoperiostosis, Rieger syndrome, spinal column disease, intervertebral disk hernia, scoliosis, spina bifida, spondylitis, ankylosing spondylitis, spondyloarthropathy, reactive arthritis, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, or spondylosis.

[0091] The term “micronutrient deficiency” refers to the lack of sufficient micronutrients required for optimal health. In humans and other animals they include both vitamin deficiencies and mineral deficiencies. In certain embodiments, micronutrient deficiency causes or exacerbates disease. In some embodiments, micronutrients include iodine, iron, zinc, calcium, selenium, fluorine, and vitamins A, B6, B12, Bl, B2, B3, B9 and C. In certain embodiments, micronutrient deficiencies are caused by long-term shortages of nutritious food or by infections. In some embodiments, micronutrient deficiencies are caused or exacerbated by illnesses that cause rapid loss of nutrients through feces or vomit (e.g., diarrhea or malaria).

[0092] Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, or more typically, within 5%, 4%, 3%, 2%, or 1% of a given value or range of values.

[0093] Unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0015] Provided herein are metal-organic frameworks, and compositions, methods, uses, and kits thereof. The inventors have discovered that the metal-organic frameworks provided herein are biocompatible and are useful for delivery of guest molecules or other agents for the treatment and / or prevention of various diseases and conditions. The inventors have additionally discovered that further modifications of biocompatible metal-organicframeworks, such as coating with a metal polyphenol network (MPN), can modulate the stability, bioavailability, and biodistribution of the metal-organic frameworks. These developments define 'next-generation' formulations that integrate advanced materials such as MOFs to overcome long-standing limitations in nutrient compatibility (e.g., iodine-iron compatibility, provision of elemental iodine rather than iodide or iodate) and stability (e.g., when boiled, heated, exposed to light), enhance nutrient retention and absorption, and streamline production through modular, scalable synthesis. The MOFs and compositions provided herein thus enhance nutrient stability and bioavailability while simplifying manufacturing and reducing costs.Compounds

[0016] In one aspect, provided herein are metal-organic frameworks, comprising: a plurality of biocompatible metal cores comprising iron, calcium, magnesium, selenium, zinc, or a combination thereof; and a plurality of biocompatible organic ligands, each comprising at least two alkoxide or carboxylate moieties; wherein: each metal core is linked to at least one other metal core by at least one organic ligand.

[0017] In another aspect, provided herein are metal-organic frameworks, comprising: a plurality of biocompatible metal cores; a plurality of biocompatible organic ligands; and a metal-polyphenolic network (MPN) coating; wherein: each metal core is linked to at least one other metal core by at least one organic ligand, forming a particle; and the MPN coating is deposited on the surface of the particle.

[0018] In some embodiments, the organic ligand comprises one or more carboxylates. In some embodiments, the organic ligand is a polycarboxylic acid (e.g., a dicarboxylic, tricarboxylic, tetracarboxylic, pentacarboxylic, monomeric polycarboxylic acids, and anhydrides, and combinations thereof, or a polymeric polycarboxylic acids, anhydrides, copolymers, and combinations thereof). In some embodiments, the organic ligand comprises one or more alkoxides. In some embodiments, the organic ligand comprises at least one alkoxide and at least one carboxylate.

[0019] In some embodiments, the plurality of organic ligands does not comprise terephthalic acid, 2,5- dihydroxyterephthalic acid, 4,4'-oxybis(benzoic acid), trimesic acid, 1,3,5-tri (4'- carboxy-4,4'-biphenyl) benzene, 4,4',4"-benzene-l,3,5-triyl-tri-benzoic acid, or biphenylcarboxylic acid. In some embodiments, the plurality of organic ligands does not comprise a cyclodextrin. In some embodiments, the plurality of organic ligands comprises fumaric acid, 2,3-dimethylfumaric acid, aspartic acid, mesaconic acid, muconic acid, succinic acid, citric acid, ascorbic acid, curcumin, thiomalic acid, adipic acid, tartronic acid, vitamin C, or a combination thereof. In some embodiments, the plurality of organic ligands comprises fumaric acid. In some embodiments, the plurality of organic ligands comprises 2,3-dimethylfumaric acid. In some embodiments, the plurality of organic ligands comprises aspartic acid. In some embodiments, the plurality of organic ligands comprises mesaconic acid. In some embodiments, the plurality of organic ligands comprises muconic acid. In some embodiments, the plurality of organic ligands comprises succinic acid. In some embodiments, the plurality of organic ligands comprises citric acid. In some embodiments, the plurality of organic ligands comprises ascorbic acid. In some embodiments, the plurality of organic ligands comprises curcumin. In some embodiments, the plurality of organic ligands comprises thiomalic acid. In some embodiments, the plurality of organic ligands comprises adipic acid. In some embodiments, the plurality of organic ligands comprises tartronic acid. In some embodiments, the plurality of organic ligands comprises vitamin C.

[0020] In some embodiments, the plurality of organic ligands comprises a cyclodextrin. In some embodiments, the cyclodextrm is selected from:Cyclodextrin type Modification / feature a-Cyclodextrin (a-CD) Natural (6 glucose units)P-Cyclodextrin (P-CD) Natural (7 glucose units) y-Cyclodextrin (y-CD) Natural (8 glucose units)Hydroxypropyl-P-CD (HP-P-CD) Hydroxypropyl substitutionHydroxypropyl-y-CD (HP-y-CD) Hydroxypropyl substitutionSulfobutyl-ether substitutionSulfobutylether- P-CD (Captisol®) (anionic)Methyl-P-CD (M-P-CD) Methyl substitutionRandomly methylated- P-CD (RM- P-CD) Random methyl substitutionCarboxymethyl substitutionCarboxymethyl-P-CD (CM-P-CD) (anionic)Ethyl-P-CD (Et-P-CD) Ethyl substitution (hydrophobic)Cationic CDs (e.g., amino-P-CD) Amino or other cationic groupsBranched CDs Glucose side-chainsPolymeric CDs Cross-linked or grafted networksCD-based MOFs CDs as MOF linkers

[0021] In some embodiments, the cyclodextrin is a-cyclodextrin, P-cyclodextrin, y- cyclodextrin, hydroxypropyl-P-cyclodextrin, hydroxypropyl-y-cyclodextrin, sulfobutylether- P -cyclodextrin (Captisol®), methyl-P-cyclodextrin, randomly methylated-P-cyclodextrin, carboxymethyl-P-cyclodextrin, ethyl-P-cyclodextrin, a cationic cyclodextrin, a branched cyclodextrin, or a polymeric cyclodextrin. In some embodiments, the cyclodextrin is y- cyclodextrin, P-cyclodextrin, or a-cyclodextrin. In some embodiments, the cyclodextrin is y-cyclodextrin or P-cyclodextrin. In some embodiments, the cyclodextrin is y-cyclodextrin. In some embodiments, the cyclodextrin is P-cyclodextrin. In some embodiments, the cyclodextrin a-cyclodextrin.

[0022] In some embodiments, the plurality of organic ligands is homogenous. In some embodiments, the plurality of organic ligands is heterogenous.

[0023] In some embodiments, the plurality of biocompatible metal cores is homogenous. In some embodiments, the plurality of biocompatible metal cores is heterogenous.

[0024] In some embodiments, the plurality of biocompatible metal cores and the plurality of organic ligands are present at a ratio of about 1:100 to about 100:1. In some embodiments, the plurality of biocompatible metal cores and the plurality of organic ligands are present at a ratio of about 1:10 to about 10:1. In some embodiments, the plurality of biocompatible metal cores and the plurality of organic ligands are present at a ratio of about 1:10 to about 1:1.

[0025] In some embodiments of a metal-organic framework provided herein:(a) the plurality of biocompatible metal cores comprises calcium, and the plurality of organic ligands comprises vitamin C;(b) the plurality of biocompatible metal cores comprises magnesium, and the plurality of organic ligands comprises vitamin C;(c) the plurality of biocompatible metal cores comprises selenium, and the plurality of organic ligands comprises vitamin C;(d) the plurality of biocompatible metal cores comprises zinc, and the plurality of organic ligands comprises vitamin C;(e) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises vitamin C;(f) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises fumaric acid;(g) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises 2,3-dimethylfumaric acid;(h) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises L-aspartic acid;(i) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises mesaconic acid;(j) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises trans, trans-muconic acid;(k) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises curcumin;(l) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises succinic acid;(m) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises thiomalic acid;(n) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises adipic acid;(o) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises tartronic acid;(p) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises vitamin C;(q) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises fumaric acid;(r) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises 2,3-dimethyl fumaric acid;(s) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises L-aspartic acid;(t) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises mesaconic acid;(u) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises trans, trans-muconic acid;(v) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises curcumin;(w) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises succinic acid;(x) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises thiomalic acid;(y) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises adipic acid; or(z) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises tartronic acid.

[0026] In some embodiments, the plurality of biocompatible metal cores comprises magnesium, selenium, or zinc; and the plurality of organic ligands comprises a cyclodextrin. In some embodiments, the plurality of biocompatible metal cores comprises iron or calcium; and the plurality of organic ligands comprises a cyclodextrin.

[0027] In some embodiments, the plurality of biocompatible metal cores comprises iron; and the plurality of organic ligands comprises P-cyclodextrin. In some embodiments, the plurality of biocompatible metal cores comprises iron (II); and the plurality of organic ligands comprises P-cyclodextrin. In some embodiments, the plurality of biocompatible metal cores comprises iron (III); and the plurality of organic ligands comprises P- cyclodextrin.

[0028] In some embodiments, the metal-organic framework has an interplanar spacing of about 0.05 to about 0.5 nm. In some embodiments, the metal-organic framework has an interplanar spacing of about 0.1 to about 0.3 nm.

[0029] In some embodiments, the metal-organic framework further comprises a plurality of guest molecules.

[0030] In some embodiments, each of the plurality of guest molecules has a molecular weight of less than 2 kDa. In some embodiments, each of the plurality of guest molecules has a molecular weight of less than 1.5 kDa. In some embodiments, each of the plurality of guest molecules has a molecular weight of less than 1 kDa. In some embodiments, each of the plurality of guest molecules has a molecular weight of less than 750 Da. In some embodiments, each of the plurality of guest molecules has a molecular weight of less than 500 Da. In some embodiments, the plurality of guest molecules comprises guest molecules having a molecular weight of 2 Da to 2 kDa. In some embodiments, the plurality of guest molecules comprises guest molecules having a molecular weight of 2 Da to 1.5 kDa. Insome embodiments, the plurality of guest molecules comprises guest molecules having a molecular weight of 2 Da to 1 kDa. In some embodiments, the plurality of guest molecules comprises guest molecules having a molecular weight of 2 Da to 750 Da. In some embodiments, the plurality of guest molecules comprises guest molecules having a molecular weight of 2 Da to 500 kDa. In some embodiments, the plurality of guest molecules comprises guest molecules having a molecular weight of 10 Da to 1 kDa. In some embodiments, the plurality of guest molecules comprises guest molecules having a molecular weight of 10 Da to 750 Da. In some embodiments, the plurality of guest molecules comprises guest molecules having a molecular weight of 10 Da to 500 kDa.

[0031] In some embodiments, the plurality of guest molecules comprises cationic guest molecules. In some embodiments, the plurality of guest molecules comprises neutral guest molecules. In some embodiments, the plurality of guest molecules comprises anionic guest molecules.

[0032] In some embodiments, the hydrophobicity of the plurality of guest molecules is modulated based on the metal-organic framework pore environment and / or loading efficiency. In some embodiments, the hydrophobicity of the plurality of guest molecules is modulated to balance solubility and / or pore compatibility. In some embodiments, the hydrophobicity of the plurality of guest molecules is modulated for compatibility with hydrophilic metal-organic frameworks. In some embodiments, the hydrophobicity of the plurality of guest molecules is modulated for aqueous delivery. In some embodiments, the hydrophobicity of the plurality of guest molecules is modulated for hydrophobic metalorganic frameworks. In some embodiments, the hydrophobicity of the plurality of guest molecules is modulated for compatibility with lipid systems. In some embodiments, the plurality of guest molecules comprise guest molecules having a hydrophobicity of -2 to +5 logP. In some embodiments, the plurality of guest molecules comprise guest molecules having a hydrophobicity of -1 to +3 logP. In some embodiments, the plurality of guest molecules comprise guest molecules having a hydrophobicity of - 1 to +3 logP to balance solubility and pore compatibility. In some embodiments, the plurality of guest molecules comprise guest molecules having a hydrophobicity of >0 logP. In some embodiments, the plurality of guest molecules comprise guest molecules having a hydrophobicity of >0 logP in a hydrophilic metal-organic framework. In some embodiments, the plurality of guest molecules comprise guest molecules having a hydrophobicity of >0 logP for aqueous delivery. In some embodiments, the plurality of guest molecules comprise guest molecules having a hydrophobicity of >+2 logP. In some embodiments, the plurality of guestmolecules comprise guest molecules having a hydrophobicity of >+2 logP in a hydrophobic metal-organic framework. In some embodiments, the plurality of guest molecules comprise guest molecules having a hydrophobicity of >+2 logP for a lipid-compatible system.

[0033] In some embodiments, the plurality of guest molecules comprises guest molecules that interact electrostatically with the metal-organic framework.

[0034] In some embodiments, the plurality of guest molecules comprises one or more micronutrients, probiotics, natural extracts, small molecule drugs, proteins, peptides, and nucleic acids. In some embodiments, the guest molecule is a small molecule (e.g., an organic molecule, organometallic compound, or inorganic molecule), nucleic acid, protein, peptide, targeting agent, an isotopically labeled chemical compound, vaccine, an immunological agent, an guest molecule useful in bioprocessing (e.g., for intracellular manufacturing of proteins, such as a cell’s bioprocessing of a commercially useful chemical or fuel), a vitamin, a mineral, a micronutrient, a biologic, probiotic, polynucleotide, bacteria, cell, or microorganism. In some embodiments, the guest molecule is a micronutrient. In certain embodiments, the plurality of guest molecules comprises a vitamin or mineral. In some embodiments, the plurality of guest molecules comprises a vitamin. In certain embodiments, the plurality of guest molecules comprises a mineral. In some embodiments, the plurality of guest molecules comprises a vitamin, mineral, micronutrient, or probiotic. In certain embodiments, the plurality of guest molecules comprises biologic. In some embodiments, the plurality of guest molecules comprises a small molecule. In certain embodiments, the plurality of guest molecules comprises a probiotic. In some embodiments, the plurality of guest molecules comprises a polynucleotide.

[0035] In some embodiments, the plurality of guest molecules comprises one or more micronutrients selected from the group consisting of vitamin A, vitamin D, vitamin E, vitamin K, vitamin C, vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin, niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folate, folic acid), vitamin B12 (cobalamin), calcium, iron, magnesium, phosphorus, potassium, sodium, chloride, sulfur, iodine, zinc, copper, manganese, fluoride, selenium, chromium, molybdenum, choline, boron, silicon, nickel, and vanadium. In some embodiments, the plurality of guest molecules comprises one or more micronutrients selected from the group consisting of iron, iodine, zinc, vitamin B12 (cobalamin), and vitamin B9 (folate, folic acid). In certain embodiments, the plurality of guest molecules comprises vitamin A, iron, iodine, vitamin B2 (riboflavin), vitamin B7 (niacin), vitamin bl2 (cobalamin), vitamin D (cholecalcifeol), vitamin E (tocopherol), vitamin KI(phytomenadione), vitamin C (6-O-pamlmitoyl-L-ascorbic acid), or zinc. In some embodiments, the plurality of guest molecules comprises vitamin A, vitamin B2 (riboflavin), vitamin B7 (niacin), vitamin B12 (cobalamin), vitamin D (cholecalcifeol), vitamin E (tocopherol), vitamin KI (phytomenadione), or vitamin C (6-O-pamlmitoyl-L-ascorbic acid). In certain embodiments, the plurality of guest molecules comprises iron, iodine, or zinc. In some embodiments, the plurality of guest molecules comprises iron or zinc. In certain embodiments, the plurality of guest molecules comprises vitamin A. In certain embodiments, the plurality of guest molecules comprises vitamin B2 (riboflavin). In certain embodiments, the plurality of guest molecules comprises vitamin B7 (niacin). In certain embodiments, the plurality of guest molecules comprises vitamin B12 (cobalamin). In certain embodiments, the plurality of guest molecules comprises vitamin D (cholecalcifeol). In certain embodiments, the plurality of guest molecules comprises vitamin E (tocopherol). In certain embodiments, the plurality of guest molecules comprises vitamin KI (phytomenadione). In certain embodiments, the plurality of guest molecules comprises vitamin C (6-O-pamlmitoyl- L-ascorbic acid). In certain embodiments, the plurality of guest molecules comprises iron. In some embodiments, the plurality of guest molecules comprises zinc. In certain embodiments, the guest molecule is iodine.

[0036] In some embodiments, the plurality of guest molecules comprises one or more of iodine, caffeine, resveratrol, curcumin, lycopene, quercetin, beta-carotene, or lutein.

[0037] In some embodiments, the plurality of guest molecules comprises one or more probiotics selected from the group consisting of Lactobacillus casei, Lactobacillus salivarius, Bifidobacterium bifidum, and Bifidobacterium infantis.

[0038] In some embodiments, the plurality of guest molecules comprises one or more natural extracts selected from the group consisting of Curcumin, Quercetin, Epigallocatechin gallate (EGCG), Resveratrol, Berberine, Coenzyme Q10, Linalool, and Menthol. In some embodiments, the plurality of guest molecules comprises one or more natural extracts selected from the group consisting of Curcumin, Quercetin, Epigallocatechin gallate (EGCG), Resveratrol, Berberine, and Coenzyme Q10. In some embodiments, the plurality of guest molecules comprises one or more natural extracts selected from the group consisting of Resveratrol, Berberine, Linalool, and Menthol.

[0039] In some embodiments, the plurality of guest molecules comprises one or more small molecule drugs selected from the group consisting of Eluoxetine, Sertraline, Metformin, and Glipizide.

[0040] In some embodiments, the plurality of guest molecules comprises one or more proteins or peptides selected from the group consisting of Protease, Catalase, Glucagon-like peptide- 1 (GLP-1), and Growth hormone releasing hormone (GHRH).

[0041] In certain embodiments, the plurality of guest molecules comprises a polynucleotide or nucleic acid. In some embodiments, the plurality of guest molecules comprises one or more nucleic acids selected from the group consisting of DNA and RNA. In certain embodiments, the plurality of guest molecules comprises plasmid DNA (pDNA). In certain embodiments, the plurality of guest molecules comprises single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, or viral DNA. In certain embodiments, the plurality of guest molecules comprises RNA. In certain embodiments, the plurality of guest molecules comprises small interfering RNA (siRNA). In certain embodiments, the plurality of guest molecules comprises messenger RNA (mRNA). In certain embodiments, the plurality of guest molecules comprises single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or IncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, or viral satellite RNA. In certain embodiments, the plurality of guest molecules comprises an RNA that carries out RNA interference (RNAi). The phenomenon of RNAi is discussed in greater detail, for example, in the following references: Elbashir et al., 2001, Genes Dev., 15:188; Fire et al., 1998, Nature, 391:806; Tabara et al., 1999, Cell, 99:123; Hammond et al., Nature, 2000, 404:293; Zamore et al., 2000, Cell, 101:25;Chakraborty, 2007, Curr. Drug Targets, 8:469; and Morris and Rossi, 2006, Gene Ther., 13:553. In certain embodiments, upon delivery of an RNA into a subject, tissue, or cell, the RNA is able to interfere with the expression of a specific gene in the subject, tissue, or cell. In certain embodiments, the plurality of guest molecules comprises a pDNA, siRNA, mRNA, or a combination thereof.

[0042] In certain embodiments, the polynucleotide may be provided as an antisense guest molecule or RNAi. See, e.g., Fire et al., Nature 391:806-811, 1998. Antisense therapy is meant to include, e.g., administration or in situ provision of single- or double-stranded polynucleotides, or derivatives thereof, which specifically hybridize, e.g., bind, under cellular conditions, with cellular mRNA and / or genomic DNA, or mutants thereof, so as to inhibit the expression of the encoded protein, e.g., by inhibiting transcription and / or translation. See, e.g., Crooke, “Molecular mechanisms of action of antisense drugs,” Biochim. Biophys. Acta 1489(l):31-44, 1999; Crooke, “Evaluating the mechanism of action of anti-proliferative antisense drugs,” Antisense Nucleic Acid Drug Dev. 10(2): 123- 126, discussion 127, 2000; Methods in Enzymology volumes 313-314, 1999. The binding may be by conventional base pair complementarity, or, for example, in the case of binding to DNA duplexes, through specific interactions in the major groove of the double helix (i.e., triple helix formation). See, e.g., Chan et al., J. Mol. Med. 75(4):267-282, 1997.

[0043] In some embodiments, pDNA, siRNA, dsRNA, shRNA, miRNA, mRNA, tRNA, asRNA, and / or RNAi can be designed and / or predicted using one or more of a large number of available algorithms. To give but a few examples, the following resources can be utilized to design and / or predict polynucleotides: algorithms found at Alnylum Online; Dharmacon Online; OligoEngine Online; Molecula Online; Ambion Online; BioPredsi Online; RNAi Web Online; Chang Bioscience Online; Invitrogen Online; LentiWeb Online GenScript Online; Protocol Online; Reynolds et al., 2004, Nat. Biotechnol., 22:326; Naito et al., 2006, Nucleic Acids Res., 34:W448; Li et al., 2007, RNA, 13:1765; Yiu et al., 2005, Bioinformatics, 21:144; and Jia et al., 2006, BMC Bioinformatics, 7: 271.

[0044] The polynucleotide included in a composition may be of any size or sequence, and they may be single- or double- stranded. In certain embodiments, the polynucleotide includes at least about 30, at least about 100, at least about 300, at least about 1,000, at least about 3,000, or at least about 10,000 base pairs. In certain embodiments, the polynucleotide includes less than about 10,000, less than about 3,000, less than about 1,000, less than about 300, less than about 100, or less than about 30 base pairs. Combinations of the above ranges e.g., at least about 100 and less than about 1,000) are also within the scope of the invention. The polynucleotide may be provided by any means known in the art. In certain embodiments, the polynucleotide is engineered using recombinant techniques. See, e.g., Ausubel et al., Current Protocols in Molecular Biology (John Wiley & Sons, Inc., New York, 1999); Molecular Cloning: A Laboratory Manual, 2nd Ed., ed. by Sambrook, Fritsch, and Maniatis (Cold Spring Harbor Laboratory Press: 1989). The polynucleotide may alsobe obtained from natural sources and purified from contaminating components found normally in nature. The polynucleotide may also be chemically synthesized in a laboratory. In certain embodiments, the polynucleotide is synthesized using standard solid phase chemistry. The polynucleotide may be isolated and / or purified. In certain embodiments, the polynucleotide is substantially free of impurities. In certain embodiments, the polynucleotide is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% free of impurities.

[0045] The polynucleotide may be modified by physical, chemical, and / or biological means. The modifications include methylation, phosphorylation, and end-capping, etc. In certain embodiments, the modifications lead to increased stability of the polynucleotide.

[0046] Wherever a polynucleotide is employed, a derivative of the polynucleotide may also be used. These derivatives include products resulted from modifications of the polynucleotide in the base moieties, sugar moieties, and / or phosphate moieties of the polynucleotide. Modified base moieties include, but are not limited to, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine. Modified sugar moieties include, but are not limited to, 2'-fluororibose, ribose, 2'-dcoxyribosc, 3'-azido- 2',3'-dideoxyribose, 2',3'-dideoxyribose, arabinose (the 2'-epimer of ribose), acyclic sugars, and hexoses. The nucleosides may be strung together by linkages other than the phosphodiester linkage found in naturally occurring DNA and RNA. Modified linkages include, but are not limited to, phosphorothioate and 5'-N-phosphoramidite linkages. Combinations of the various modifications may be used in a single polynucleotide. These modified polynucleotides may be provided by any means known in the art; however, as will be appreciated by those of skill in the art, the modified polynucleotides may be prepared using synthetic chemistry in vitro.

[0047] The polynucleotide described herein may be in any form, such as a circular plasmid, a linearized plasmid, a cosmid, a viral genome, a modified viral genome, and an artificial chromosome.

[0048] The polynucleotide described herein may be of any sequence. In certain embodiments, the polynucleotide encodes a protein or peptide. The encoded protein may be an enzyme, structural protein, receptor, soluble receptor, ion channel, active (e.g.,pharmaceutically active) protein, cytokine, interleukin, antibody, antibody fragment, antigen, coagulation factor, albumin, growth factor, hormone, and insulin, etc. The polynucleotide may also comprise regulatory regions to control the expression of a gene. These regulatory regions may include, but are not limited to, promoters, enhancer elements, repressor elements, TATA boxes, ribosomal binding sites, and stop sites for transcription, etc. In certain embodiments, the polynucleotide is not intended to encode a protein. For example, the polynucleotide may be used to fix an error in the genome of the cell being transfected.

[0049] In certain embodiments, the polynucleotide comprises a sequence encoding an antigenic peptide or protein. A composition containing the polynucleotide can be delivered to a subject to induce an immunologic response sufficient to decrease the chance of a subsequent infection and / or lessen the symptoms associated with such an infection. The polynucleotide of these vaccines may be combined with interleukins, interferon, cytokines, and / or adjuvants described herein.

[0050] The antigenic protein or peptides encoded by the polynucleotide may be derived from bacterial organisms, such as Streptococccus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphtheriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Neisseria meningitidis, Neisseria gonorrhoeae, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio cholerae, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium leprae, Treponema pallidum, Leptospirosis interrogans, Borrelia burgdorferi, and Camphylobacter jejuni; from viruses, such as smallpox virus, influenza A virus, influenza B virus, respiratory syncytial virus, parainfluenza virus, measles virus, HIV virus, varicella- zoster virus, herpes simplex 1 virus, herpes simplex 2 virus, cytomegalovirus, Epstein-Barr virus, rotavirus, rhinovirus, adenovirus, papillomavirus, poliovirus, mumps virus, rabies virus, rubella virus, coxsackieviruses, equine encephalitis virus, Japanese encephalitis virus, yellow fever virus, Rift Valley fever virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus; and from fungal, protozoan, or parasitic organisms, such as Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroides, Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamydial psittaci, Chlamydial trachomatis, Plasmodium falciparum, Trypanosoma brucei,Entamoeba histolytica, Toxoplasma gondii, Trichomonas vaginalis, and Schistosoma mansoni.

[0051] In some embodiments, the plurality of guest molecules comprises one or more nucleic acids selected from the group consisting of plasmids encoding CRISPR / Cas9 components and small interfering RNAs (siRNAs) targeting oncogenes.

[0052] In some embodiments, the organic ligand enables increased loading of the plurality of guest molecules. In some embodiments, the organic ligand stabilizes the plurality of guest molecules. In some embodiments, the organic ligand stabilizes hydrophobic guest molecules. In some embodiments, the organic ligand stabilizes labile guest molecules.

[0053] In some embodiments, the plurality of guest molecules is loaded in the metal-organic framework at about 0 g / g to about 2 g / g. In some embodiments, the plurality of guest molecules is loaded in the metal-organic framework at about 0.01 g / g to about 2 g / g. In some embodiments, the plurality of guest molecules is loaded in the metal-organic framework at about 0.1 g / g to about 2 g / g. In some embodiments, the plurality of guest molecules is loaded in the metal-organic framework at about 1 g / g to about 1.5 g / g. In some embodiments, the plurality of guest molecules is loaded in the metal-organic framework at about 1.00 g / g to about 1.20 g / g.

[0054] In certain embodiments, the metal-organic framework is thermally stable, hydrolytically stable, light stable, and / or oxidatively stable. In some embodiments, the composition is thermally stable. In certain embodiments, the metal-organic framework is hydrolytically stable. In some embodiments, the metal-organic framework is light stable. In certain embodiments, the metal-organic framework is oxidatively stable.

[0055] In some embodiments, the metal-organic framework improves the thermal stability, hydrolytic stability, light stability, and / or oxidative stability of the guest molecules.

[0056] In certain embodiments, the metal-organic framework degrades under acidic conditions. In some embodiments, the acidic conditions have a pH less than 7.0, less than 6.5, less than 6.0, less than 5.5, less than 5.0, less than 4.5, less than 4.0, less than 3.5, less than 3.0, less than 2.5, less than 2.0, less than 1.5, less than 1.4, less than 1.3, or less than 1.2. In certain embodiments, the acidic conditions have a pH less than 7.0. In some embodiments, the acidic conditions have a pH less than 6.5. In certain embodiments, the acidic conditions have a pH less than 6.0. In some embodiments, the acidic conditions have a pH less than 5.5. In certain embodiments, the acidic conditions have a pH less than 5.0. In some embodiments, the acidic conditions have a pH less than 5.0. In certain embodiments, the acidic conditions have a pH less than 4.5. In some embodiments, the acidic conditions have a pH less than 4.0In certain embodiments, the acidic conditions have a pH less than 3.5. In some embodiments, the acidic conditions have a pH less than 3.0. In certain embodiments, the acidic conditions have a pH less than 2.5. In some embodiments, the acidic conditions have a pH less than 2.0. In certain embodiments, the acidic conditions have a pH less than 1.5. In some embodiments, the acidic conditions have a pH less than 1.4. In certain embodiments, the acidic conditions have a pH less than 1.3. In some embodiments, the acidic conditions have a pH less than 1.2. In certain embodiments, the acidic conditions have a pH less than 1.1. In some embodiments, the acidic conditions have a pH less than 1.0.

[0057] In some embodiments, the metal-organic framework is stable at about 0 °C to about 50 °C. In some embodiments, the metal-organic framework is stable at about 22 °C to about 50 °C. In some embodiments, the metal-organic framework is stable at about 22 °C to about 40 °C.

[0058] In some embodiments, the metal-organic framework is stable at about 0% to about 90% relative humidity. In some embodiments, the metal-organic framework is stable at about 0% to about 80% relative humidity. In some embodiments, the metal-organic framework is stable at about 0% to about 70% relative humidity. In some embodiments, the metal-organic framework is stable at about 0% to about 60% relative humidity.

[0059] In some embodiments, the metal-organic framework is stable for at least 10 weeks. In some embodiments, the metal-organic framework is stable for at least 8 weeks. In some embodiments, the metal-organic framework is stable for at least 6 weeks. In some embodiments, the metal-organic framework is stable for at least 4 weeks. In some embodiments, the metal-organic framework is stable for at least 2 weeks. In some embodiments, the metal-organic framework is stable for at least 1 week.

[0060] In some embodiments, the metal-organic framework is stable for up to 8 weeks. In some embodiments, the metal-organic framework is stable for up to 10 weeks. In some embodiments, the metal-organic framework is stable for up to 3 months. In some embodiments, the metal-organic framework is stable for up to 6 months.

[0061] In some embodiments, stability of the metal-organic framework is assessed by percent recovery of the guest molecule.

[0062] In certain embodiments, degradation of the metal-organic framework produces one or more biocompatible byproducts. In certain embodiments, degradation of the metal-organic framework produces one or more natural byproducts.

[0063] In some embodiments, the metal-organic framework releases the guest molecule or degrades under physiological conditions. In some embodiments, the metal-organicframework releases the guest molecule or degrades under acidic conditions. In some embodiments, the metal-organic framework releases the guest molecule or degrades upon treatment with simulated gastric fluid (SGF).

[0064] In some embodiments, the metal-organic framework is in the form of a particle.

[0065] In some embodiments, the metal-organic framework has a particle size of about 0.1 pm to about 50 pm. In some embodiments, the metal-organic framework has a particle size of about 0.1 pm to about 20 pm. In some embodiments, the metal-organic framework has a particle size of about 0.1 pm to about 5 pm. In some embodiments, the metal-organic framework has a particle size of about 0.1 pm to about 1 pm. In some embodiments, the metal-organic framework has a particle size of about 0.5 pm to about 5 pm. In some embodiments, the metal-organic framework has a particle size of about 0.5 pm to about 10 pm. In some embodiments, the metal-organic framework has a particle size of about 0.5 pm to about 20 pm. In some embodiments, the metal-organic framework has a particle size of about 1 pm to about 5 pm. In some embodiments, the metal-organic framework has a particle size of about 1 pm to about 10 pm. In some embodiments, the metal-organic framework has a particle size of about 1 pm to about 20 pm. In some embodiments, the metal-organic framework has a particle size of about 5 pm to about 20 pm. In some embodiments, the metal-organic framework has a particle size of about 5 pm to about 50 pm. In some embodiments, the metal-organic framework has a particle size of about 10 pm to about 20 pm. In some embodiments, the metal-organic framework has a particle size of about 10 pm to about 50 pm.

[0066] In some embodiments, the metal-organic framework has a Brunauer-Emmett-Teller (BET) surface area of about 50 m2 / g to about 2,000 m2 / g. In some embodiments, the metalorganic framework has a BET surface area of about 100 m2 / g to about 1,000 m2 / g. In some embodiments, the metal-organic framework has a BET surface area of about 300 m2 / g to about 700 m2 / g. the metal-organic framework has a BET surface area of about 50 m2 / g to about 200 m2 / g. the metal-organic framework has a BET surface area of about 100 m2 / g to about 300 m2 / g. the metal-organic framework has a BET surface area of about 200 m2 / g to about 500 m2 / g. the metal-organic framework has a BET surface area of about 400 m2 / g to about 800 m2 / g. the metal-organic framework has a BET surface area of about 750 m2 / g to about 1,500 m2 / g. the metal-organic framework has a BET surface area of about 1,000 m2 / g to about 2,000 m2 / g.

[0067] In some embodiments, the metal-organic framework further comprises a metalpolyphenol network (MPN) coating. In some embodiments, the MPN comprises a plurality of biocompatible metal ions and a plurality of biocompatible polyphenols.

[0068] In some embodiments, the metal-polyphenol network comprises a plurality of biocompatible metal ions, wherein the biocompatible metal ions have or impart one or more of the following properties: safe for consumption, food grade, anti-microbial, immune- supportive, and / or antioxidant activity. In some embodiments, the metal-polyphenol network comprises a plurality of biocompatible metal ions, wherein the biocompatible metal ions perform one or more of the following functions: promote biocompatibility, provide structural support, improve mechanical strength, regulate cargo release, and / or perform nutritional or anti-microbial functions.

[0069] In some embodiments, the plurality of biocompatible metal ions comprises biocompatible alkali metal ions, alkaline earth metal ions, and / or transition metal ions. In some embodiments, the plurality of biocompatible metal ions comprises biocompatible alkali metal ions. In some embodiments, the plurality of biocompatible metal ions comprises biocompatible alkaline earth metal ions. In some embodiments, the plurality of biocompatible metal ions comprises biocompatible transition metal ions. In some embodiments, the plurality of biocompatible metal ions comprises one or more of calcium, magnesium, zinc, iron, copper, and manganese. In some embodiments, the plurality of biocompatible metal ions comprises one or more of Ca2+, Mg2+, Zn2+, Fe2+, Fe3+, Cu2+, and Mn2+.

[0070] In some embodiments, the plurality of biocompatible metal ions comprises Ca2+. In some embodiments, the metal-polyphenol network comprises a plurality of biocompatible metal ions, wherein the biocompatible metal ions comprise calcium (Ca2+), which is safe, food-grade, and / or promotes biocompatibility. In some embodiments, the plurality of biocompatible metal ions comprises Mg2+. In some embodiments, the metal-polyphenol network comprises a plurality of biocompatible metal ions, wherein the biocompatible metal ions comprise magnesium (Mg2+), which is mild and biocompatible and / or useful for structural support. In some embodiments, the plurality of biocompatible metal ions comprises Zn2+. In some embodiments, the metal-polyphenol network comprises a plurality of biocompatible metal ions, wherein the biocompatible metal ions comprise zinc (Zn2+), which has antimicrobial and immune- supporting properties. In some embodiments, the plurality of biocompatible metal ions comprises Fe2+. In some embodiments, the plurality of biocompatible metal ions comprises Fe3+. In some embodiments, the metal-polyphenolnetwork comprises a plurality of biocompatible metal ions, wherein the biocompatible metal ions comprise iron (Fe2+ / Fe3+), whose redox behavior can be manipulated. In some embodiments, the plurality of biocompatible metal ions comprises Cu2+. In some embodiments, the metal-polyphenol network comprises a plurality of biocompatible metal ions, wherein the biocompatible metal ions comprise copper (Cu2+), which has antioxidant properties. In some embodiments, the plurality of biocompatible metal ions comprises Mn2+. In some embodiments, the metal-polyphenol network comprises a plurality of biocompatible metal ions, wherein the biocompatible metal ions comprise manganese (Mn2+), which has antioxidant activity.

[0071] In some embodiments, the metal-polyphenol network comprises a plurality of biocompatible polyphenols, wherein the biocompatible polyphenols have or impart one or more of the following properties: antioxidant activity, stabilizing activity, enhanced targeting, enhanced bioactivity, controlled release, strong metal coordination or chelation, antiinflammatory activity, UV-protective activity, and / or compatibility (e.g., with bioactive metal ions, MOF, or guest molecules).

[0072] In some embodiments, the plurality of biocompatible polyphenols comprises one or more of tannic acid, gallic acid, a catechin, quercetin, ellagic acid, or ferulic acid. In some embodiments, the plurality of biocompatible polyphenols comprises tannic acid. In some embodiments, the plurality of biocompatible polyphenols comprises gallic acid. In some embodiments, the plurality of biocompatible polyphenols comprises a catechin. In some embodiments, the plurality of biocompatible polyphenols comprises quercetin. In some embodiments, the plurality of biocompatible polyphenols comprises ellagic acid. In some embodiments, the plurality of biocompatible polyphenols comprises ferulic acid.

[0073] In some embodiments, the MPN coating comprises Fe3+ions and tannic acid.

[0074] In some embodiments, the MOF acts as a host matrix and the MPN provides a selective barrier or functional shell. In some embodiments, surface interactions of the MPN coating with the MOF particle improve release kinetics of a plurality of guest molecules.

[0075] In some embodiments, the thickness of the MPN coating is controlled.

[0076] In some embodiments, the MPN comprises a plurality of biocompatible metal ions and a plurality of biocompatible polyphenols, and the biocompatible polyphenols coordinate to the biocompatible metal cores of the metal-organic framework. In some embodiments, the MPN comprises a plurality of biocompatible metal ions and a plurality of biocompatible polyphenols, and one or more biocompatible polyphenols coordinate to one or more biocompatible metal cores of the metal-organic framework. In some embodiments, the MPNand metal-organic framework are coupled through covalent-like coordination bonds. In some embodiments, the MPN and metal-organic framework interact primarily through covalent- like coordination bonds rather than hydrogen bonding or weak adsorption. In some embodiments, the MPN and metal-organic framework interact primarily through covalent- like coordination bonds, and hydrogen bonding or weak adsorption comprise secondary interactions.

[0077] In some embodiments, the MPN coating is layered on the surface of the particle. In some embodiments, the MPN coating comprises one or more layers. In some embodiments, the MPN coating comprises one layer. In some embodiments, the MPN coating comprises two or more layers. In some embodiments, each layer of the MPN coating has the same composition. In some embodiments, at least one layer of the MPN coating has a different composition.

[0078] In some embodiments, the MPN coating is about 10 nm to about 1 pm thick. In some embodiments, the MPN coating is about 10 nm to about 20 nm thick. In some embodiments, the MPN coating is about 20 nm to about 100 nm thick. In some embodiments, the MPN coating is about 100 nm to about 500 nm thick. In some embodiments, the MPN coating is about 500 nm to about 1 pm thick.

[0079] In some embodiments, the MPN coating improves the mucosal adhesion, prolongs gastrointestinal retention, enhances intestinal interaction, and / or extends fecal retention of the metal-organic framework relative to an uncoated metal-organic framework.

[0080] In some embodiments, gastrointestinal retention of the metal-organic framework is about 2 to about 6 hours. In some embodiments, gastrointestinal retention of the metalorganic framework is about 2 to about 4 hours. In some embodiments, gastrointestinal retention of the metal-organic framework is about 6 to about 12 hours. In some embodiments, gastrointestinal retention of the metal-organic framework is about 8 to about 12 hours.

[0081] In some embodiments, the MPN coating enhances localization in the intestine and / or improves biodistribution of the metal-organic framework relative to an uncoated metalorganic framework.

[0082] In some embodiments, the metal-organic framework accumulates in the intestine and liver. In some embodiments, the metal-organic framework does not significantly accumulate in the heart, spleen, lung, and / or kidneys.

[0083] In some embodiments, the MPN coating enhances interaction with nutrient absorption pathways relative to an uncoated metal-organic framework. In some embodiments, the MPNcoating improves resistance to enzymatic degradation. In some embodiments, the MPN coating increases the stability of the metal-organic framework relative to an uncoated metalorganic framework. In some embodiments, the MPN coating slows degradation of the metalorganic framework relative to an uncoated metal-organic framework. In some embodiments, the MPN coating extends release of a guest molecule in the metal-organic framework relative to an uncoated metal-organic framework.

[0084] In some embodiments, the metal-organic framework further comprises a near-infrared (NIR) fluorescent dye.

[0085] In some embodiments, the metal-organic framework is any metal-organic framework provided herein. In some embodiments, the metal-organic framework is NuMOF-1, NuMOF-2, NuMOF-3, NuMOF-4, NuMOF-5, NuMOF-6, NuMOF-7, NuMOF-8, NuMOF-9, NuMOF-10, NuMOF-11, NuMOF-12, NuMOF-13, NuMOF-14, NuMOF-15, NuMOF-16, NuMOF-17, NuMOF-18, or NuMOF-19. In some embodiments, the metal-organic framework is NuMOF-1, NuMOF-2, NuMOF-3, NuMOF-4, NuMOF-5, NuMOF-6, NuMOF-7, NuMOF-8, NuMOF-9, or NuMOF-10. In some embodiments, the metal-organic framework is NuMOF-1, NuMOF-2, NuMOF-3, NuMOF-4, or NuMOF-19. In some embodiments, the metal-organic framework is NuMOF-11, NuMOF-12, NuMOF-13, NuMOF-14, NuMOF-15, NuMOF-16, NuMOF-17, or NuMOF-18. In some embodiments, the metal-organic framework is CD-MOF. In some embodiments, the metal-organic framework is MPN / CD-MOF.Compositions and. Administration

[0086] The present disclosure provides compositions (e.g., pharmaceutical and nutraceutical compositions) comprising a compound (e.g., a metal-organic framework) provided herein, and an excipient.

[0087] In another aspect, provided herein are compositions comprising a metal-organic framework provided herein and an excipient.

[0088] In some embodiments, the composition is a nutraceutical composition. In some embodiments, the composition is a pharmaceutical composition.

[0089] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing a compound, agent, or particle described herein (z.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, ifnecessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0090] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0091] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0092] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents such as calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0093] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0094] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0095] The injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0096] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0097] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0098] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin andbentonite clay, and (II) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0099] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0100] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0101] Dosage forms for topical and / or transdermal administration of a compound, agent, or particle described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can beprepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0102] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum comeum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound, agent, or particle in powder form through the outer layers of the skin to the dermis are suitable.

[0103] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0104] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0105] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0106] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0107] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0108] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient.Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0109] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1- 1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.

[0110] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation .

[0111] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0112] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0113] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is thelifetime of the subject, tissue, or cell. In certain embodiments, a dose e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0114] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0115] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that treat a disease in a subject in need thereof, prevent a disease in a subject in need thereof, or reduce the risk to develop a disease in a subject in need thereof, improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[0116] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g.,combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease (e.g., lung disease or liver disease). Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0117] Additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal antiinflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti-pyretic s, hormones, and prostaglandins. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is an binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferaseinhibitors, histone deacetylase inhibitors (HD AC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.Food Products, Beverages, and Nutritional Supplements

[0118] In another aspect, provided herein are food products comprising a metal-organic framework provided herein and an excipient.

[0119] In another aspect, provided herein are beverages comprising a metal-organic framework provided herein and water.

[0120] In another aspect, provided herein are nutritional supplements comprising a metalorganic framework provided herein and an excipient.

[0121] In some embodiments, the food product, beverage, or nutritional supplement comprises an additive. In some embodiments, the additive is a colorant, flavoring agent (e.g., a sweetener, salt, or spice), cooling agent, or preservative.

[0122] In some embodiments, the nutritional supplement comprises a vitamin, mineral, botanical, herb, amino acid, or probiotic.

[0123] In some embodiments, the food product further comprises one or more of a sweetener, colorant, flavoring agent, cooling agent, or preservative.

[0124] In some embodiments, the excipient is a foodstuff. In some embodiments, the foodstuff comprises one or more of a fruit, vegetable, carbohydrate, grain, or starch, protein, fat or oil, and dairy or non-dairy alternative. In some embodiments, the foodstuff comprisesa protein, carbohydrate, or fat. In some embodiments, the protein comprises an animal protein. In some embodiments, the protein comprises a plant-based protein. In some embodiments, the protein comprises beef, poultry, pork, game, fish, seafood, tofu, seitan. In some embodiments, the foodstuff comprises a carbohydrate. In some embodiments, the foodstuff comprises a starch. In some embodiments, the foodstuff comprises a grain. In some embodiments, the foodstuff comprises rice, pasta, bread, or potatoes. In some embodiments, the foodstuff comprises fruit or vegetable. In some embodiments, the foodstuff comprises a fat or oil. In some embodiments, the foodstuff comprises a plantbased fat. In some embodiments, the foodstuff comprises an animal fat. In some embodiments, the foodstuff comprises a sauce.

[0125] In some embodiments, the beverage further comprises one or more of a sweetener, colorant, flavoring agent, cooling agent, or preservative.

[0126] In some embodiments, the beverage is a non-alcoholic beverage. In some embodiments, the beverage is an alcoholic beverage. In some embodiments, the beverage comprises a juice, syrup, carbonated water, carbonated soft drink, coffee, tea, milk, liquor, beer, or wine.

[0127] In some embodiments, the composition, food product, beverage, or nutritional supplement of any preceding claim, further comprising one or more micronutrients, probiotics, natural extracts, small molecule drugs, proteins, peptides, and nucleic acids. In some embodiments, the composition, food product, beverage, or nutritional supplement of any preceding claim, further comprising one or more micronutrients selected from the group consisting of iron, iodine, zinc, vitamin B12 (cobalamin), and vitamin B9 (folate, folic acid). In some embodiments, the composition, food product, beverage, or nutritional supplement of any preceding claim, further comprising one or more natural extracts selected from the group consisting of Curcumin, Quercetin, Epigallocatechin gallate (EGCG), Resveratrol, Berberine, and Coenzyme Q10.

[0128] In some embodiments, the composition, food product, beverage, or nutritional supplement of any preceding claim, wherein the composition, food product, beverage, or nutritional supplement is non-perishable. In some embodiments, composition, food product, beverage, or nutritional supplement of any preceding claim, wherein the composition, food product, beverage, or nutritional supplement is stable at room temperature. In some embodiments, the composition, food product, beverage, or nutritional supplement of any preceding claim, wherein the composition, food product, beverage, or nutritional supplement is stable at around 70 °F. In some embodiments, the composition, food product,beverage, or nutritional supplement of any preceding claim, wherein the composition, food product, beverage, or nutritional supplement is stable at up to about 80 °F. In some embodiments, the composition, food product, beverage, or nutritional supplement of any preceding claim, wherein the composition, food product, beverage, or nutritional supplement is stable at up to about 85 °F. In some embodiments, the composition, food product, beverage, or nutritional supplement is stable for at least 4 weeks. In some embodiments, the composition, food product, beverage, or nutritional supplement is stable for at least 6 weeks. In some embodiments, the composition, food product, beverage, or nutritional supplement is stable for at least 8 weeks. In some embodiments, the composition, food product, beverage, or nutritional supplement is stable for at least 2 months. In some embodiments, the composition, food product, beverage, or nutritional supplement is stable for at least 3 months.Kits

[0129] In another aspect, provided herein are kits comprising: a metal-organic framework, a composition, a food product, a beverage, or a nutritional supplement provided herein; and instructions for using the metal-organic framework, composition, food product, beverage, or nutritional supplement.

[0130] The kits provided may comprise a composition or compound (e.g., a metal-organic framework provided herein) described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising an excipient for dilution or suspension of a composition or compound (e.g., a metal-organic framework provided herein) described herein. In some embodiments, the composition or compound (e.g., a metal-organic framework provided herein) provided in the first container and the second container are combined to form one unit dosage form.

[0131] Thus, in one aspect, provided are kits including a first container comprising a compound (e.g., a metal-organic framework provided herein) or composition described herein. In certain embodiments, the kits are useful for treating a disease, disorder, or condition in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease, disorder, or condition in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease, disorder, or condition in a subject in need thereof. In some embodiments, the disease, disorder, orcondition is a micronutrient deficiency. In certain embodiments, the kits are useful for delivering an agent to a subject. In certain embodiments, the kits are useful for delivering a micronutrient to a subject. In certain embodiments, the kits are useful for delivering a vitamin to a subject. In certain embodiments, the kits are useful for delivering a mineral to a subject.

[0132] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease, disorder, or condition in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease, disorder, or condition in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease, disorder, or condition in a subject in need thereof. In some embodiments, the disease, disorder, or condition is a micronutrient deficiency. In certain embodiments, the kits and instructions provide for delivering an agent to a subject. In certain embodiments, the kits and instructions provide for delivering a micronutrient to a subject. In certain embodiments, the kits and instructions provide for delivering a vitamin to a subject. In certain embodiments, the kits are useful for delivering a mineral to a subject. A kit described herein may include one or more additional agents described herein as a separate composition.Methods and Uses

[0133] In another aspect, provided herein are methods of delivering an agent to a subject, comprising administering to the subject a metal-organic framework, a composition, a food product, a beverage, or a nutritional supplement provided herein.

[0134] In another aspect, provided herein are methods of treating or preventing a disease, disorder, or condition in a subject, comprising administering to the subject a metal-organic framework, a composition, a food product, a beverage, or a nutritional supplement provided herein.

[0135] In some embodiments, the agent is one or more components of the metal-organic framework. In some embodiments, the agent is one or more components of the metalorganic framework selected from the plurality of biocompatible metal core, biocompatible organic ligands, and guest molecules. In some embodiments, the agent is a biocompatible metal of the metal-organic framework. In some embodiments, the agent is an organic ligandof the metal-organic framework. In some embodiments, the agent is a biocompatible organic ligand of the metal-organic framework. In some embodiments, the agent is a guest molecule of the metal-organic framework.

[0136] In some embodiments, the subject is a human. In some embodiments, the subject is a mammal. In some embodiments, the subject is an adult. In some embodiments, the subject is age 18-65. In some embodiments, the subject is less than 18 years of age. In some embodiments, the subject is above 65 years of age. In some embodiments, the subject has a micronutrient deficiency.

[0137] In certain embodiments, the disease, disorder, or condition is a micronutrient deficiency, genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, metabolic disorder, inflammatory disease, or autoimmune disease. In some embodiments, the disease, disorder, or condition is a micronutrient deficiency. In some embodiments, the micronutrient deficiency is a vitamin or mineral deficiency. In certain embodiments, the micronutrient deficiency is a vitamin deficiency. In some embodiments, the micronutrient deficiency is a mineral deficiency. In some embodiments, the micronutrient deficiency is vitamin A deficiency, vitamin D deficiency, vitamin E deficiency, iron deficiency, or zinc deficiency. In some embodiments, the micronutrient deficiency is iron deficiency, iodine deficiency, or zinc deficiency. In certain embodiments, the micronutrient deficiency is vitamin A deficiency. In some embodiments, the micronutrient deficiency is iron deficiency. In certain embodiments, the micronutrient deficiency is iodine deficiency. In some embodiments, the micronutrient deficiency is vitamin B2 (riboflavin) deficiency. In certain embodiments, the micronutrient deficiency is vitamin B7 (niacin) deficiency. In some embodiments, the micronutrient deficiency is vitamin bl2 (cobalamin) deficiency. In certain embodiments, the micronutrient deficiency is vitamin D (cholecalcifeol) deficiency. In some embodiments, the micronutrient deficiency is vitamin E (tocopherol) deficiency. In certain embodiments, the micronutrient deficiency is vitamin KI (phytomenadione) deficiency. In some embodiments, the micronutrient deficiency is vitamin C (6-O-pamlmitoyl-L-ascorbic acid) deficiency. In certain embodiments, the micronutrient deficiency is zinc deficiency.

[0138] In some embodiments, the metal-organic framework, composition, food product, beverage, or nutritional supplement is orally administered to the subject.EXAMPLESExample 1. Ferrous Nutritional Metal Organic Framework (NuMOF) as Fortified Supplements

[0139] Micronutrient deficiencies, notably in iron and iodine, constitute significant global health challenges, impacting billions and leading to critical health issues. Iron deficiency impairs immune functions and development, affecting two billion people, while iodine deficiency, affecting brain development, also plagues two billion worldwide. Despite the success of strategies like salt iodization recommended by the World Health Organization, traditional iron fortification has been struggling due to iron’s poor palatability and high reactivity between iron and iodine. This example explored Metal-Organic Frameworks (MOFs) for developing double-fortified salt (DFS), addressing these deficiencies more effectively. MOFs have been recognized for their stability and high adsorption capacity. The MOFs provided herein overcame the hurdles of conventional fortification, including high reactivity and low stability of iron and iodine under cooking and storage conditions. Using Large Language Model (LLM) and machine learning, fumaric acid was identified as a biocompatible organic ligand for synthesizing Fe(II) MOFs. A vitamin C-facilitated synthesis method for Fe(II) MOFs was also developed, eliminating the need for an oxygen-free environment, which thus simplified the production process with an aim to boost future commercial viability and sustainability. The synthesized fumaric acid Fe(II) MOF exhibited stability and controlled nutrient release under adverse conditions, thereby enhancing micronutrient bioavailability. In vivo studies validated the efficient release and absorption of iodide. This example indicates that DFS based on MOFs may be used in food fortification technologies to address global micronutrient shortages.

[0140] This example describes Metal-Organic Frameworks! / (I, JJ) (MOFs) as carrier materials to overcome technical barriers faced by iron food fortification and contribute to the global micronutrient deficiency crisis. MOFs constitute a porous extended network constructed from metal ions and organic ligands. The prevailing characteristic of most MOFs is their robust thermal and aqueous stability(J2), allowing them to endure extreme environmental conditions while maintaining structural integrity. Concurrently, the specific surface area of the porous MOF structure facilitates efficient adsorption of guest molecules, such as iodine compounds(J3). Some MOFs present pH-responsiveness(J4), giving the potentiality of controlled release. The inventors sought to harness these properties to develop a new generation of DFS.

[0141] To ascertain biocompatible organic ligands for the synthesis of iron-based MOFs with sufficient thermal and aqueous stability for DFS applications, prompt engineering with advanced information from literature and / or ChatGPT was used to extract information (FIGs. 1A, 16). This approach facilitated the development of a machine learning (ML) model dedicated to predicting the water stability of MOFs (FIGs. IB, 16, Tables 3-5), backed by datasets coming from existing literature(75). Leveraging this model, iron MOFs synthesized from 50 different ligands were assessed for water stability. NuMOF-1 was selected for further development as a double fortified salt with iron and iodine (FIG. 1C). After thorough evaluation of various parameters, fumaric acid was identified as a biocompatible organic ligand due to its proven food safety and economic feasibility. Notably, fumaric acid has been a trusted food acidifier since 1946, ensuring safety and widespread adoption in the food industry.

[0142] To facilitate the utilization of iron(II) MOFs as a practical component in DFS products, the scalability and economic viability of their synthesis are relevant considerations. Using the vitamin C-assisted method, the synthetic yield of NuMOF-1 was approximately 70%. Preliminary cost analysis based on lab-scale production estimated the cost at ~$34 to ~$45 USD per kg of NuMOF-1 (Table 8), with anticipated cost reductions upon process scale-up and solvent recycling. These values are competitive with current encapsulated DFS technologies. Historically, the synthesis of iron(II) MOFs has faced considerable challenges, particularly due to the propensity of Fe2+ions to oxidize to Fe3+ions, which compromises their absorption and bioavailability. Standard synthesis procedures have thus mandated the use of an oxygen-free environment to preserve the iron(II) valence state, a requirement that entails substantial cost and energy, especially when considering the scale necessary for commercial production. Addressing this synthesis challenge, an efficient and environmentally friendly method was developed that includes introducing reducing agent vitamin C to reduce iron(III) in the MOF to iron(II) without the need for an oxygen-free environment. This synthesis method not only eliminates the need for expensive, energy- intensive anoxic conditions, thereby simplifying the process and aligning with sustainable manufacturing, but also significantly advances the commercial viability of iron(II) MOF- based DFS products. Utilizing the vitamin C-facilitated synthesis method, MOFs preserving nearly 100% of the iron(II) status were synthesized.

[0143] The fumaric acid iron(II) MOF (NuMOF-1), both alone and when combined with various iodine compounds, displayed remarkable stability and controlled release, even under harsh conditions typical in food matrices or cooking, such as boiling water, oven heating,light exposure, or oxidants. Vitamin C was incorporated to reduce NuMOF-1, effectively preserving its iron(II) valence and ensuring high bioavailability, while maintaining the crystal structure. It successfully preserved its iron(II) valence state and crystal structure, while keeping the iodine compounds absorbed and stable. In addition, it prevented iron ions from interacting with polyphenols — common in many foods — which can reduce iron’s water solubility and bioavailability. This protective ability highlights the MOF’s ability to fortify foods in regions with polyphenol-rich diets. Moreover, the selective release of iron ions and iodine compounds in simulated gastric fluid confirmed their bioaccessibility in the digestive system. An in vivo experiment demonstrated that iodide released from the MOF was absorbed as efficiently as free-form iodide, affirming the maintained bioavailability of these micronutrients. These findings support that MOFs successfully overcome the longstanding challenge of maintaining the stable coexistence of iodine and iron for extended periods, specifically within the context of food fortification for DFS purposes. A detailed comparison between NuMOF-1 and conventional dual-fortification strategies is provided in Table 9, emphasizing its superior nutrient retention, compatibility, and simplified processing compared to existing formulations.Machine learning model-backed, design of iron MOFs

[0144] To identify a suitable ligand pool for iron MOFs, a machine learning (ML) model (J6) was used to predict the water stability of iron MOFs based on ligand characteristics. Initially, a comprehensive review of the literature was conducted to compile a database of iron MOFs and their corresponding ligands for the ML model (Tables 1-3). Given the absence of a standardized criterion for assessing the water stability of Metal-Organic Frameworks (MOFs), various methodologies are employed by researchers, encompassing techniques such as Powder X-ray Diffraction (PXRD) (J5), Scanning Electron Microscopy (SEM), Brunauer-Emmett-Teller (BET) surface area analysis, and water recovery experiments. This diversity in assessment parameters underscores the need for a systematic approach to gather performance data and evaluate the water stability of MOFs. The inventors devised a collaborative data mining protocol between human annotators and ChatGPT (FIG. 8). Initially, human researchers identified documents referencing iron-based MOFs (Table 1). Subsequently, leveraging the sophisticated text mining capabilities of ChatGPT (J 7, 18), relevant water stability data associated with MOFs were systematically extracted (Table 2). To establish a water stability ranking of MOFs, specific ranking criteria were provided to ChatGPT (Table 3), alongside illustrative examples (FIG. 13). To ensure communicationand output alignment between human annotators and the machine learning model, four distinct sets of prompts denoted as Prompts A-D were formulated (FIGs. 9-14), a process referred to prompt engineering.

[0145] Utilizing ChatGPT, water stability data were acquired for 28 iron-based Metal- Organic Frameworks (MOFs) from literature. Subsequently, leveraging these data alongside chemical descriptors of MOFs (Table 5), a database was established and a machine learning model was trained to predict the water stability of MOFs. Employing this model, predictions were performed using 10 small molecule ligands derived from food sources (Table 4), to identify suitable ligands conducive to obtaining MOFs characterized by high water stability.

[0146] Leave-one-out (LOO) cross-validation was used for feature selection, model selection, and hyperparameter tuning. Analysis of feature importance via Gini importance in random forest models identified PEOE_VSA3, PEOE_VSA9, and BCUT2D_MRHI as the top three contributors to water stability (FIG. 15 for distribution and FIG. 16 for the Gini importance). PEOE_VSAs such as PEOE_VSA3 (79) and PEOE_VSA9 are Molecule Operating Environment (MOE)-type descriptors that quantify partial charges and contributions of molecular surface areas (79), capturing local electronic environments that can influence metal-ligand interactions and solvation behavior. BCUT2D_MRHI (20) is a BCUT (Burden CAS University of Texas) descriptor(20) indicating the highest eigenvalue weighted by Crippen's molar refractivity, and is linked to ligand polarizability, a relevant property for water stability in MOFs (27). MinAbsPartialCharge and MaxPartialCharge were also included to capture polarity extremes that may impact water interactions. The pairwise correlation matrix of these top six features and solubility classes is shown in FIG. 15, revealing both feature distributions and interdependencies. The confusion matrix in FIG. 16 demonstrates reliable predictive performance across stability classes, supporting the validity of the ML-guided ligand screening. Subsequently, employing the trained model, the water stability of iron-based MOFs corresponding to 10 food-derived ligands was predicted (Table 5). Concurrently, utilizing these 10 ligands, 5 iron-based MOFs were prepared (PXRD showed in FIGs. 19A-19B) via hydrothermal synthesis and their stability in water were assessed. The predicted outcomes were compared against the experimental results, summarized in Table 6. The model demonstrated a prediction accuracy of up to 80 to 90% for the water stability of iron-based MOFs (FIGs. 15 and 17).

[0147] Based on the economic viability and safety profile of the ligands, a fumaric acidbased iron MOF was further developed as a carrier for double fortified salt. Fumaric acid hasbeen acknowledged as a dependable food acidifier since 1946, ensuring its safety and broad acceptance within the food industry.Vitamin C base-facilitated iron (II) MOF synthesis.

[0148] Divergent outcomes were observed when employing fumaric acid alongside ferrous salts (FeCh, FeSCU or Mohr’s salt ((NFU Fe^CU riFFO)) in aqueous versus dimethylformamide (DMF) solutions (FIGs. 2A, 18A-18C). Specifically, a red precipitate formed in aqueous solution, while a black precipitate resulted from DMF solution (FIGs. 18A-18C). Characterization of the products revealed minimal disparities in their powder X- ray diffraction (pxrd), Fourier-transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM) profiles (FIGs. 19A-21B). Differentiation of iron status was achieved through high-energy X-ray photoelectron spectroscopy (XPS), with binding energies of 711.6 and 709.86 indicative of Fe(III) and Fe(II) states, respectively (FIGs. 22 and 23).

[0149] To further elucidate the valence state transition of iron during the formation of Fe(III) MOF, the iron valence states in solution were compared using a colorimetric iron assay kit. Despite the formation of Fe(III) MOF, the iron valence state in the solution persisted as Fe(II) (FIG. 24). Without wishing to be bound by any particular theory, the inventors posited that ligand deprotonation influences the valence state of iron MOFs (FIG. 2C). In aqueous environments, iron typically coordinates with water molecules in a stable six-coordination manner, impeding oxidation by oxygen. However, the presence of ligands disrupts this equilibrium, allowing oxygen to approach the Fe center and oxidize Fe(II) to Fe(III). To validate this hypothesis, the adsorption free energies of H2O on Fe(II) complexes were compared with and without ligand deprotonation, respectively. Ligand deprotonation significantly reduced the adsorption free energies of H2O from +38.1 to -14.6 kJ / mol. The corresponding free energy barrier for H2O adsorption is +55.2 and +3.2 kJ / mol for protonated and deprotonated ligands, respectively, indicating a mitigation of the steric hindrance of the ligand, facilitating Fe(II) oxidation (FIGs. 25, 39A-39C).

[0150] In an effort to render the MOF synthesis process more environmentally friendly for the food industry, the use of alternative alkaline aqueous solutions such as NaOH or NaHCOa to deprotonate the ligand were evaluated. However, excess OH ion led to the production of Fe(OH)2, diminishing MOF yield and resulting in a mixed valence state (FIG. 25, 26A-26B). To overcome this hurdle, the food-grade reducing agent ascorbic acid was introduced to reduce Fe(III) from MOF (FIGs. 2A-2B, 3B). This approach resulted in the transformation of Fe(III) to Fe(II) MOF without altering morphology or PXRD patterns (FIGs. 26A-26B, 27A-27B). Fe(II) status was confirmed via high-energy XPS (FIG. 28). This approachtherefore expands the chemical repertoire for synthesizing iron(II) MOFs with food-grade and cost-effective compounds.

[0151] The synthetic approach was extended to include additional ligands — aspartic acid, mesaconic acid, muconic acid, and dimethyl fumaric acid — yielding NuMOF-2, -3, -4, and -5 (as shown in FIG. 2D). These MOFs were characterized through PXRD and morphology analysis (as shown in FIGs. 29, 30, 31, 36, 37, 41, and 42).

[0152] Through experimental and computational analyses, this example presents an innovative approach to synthesizing Fe(II) MOFs devoid of previously energy-intensive air- free conditions. This method logy effectively stabilized Fe(II) ions, broadening the potential applications of Fe(II) MOFs across environmental and biological domains. This approach afforded multiple advantages: it reduces the reliance on expensive and energy-intensive oxy gen-depleted environments, streamlining the synthesis process and facilitating more sustainable manufacturing practices. This advancement enhances the commercial feasibility of Fe(II) MOF-based double fortified salt (DFS) products, offering a simpler and more sustainable route to their production.Characterization of NuMOF-1

[0153] Following the successful synthesis of Fe(II) fumarate MOF, NuMOF-1, a comprehensive characterization was conducted using various physical and spectroscopic techniques to elucidate its structural and morphological properties. Powder X-ray diffraction (PXRD) analysis revealed sharp diffraction peaks closely matching simulated patterns, indicative of NuMOF-l’s highly crystalline nature and dual-pore structure (FIG. 3A).Fourier transform infrared (FT-IR) spectroscopy demonstrated the disappearance of the hydroxyl group on the carboxyl group of fumaric acid, affirming complex formation with iron (FIGs. 20A-20B). High-resolution transmission electron microscopy (HRTEM) imaging unveiled a distinct interplanar spacing of 0.23 nm, confirming the ordered crystal structure of NuMOF-1 (FIG. 3B, FIG. 3C, and FIG. 32).

[0154] Furthermore, surface morphology analysis via scanning electron microscopy (SEM) coupled with energy-dispersive X-ray (EDX) spectroscopy revealed an elemental Fe / C ratio of approximately 0.125, consistent with the crystal composition (FIGs. 3D-3E, FIG. 33A- 33B, and Table 7). The valence state of NuMOF-1 was verified using X-ray photoelectron spectroscopy (XPS), with the Fe 2p spectrum exhibiting peaks at 709.7 eV and 723.6 eV corresponding to ferrous iron(II) (FIG. 3F). The XPS survey spectrum delineated peaks associated with Fe, Cl, and C, N, and O elements (FIG. 3G). Additionally, the microporousand mesoporous characteristics of NuMOF-1 were examined through low-temperature (77 K) nitrogen adsorption studies employing Brunauer, Emmett, and Teller (BET) characterization (FIG. 3H). The adsorption data manifested a sharp uptake at low pressures (below P / PO = 0.01), indicative of micropores (Type I), followed by a pressure step (Type IV) at P / PO = 0.3- 0.35bar, suggesting the presence of mesopores alongside micropores.Iodine loading in NuMOF-1

[0155] For the implementation of double fortified salt (DFS) application, iodine loading capacity, stability, and controlled release were assessed within the NuMOF platform. Experimental investigation into the kinetics of the iodine adsorption process revealed that NuMOF- l-Fe(III) achieved a maximum or equilibrium adsorption capacity of 1.15 g / g within a 40-hour timeframe, while vitamin C-reduced NuMOF-1 achieved I2 loading capacity of 1.09 g / g (FIG. 4A). These results demonstrate that the vitamin C reduction process does not significantly affect the iodine loading capacity. Subsequently, the status and binding characteristics of NuMOF-1 and entrapped iodine compounds were meticulously examined employing X-ray photoelectron spectroscopy (XPS). Furthermore, thermogravimetric analysis (TGA) characterization of NuMOF-1 loaded with iodine, iodide, and iodate showcased varying adsorption efficiencies, with MOF demonstrating efficiencies of 18.18%, 7.84%, and 8.12% for iodine, iodide, and iodate, respectively (FIG. 4H). This highlights the selective and efficient adsorption of iodine species by the NuMOF, with elemental iodine (I2) showing the highest affinity, and thus its potential for optimized iodine fortification strategies. Comparative analysis between NuMOF-1 and I2@NUMOF-1 via XPS survey spectra distinctly displayed iodine characteristic peaks in the latter (FIG. 34). Additionally, the Fe 2p peak of iodine-loaded NuMOF-1 exhibited a subtle shift to higher binding energy (Fe 2p3 / 2 shifted from 709.90 to 710.12 eV), suggesting an increment in positive charge on the Fe atom post-iodine loading and subsequent redistribution of charge within the Fe cluster (FIG. 4B). Moreover, the I 3d XPS spectrum of 12 @ NuMOF-1 featured prominent peaks at 617.8 and 629.1 eV, corresponding to the I 3d5 / 2 and I 3d3 / 2 orbitals of the iodine molecule, further corroborating the presence of adsorbed iodine species (FIG. 4C). This indicates that iodine was successfully incorporated into the NuMOF platform with a high adsorption capacity, demonstrating the platform's potential for efficient iodine loading.

[0156] Color-coded Raman mapping of I2@NUMOF-1 unveiled a spatial distribution of absorbed iodine species with significant intensity bands (FIG. 4D and FIG. 35).Furthermore, the Raman spectrum of I2@NUMOF- 1 depicted noticeable bands at 94.3,-128.6, and 175.8 cm'1post-iodine adsorption, indicative of robust charge transfer interactions between iodine and NuMOF-1, along with the prevalence of anionic polynuclear iodide species (FIG. 4E). Specifically, the bands at 94.3 and -128.6 cm'1were attributed to the symmetric and asymmetric stretching vibrations of I3-, respectively, while the band at 175.8 cm'1corresponded to the stretching vibration of 15 -poly iodide (FIG. 4E). Furthermore, peaks corresponding to the symmetric and asymmetric stretching vibration bands of [hCl]' at 150.6 cm'1, alongside a peak related to the stretching vibration band of [2I2C1]' at 203.8 cm'1, were observed, indicating potential interactions of iodine with free chloride ions. This suggests that the interaction between iodine and the NuMOF framework alters the electronic environment around the Fe atoms, confirming iodine's successful integration into the NuMOF structure.

[0157] Additionally, attempts were made to load KI and KIO3 into the NuMOF-1. Raman spectra of NuMOF-1 loaded with iodine, iodide, and iodate exhibited characteristic peaks at 98, 105, and 739 cm'1, respectively, corresponding to vibration modes of iodine species within the MOF matrix (FIG. 4F). Fourier-transform infrared spectroscopy (FTIR) results demonstrated that neither I2, KI, nor KIO3 elicited any discernible effect on the chemical structure of NuMOF (FIG. 4G). This reveals that iodine forms stable charge-transfer complexes within the NuMOF, reinforcing the material’s capacity to support diverse iodine species critical for controlled release applications.Stabilization of iron and, iodine in NuMOF-1

[0158] In existing systems, iodine compounds within DSF are susceptible to degradation induced by elevated temperature, moisture, ultraviolet (UV) radiation, or oxidizing agents during cooking and storage practices, potentially resulting in alterations of oxidation states and subsequent iodine sublimation. For instance, potassium iodate may readily dissolve upon exposure to ferric iron, consequently undergoing reduction to iodine, whereas potassium iodide is susceptible to oxidation by ferrous iron, leading to iodine formation. Exposure to high temperatures and humidity exacerbates iodine volatility and reduction. Hence, the protective capabilities of NuMOF-1 towards iodine were evaluated under diverse environmental conditions, with the aim of enhancing iodine stability and sustaining its concentration in the DFS application.

[0159] Initially, protection of iodine cargo was assessed in boiling water for 2 hours, as a mimic of cooking practices with exposure to high temperature and moisture. NuMOF-1 demonstrated considerable protection for iodine, with recovery rates nearing 100%, a hugecontrast to the free-form iodine compounds (FIG. 5A). Subsequently, recovery of iodine cargo was evaluated within a 100°C oven for 2 hours, simulating exposure to elevated temperatures. NuMOF-1 exhibited over 5-fold and 18-fold enhanced recovery of iodine compared to its unencapsulated counterpart (FIG. 5B). Additionally, the sample was subjected to simulated solar irradiation to simulate the intense light exposure. Exposure to simulated solar light (280 mW / cm2) revealed a significant increase in the recovery of iodine and potassium iodate within NuMOF-1 compared to the free-form, with enhancements exceeding 15 times and 3 times, respectively (FIG. 5C).

[0160] Polyphenolic compounds from dietary sources present in food are recognized for impeding iron bioavailability in the human body due to formation of insoluble complexes(22- 24), which has also hindered the development of iron-fortified foods. The interaction of polyphenolic compounds, including tannic acid, curcumin, ellagic acid, quercetin, and catechin, with free-form iron salts (FeCh) was assessed (FIGs. 5D-5F). Rapid reaction kinetics leading to the formation of insoluble complexes and reduced recovery rates of these polyphenols were observed in aqueous solutions, which also caused a noticeable color change (FIG. 5F). Incorporating the iron salts (e.g., FeCh) into iron MOFs before introducing them to solutions containing polyphenolic compounds significantly minimized the formation of insoluble complexes. A majority of the polyphenols, including tannic acid, curcumin, ellagic acid and quercetin, remained over 80% soluble, as confirmed by both the quantification of free polyphenols in the solution phase and colorimetric measurements. This phenomenon indicates that the structure of iron MOFs such as NuMOF-1 provides a protective effect, stabilizing the iron ions in solutions rich in polyphenols.

[0161] The World Health Organization’s guidance set of conditions for accelerated stability testing of medicinal products in hot climate regions or global markets is 75% relative humidity (rH) at 40°C. In order to explore the stability of I2, KI and KIO3 in NuMOFs under long-term harsh storage conditions and normal storage conditions, the I2@NUMOF-1 was exposed to a simulated high temperature and high humidity environment (75% rH at 40°C, FIG. 5G) and, in some instances, recovery of elemental iodine was assessed under normal storage conditions (75% rH at 25 °C, FIG. 5H). Iodine in NuMOF was more stable than in free iron salt (FeCh), and the iodine recovery rate in NuMOF remained above 90% after 8 weeks. However, the recovery of iodine in iron salt (FeCh) was less than 5% within a week. At the same time, in free iron salt, KI was oxidized to h by oxygen while KIO3 was easily reduced to h by Fe(II). readily sublimated in the exposed environment, causing the loss of iodine. The recovery rate of iodine after 8 weeks was less than 40%. The strong adsorptionproperties of NuMOF provided significant protection for iodine. Additionally, the large surface area of NuMOF provides room to absorb L and prevents its sublimation.

[0162] Concurrently, an investigation into the stability of valence states within NuMOFs synthesized through varying methodologies was conducted (FIG. 51). It was observed that NuMOF- 1 synthesized in aqueous and dimethylformamide (DMF) solvents exhibited Fe(II) ratios of 20% and 55%, respectively. Conversely, NuMOF-1 synthesized via vitamin C reduction demonstrated an approximate Fe(II) content of 95%. Due to the protective influence of vitamin C, the Fe(II) species remained stable, with the Fe(II) ratio sustaining at 90% even after an 18- week duration.Release and, absorption of iron and, iodine from NuMOF-1.

[0163] Building on the effective stabilization of iron and iodine by NuMOF-1, the release, absorption, and bioavailability of these micronutrients from NuMOF-1 were assessed. Initially, SGF at 37 °C was employed as an in vitro model to simulate the digestive process, particularly mimicking the conditions when NuMOFs are ingested and reach the stomach. Subsequently, to evaluate the bioavailability of iron ions released from the NuMOFs after SGF treatment, Caco-2 cells were used as an in cellulo model(25). Furthermore, an in vivo mouse model was implemented to examine the release and absorption of iodine from NuMOF, comparing it to the bioavailability of free-form iodine.

[0164] The coordination between fumaric acid and iron within NuMOF-1 conferred the ability to achieve pH-dependent release of iron. The pH-responsive release dynamics showed an inverse correlation between pH levels and the stability of iron MOFs, with lower pH environments facilitating heightened concentration of iron ions determined with ICP MS (FIG. 6A). In vitro release studies of iron conducted under various conditions confirmed the stability of NuMOF-1 in aqueous solutions, demonstrating no structural compromise even under exposure to room temperature (RT; 25 °C) or boiling water (100 °C) (FIG. 6B).Without wishing to be bound by any particular theory, the inventors ascribed this resilience to the formation of stronger coordination bonds between iron ions and the carboxyl groups in comparison to interactions with water molecules. Exposure to SGF, on the other hand, induced a significant release of iron ions into the aqueous solution. This phenomenon was attributed to the protonation of carboxyl groups in fumaric acid, which breaks the formation of coordination bonds with metal ions. The release pattern of iodine closely mirrors that of iron (FIG. 6C). Upon exposure to SGF conditions, NuMOF-1 underwent structural collapse, leading to the rapid release of iodine initially loaded within the MOF structures into thesurrounding solution. The treatment of water, either in boiling condition or room temperature, however, led to minimal release of iodine (FIG. 6B). Such contrast demonstrated robust interactions between the NuMOF-1 and loaded iodine compounds, rendering high stabilization efficacy.

[0165] The iodine and iron molecules released from NuMOF-1 after the treatment of SGF were subject to absorption. Caco-2 cells were used as an in cellulo model to evaluate bioavailability of the released iron (FIG. 6D). The cell uptake assay revealed a notable augmentation in iron absorption from multiple MOFs in comparison to iron salts (FIG. 6E). This enhancement was hypothesized to attribute to the augmented solubility of iron facilitated by ligand interactions.

[0166] To assess the bioavailability of iodine and iron molecules released from NuMOF-1 following SGF treatment, Caco-2 cells were used as an in cellulo model for evaluating the iron's bioavailability (FIG. 6D). The valence state of iron ions and the role of ligands in iron uptake were evaluated. Initially, the NuMOFs (e.g., NuMOF-1) underwent SGF treatment to mimic stomach conditions, followed by neutralization and quantification of the iron concentration in the solution. This solution, primarily containing iron ions and ligands from the NuMOFs, was then applied to the cells. The results indicated that the presence of Fe2+and Fe3+alone led to a modest increase in cellular iron concentration (FIG. 6E), suggesting slower uptake kinetics potentially due to the cellular iron absorption process. In contrast, NuMOFs significantly enhanced iron uptake by Caco-2 cells, with an observed 4-fold increase in absorption compared to the free-form iron salt control (FeCh and FeCE). Without wishing to be bound by any particular theory, this improved cellular iron absorption is likely facilitated by the ligands, which have been shown to enhance iron uptake in human epithelial cells(26). Further investigation using confocal imaging revealed the uptake by Caco-2 cells of a model fluorescent small molecule, fluorescein, which served as a cargo within NuMOF-1 and was released upon SGF treatment (FIG. 6F).

[0167] SEM imaging was employed to observe the morphological changes in NuMOF-1 crystals (FIG. 6G). Exposure to simulated gastric fluid (SGF) led to visible structural disintegration, evidenced by the appearance of cracks and irregular fragments in the NuMOF- 1 crystals. In contrast, treatments with room temperature and boiling water preserved the structural integrity of the crystals, despite the presence of minor flocs in the boiling water samples, indicating the crystals largely remained intact.

[0168] Further, an in vivo model was used to assess the release and absorption of targeted iodine cargo from NuMOF-1. Mice were orally administered with radiolabeled iodide,Na125I, in both its free form and encapsulated within NuMOF-1, either Fe2+or Fe3+. The biodistribution and absorption of iodide were monitored over time through real-time microSPECT / CT imaging, which allowed for the differentiation between encapsulated and released iodine based on signal intensity (27). The imaging revealed that free Na125! rapidly localized in the stomach and then accumulated in the thyroid gland before being cleared via the kidneys (FIG. 7A). In contrast, Na125I encapsulated in the NuMOF-1 showed delayed gastric release from 3 hours to 8 hours, extended retention in the stomach, enhanced accumulation in the thyroid, and eventual renal clearance (FIG. 7A). Quantification of temporal images demonstrated that the NuMOF-1 enabled controlled iodine release, mirroring the absorption kinetics of free Na125I in the gastrointestinal tract (FIG. 7B). Further biodistribution studies highlighted a significant concentration of125I in the thyroid, surpassing that in other organs, with the iodine uptake from the MOF showing no significant difference from free Na125I (FIG. 7C). This indicated that the MOF effectively released iodine without hindering its absorption, confirming the potential of NuMOF-1 for targeted iodine delivery and suggesting its suitability for applications in iodine supplementation.Materials

[0169] From a materials safety perspective, all components used in the synthesis of NuMOF-1 — including fumaric acid and iron(III) chloride — are recognized as generally regarded as safe (GRAS) by the U.S. Food and Drug Administration. Fumaric acid is widely used as a food additive, and iron salts are commonly employed in food fortification. NuMOF- 1 particles are within the microscale range, not nanoscale, which reduces the risk of systemic absorption or unintended bioaccumulation. Microscale particles are considered safer for gastrointestinal exposure than nanoparticles, as supported by prior studies (52).

[0170] This example demonstrates the potential of a NuMOF platform as a solution for developing double-fortified salt (DFS) to address global micronutrient deficiencies in iron and iodine. NuMOF-1 exhibited excellent stability and controlled release of these nutrients, significantly improving iodine retention under various conditions such as boiling, oven heating, and light exposure. The use of vitamin C in the synthesis process enhanced the stability of Fe(II), eliminating the need for oxygen-free conditions and simplifying production. In vitro and in vivo studies confirmed the bioavailability and efficient absorption of iron and iodine, highlighting the protective capabilities of NuMOF-1 against environmental factors like oxidation and sublimation.

[0171] Furthermore, the current synthesis achieves a 70% yield with an estimated production cost of $34 / kg at laboratory scale. These metrics suggest that the NuMOF platform may undergo cost-effective scale-up using existing manufacturing infrastructure.Reagents

[0172] Fumaric acid (>99.0%), L-aspartic acid (reagent grade, >98%), mesaconic acid (99%), trans, trans-muconic acid (98%), ammonium iron(II) sulfate hexahydrate ((NFU)2Fe(SO4)2- 6H2O, 99%), iron(II) chloride tetrahydrate (FeCh- 4FhO, 99.99%), iron(III) chloride hexahydrate (FcCI v 6H2O, >98%), fluorescein (C20H12O5), N,N-dimethylformamide (HCON(CH3)2, >99.9%), potassium iodide (KI, >99.0%), potassium iodate (KIO3, 99.5%), iodine (I2, >99.0%), tannic acid (C76H52O46), curcumin (C21H20O6), ellagic acid (CuHeOs, >95%), quercetin (C15H10O7, >95%), catechin (C15H14O6) were purchased from SIGMA- ALDRICH®. All reagents were used as purchased without further purification. Simulated gastric fluid (SGF) was purchased from R RICCA CHEMICAL COMPANY®. Iron Assay Kit (Colorimetric) was purchased from ABCAM®.MethodsHuman-ChatGPT collaborative data mining.Article Retrieval

[0173] Iron MOF related papers and their corresponding supporting documents were obtained from different journals. The papers, published between May 2004 and March 2024, were downloaded in PDF format. Satisfactory and comparative results were obtained, culminated in a summary description of water stability data (see Table 8). Ranking criteria were defined (refer to Table 9) and then all iron MOFs were ranked based on the provided text data.Prompt Engineering

[0174] In this example, GPT-4, a state-of-the-art large language model (LLM), was applied to undertake data mining initiatives. Developed and maintained by OpenAI, GPT-4 operates as a web-based chatbot accessible via the OpenAI website chat.openai.com. This methodology adopts a collaborative human-GPT paradigm, as outlined in FIG. 8. Initially, human experts meticulously curate literature pertinent to Iron MOF, synthesizing their insights into a comprehensive summary, as delineated in Table 1.

[0175] To refine the precision and relevance of GPT-4's outputs, Prompt engineering was implemented, comprising Prompts A to D:Prompt A: Minimizing Hallucinations

[0176] Prompt A underscored the importance of minimizing hallucinations. By furnishing explicit instructions, ChatGPT was converted into ChemGPT, an Al assistant adept in chemistry and specializing in MOF research. This domain- specific refinement ensured that ChemGPT’ s responses remain anchored within the professional realm of MOFs, thereby mitigating the risk of extraneous or irrelevant content. Subsequent analysis, as depicted in FIG. 9 and FIG. 10, validated the efficacy of this instructional intervention, demonstrating enhanced coherence and accuracy in ChemGPT's responses within the MOF domain. Furthermore, a proactive mechanism was instituted, as illustrated in FIG. 11, involving prompt correction and retraining of the model through dialogue, thus fostering continuous refinement aimed at minimizing GPT-4’s hallucinations and augmenting the fidelity of its outputs.Prompt B: Data Extraction

[0177] Prompt B revolved around data extraction. GPT was tasked with extracting textual data from the literature related to the water stability of MOFs. However, the initial outputs provided by GPT appeared to be relatively general and broad (refer to FIG. 13). To facilitate the comparison of these text data, restrictions and requirements were imposed on the output content, the format of the output was standardized, and examples of desired output text were provided (refer to FIG. 14). Subsequently, satisfactory and comparative results were obtained, culminating in a summary description of water stability data (see Table 1).Prompt C: Ranking

[0178] Prompt C aimed to rank MOFs based on water stability data. The ranking criteria were defined (refer to Table 2) and then GPT was trained using examples from the literature. Targeted questions were used to ensure GPT comprehended the criteria and examples. Finally, GPT ranked all iron MOFs based on provided text data.Prompt D: Structured Output Requesting

[0179] Prompt D entailed requesting structured output from GPT. Prompts were designed to pair MOF-related information, such as name, ligand, ligand smiles, water stability description, water stability, and ranking. This structured output format streamlined data processing for subsequent machine learning model generation, significantly enhancing efficiency.Machine Learning Methods

[0180] To accurately represent iron metal-organic frameworks (MOFs) for predicting water stability, the organic ligand and MOF formation conditions were modulated, including the molar ratios. For solvents, the dielectric constant of the solvent molecules was used as afeature. Acidity was represented with a value of 1 for acidic conditions, 0 for neutral, and -1 for basic conditions. For the organic ligands, two sets of popular physicochemical descriptors were utilized: RD Kit 2D descriptors and Mordred descriptors. After removing non-variant features, the RD Kit 2D set comprised 149 descriptors, while the Mordred set included 1,391 descriptors.

[0181] Feature importance was assessed using Gini importance derived from a random forest model, an ensemble method that averages predictions from multiple decision tree models to improve prediction accuracy. Gini importance, also known as mean decrease in impurity, is defined by the total decrease in node impurity (weighted by the probability of reaching that node), averaged over all trees in the ensemble. Additionally, the feature weights were examined using a LI regularized linear model (Lasso), which incorporates an LI penalty to encourage sparsity in the coefficients.

[0182] Extensive hyperparameter tuning was performed for both methods, including optimization of the number of principal components used as inputs, using leave-one-out cross-validation on the training data. The best model for screening achieved a one-vs-remain area under the receiver operating characteristic curve (AUC ROC) of 0.702. All machine learning models employed in this example were implemented in Python using the scikit-leam library. The RDKit 2D descriptors were obtained via the RDKit library, and the Mordred descriptors were sourced from the Mordred library.General procedure for iron MOFs synthesis and their water stability for ML model.

[0183] A solution comprising 1 mmol of FeCL-bFEO and 1 mmol of food- grade ligands (see FIGs. 9, 15) dissolved in 3 mL of distilled water was prepared. Optionally, 0.5 mL of 2 M sodium hydroxide was added to the solution. This solution was then transferred into a 12 mL reaction vessel and subjected to a temperature of 90°C for a duration of 10 hours.Following the reaction period, the resultant products were separated via centrifugation at 10,000 rpm for 3 minutes and subsequently washed with fresh ethanol three times to remove impurities. The purified nanocrystals were then dried at 40 °C under vacuum conditions until reaching a constant weight.

[0184] Iron MOF samples (approximately 20 mg) were weighed and transferred into a 50 mL centrifuge tube. Subsequently, 20 mL of deionized (DI) water was added to the tube, and the solution was allowed to incubate at room temperature overnight. Following incubation, the solution was centrifuged, and the supernatant was carefully removed. The precipitate containing the iron MOF was then weighed. The recovery of iron MOF was calculated using the formula:

[0185] Where Wi represents the initial weight of iron MOF, and W2 represents the weight of iron MOF after overnight incubation in water.Synthesis of NuMOF-1

[0186] Hydrothermal Synthesis. A solution containing 1 mmol of iron(II) sulfate heptahydrate (Fe(SO4)2- 6H2O) and 1 mmol of fumaric acid dissolved in 3 mL of distilled water was meticulously prepared. Optionally, 0.5 mL of 2 M sodium hydroxide could be added. This solution was subsequently transferred into a 12 mL reaction vessel and subjected to hydrothermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 3,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. The purified nanocrystals were subsequently dried at 40°C under vacuum conditions until reaching a constant weight.

[0187] Solvent Thermal Synthesis. A solution comprising 1 mL containing 1 mmol of iron(II) sulfate heptahydrate (Fe(SO4)2- 6H2O) and 1 mmol of fumaric acid dissolved in 2 mL of N,N-Dimethylformamide (DMF) was meticulously prepared. Optionally, 0.5 mL of 2 M sodium hydroxide could be added. This solution was then transferred into a 12 mL reaction vessel and subjected to thermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 10,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. Subsequently, the purified nanocrystals were dried at 40°C under vacuum conditions until reaching a constant weight.Synthesis of NuMOF-2.

[0188] A solution comprising 1 mL containing 1 mmol of iron(II) sulfate heptahydrate (Fe(SO4)2-6H2O) and 1 mmol of L-aspartic acid dissolved in 2 mL of N,N- Dimethylformamide (DMF) was meticulously prepared. Optionally, 0.5 mL of 2 M sodium hydroxide could be added. This solution was then transferred into a 12 mL reaction vessel and subjected to thermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 10,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. Subsequently, the purified nanocrystals were dried at 40°C under vacuum conditions until reaching a constant weight.Synthesis of ferrous NuMOF-3.

[0189] A solution comprising 1 mL containing 1 mmol of iron(II) sulfate heptahydrate (Fe(SO4)2-6H2O) and 1 mmol of mesaconic acid dissolved in 2 mL of N,N- Dimethylformamide (DMF) was meticulously prepared. Optionally, 0.5 mL of 2 M sodium hydroxide could be added. This solution was then transferred into a 12 mL reaction vessel and subjected to thermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 10,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. Subsequently, the purified nanocrystals were dried at 40°C under vacuum conditions until reaching a constant weight.Synthesis of ferrous NuMOF-4.

[0190] A solution comprising 1 mL containing 1 mmol of iron(II) sulfate heptahydrate (Fe(SO4)2-6H2O) and 1 mmol of trans, trans-muconic acid dissolved in 2 mL of N,N- Dimethylformamide (DMF) was meticulously prepared. Optionally, 0.5 mL of 2 M sodium hydroxide could be added. This solution was then transferred into a 12 mL reaction vessel and subjected to thermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 10,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. Subsequently, the purified nanocrystals were dried at 40°C under vacuum conditions until reaching a constant weight.Synthesis of ferrous NuMOF-19.

[0191] A solution comprising 1.0 mL containing 1.0 mmol of iron(II) sulfate heptahydrate (Fe(SO4)2-6H2O) and 1.0 mmol of 2,3-dimethylfumaric acid dissolved in 2.0 mL of N,N- Dimethylformamide (DMF) was meticulously prepared. Optionally, 0.5 mL of 2.0 M sodium hydroxide could be added. This solution was then transferred into a 12.0 mL reaction vessel and subjected to thermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 10,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. Subsequently, the purified nanocrystals were dried at 40°C under vacuum conditions until reaching a constant weight.Reduction of NuMOFs.

[0192] NuMOFs (approximately 20 mg) were introduced into a uniformly mixed solution containing 10 mg / mL ascorbic acid and incubated for three minutes. The mixture underwent centrifugation at 2000 rpm to eliminate any unreacted components. Subsequently, the resultant material was subjected to a triple wash with fresh deionized water (DI) tothoroughly remove residual impurities. Finally, the purified nanocrystals were dried at 40°C under vacuum conditions until reaching a constant weight.Characterization of NuMOF.Powder X-ray Diffraction (PXRD) Analysis of NuMOF Samples.

[0193] PXRD patterns of both pre- and post- iodine loaded NuMOF samples were obtained using a Rigaku SmartLab instrument equipped with a Cu anode and a Ni filter (Cu Ka radiation). The instrument operated at a scan rate of 57min. Crystalline powder samples were mounted on zero-background holders and levelled using a spatula prior to measurement. The PXRD patterns were recorded within the range of 5 to 20° with 751 steps, each taken at an increment of approximately 0.02° per step. The acquisition time per step was set to one second, resulting in a total measurement time of 10 minutes.Fourier Transform Infrared Spectroscopy (FT-IR).

[0194] FT-IR measurements were conducted using a Thermo Fisher IS50R Bench instrument with a measurement range of 12,500 cm1to 50 cm-1. The obtained FT-IR data were reported using a wavenumber (cm ') scale within the range of 4000 to 400 cm Thermogravimetric Analysis (TGA).

[0195] TGA of NuMOFs was performed on a PerkinElmer Pyris 1 Thermogravimetric Analyzer with a heating rate of 10 °C per minute, ranging from 50 °C to 600 °C under a nitrogen flow of 20 mL min *. Ultrahigh-purity-grade nitrogen gas (N2) was utilized during the TGA measurement process.Morphological Characterization.

[0196] The morphology and dimensions of NuMOF samples following synthesis and posttreatments were assessed using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). For SEM imaging, samples underwent gold coating prior to examination. A Zeiss Crossbeam 540 SEM equipped with a STEM stage and detector was utilized for SEM imaging. For TEM analysis, a JEOL 2100 field emission gun (FEG) TEM operating at an acceleration voltage of 200 kV was employed. The instrument boasted an ultimate point-to-point resolution of 0.23 nm, enabling the visualization of lattice fringes at a resolution of 0.1 nm. High-resolution TEM (HRTEM) was conducted to capture lattice fringes of NuMOF samples at this 0.1 nm resolution.

[0197] Raman microscopy was utilized to characterize iodine loaded in the NuMOF samples, employing an excitation wavelength of 532 nm with a power of 50 mW. Spectra were acquired using a Renishaw Invia Reflex Raman Confocal Microscope equipped with a Renishaw HSES motorized stage and a l” CCD array detector covering a range of 200 nm to1064 nm. Raman mapping images were obtained with wavelength transfer and photoluminescence ranges of 50 to 4000 cm1and 330 nm to 1.6 microns, respectively. The system utilized holographic reflectance gratings (1200 lines / mm) and a Renishaw Centrus 3692A6 detector master.

[0198] Survey and high-energy X-ray photoelectron spectroscopy (XPS) spectra were collected using a PHI Versaprobe II XPS instrument equipped with monochromated Al K- alpha X-radiation as the excitation source.

[0199] Gas sorption analyses were conducted using a QUANTACHROME® Instruments Autosorb-iQ instrument (Boynton Beach, Florida, USA) with extra-high purity gases. Prior to measurement, samples were activated and outgassed at 120°C for 8 hours. The Brunauer- Emmett-Teller (BET) surface area and total pore volume were determined from N2 sorption isotherms measured at 77 K. Pore size distribution was calculated utilizing the Quenched Solid Density Functional Theory (QSDFT) model, specifically designed for a carbon model containing cylindrical pores, within the QUANTACHROME® ASiQwin 5.0 software package.Release and Stability StudiesIron release and stability.

[0200] NuMOF samples weighing 4 mg each were measured into 50 mL tubes and suspended in 40 mL of water at room temperature (RT), 100 °C, and simulated gastric fluid (SGF) at 37°C. At specified time intervals (0, 10, 30, and 60 minutes), the samples were centrifuged at 4000 rpm for 5 minutes, and 1 mL of the supernatant was collected for analysis. Subsequently, the samples were replenished with 1 mL of fresh release medium. The quantification of iron release was performed using inductively coupled plasma atomic emission spectroscopy (ICP-AES) to determine absolute iron concentrations. Cumulative release and recovery were calculated as the total amount of micronutrient released at each time point relative to the initially added iron amount.Iodine iodide and iodate loading of NuMOF.

[0201] A vial containing 50 mg of NuMOF and 500 mg of solid iodine was sealed within a bottle and maintained at 80°C for iodine capture. Following the unsealing of the bottle, the vial was removed and placed in an 80°C oven for 2 minutes to eliminate any free iodine vapor. Subsequently, the vial was covered and allowed to cool to room temperature before being weighed.

[0202] For iodide capture, 10 mg of NuMOF was immersed in a 50 mL saturated solution of potassium iodide (KI) and incubated within a dark container overnight. Similarly, another 10mg of NuMOF was submerged in a 50 mL saturated solution of potassium iodate (KIO3) and subjected to overnight incubation within a dark container to obtain KIO3@ NuMOF.Iodine release and stability.

[0203] NuMOF samples containing I2, weighing approximately 4 mg each, were accurately measured and transferred into 50 mL tubes, with the exact values recorded for subsequent analysis. These NuMOF samples were then incubated with 40 mL of water under three different conditions: room temperature (RT), 100°C, and simulated gastric fluid (SGF) at 37°C. After specific incubation times (10, 30, 60, 90, and 120 minutes), the tubes were centrifuged at 3000 rpm for 3 minutes, and 1 mL of the supernatant was collected for analysis. Subsequently, the samples were replenished with 1 mL of fresh release medium. The quantification of iron release was performed using inductively coupled plasma mass spectrometry (ICP-MS) to determine the absolute iodine concentrations. Cumulative release and recovery were calculated as the total amount of micronutrient released at each time point relative to the initially added iron amount.Stability test under boiling water, oven, and irradiation.

[0204] NuMOFs containing iodine, iodide, or iodate were dispersed in 1 mL of water and then heated at 100°C in a thermomixer set at 500 rpm for predetermined durations (0.5, 1, 2, and 5 hours). The tube caps had holes to facilitate oxygen exchange, and 0.2 mL of water was added every 30 minutes to compensate for evaporation. After centrifugation at 4,000 rpm for 5 minutes, the supernatant was transferred into a new tube.

[0205] For samples containing iodine, iodide, or iodate, approximately 10 mg of NuMOFs were weighed and added to vials before being placed into an oven set at 100°C. After incubating for 1 hour, the samples were dissolved in a 4 mL ethanol / water solution (1:1 ratio). The concentration of iodine was determined using UV spectrophotometry at 461 nm.

[0206] A 300 W Xenon arc-based solar simulator was obtained from SOLAR LIGHT® (Glenside, PA; airmass (AM) simulator model 16S-300-002). The simulator was equipped with AMO and AM1.5 filters, with a spectral range from 290 to 2,800 nm. The irradiance at the focus point was 670 mW / cm2, and it was recorded using a PM A 2100 data logging radiometer. A Peltier thermoelectric cooling module with a temperature range from -20 to 100°C (CP-200HT-TT) was used along with an external bipolar temperature controller (TC- 720-OEM) from TE TECHNOLOGY, INC.® (Traverse City, MI). The solar spectrum at the focus point was measured using a Flame-S-VIS-NIR-ES with a cosine corrector from OCEAN OPTICS® (Dunedin, FL).

[0207] NuMOF samples containing I2, KI, or KIO3 were placed at the focus point in borosilicate flat-bottom 4-mL scintillation vials and irradiated at 670 mW / cm2for 30 minutes. The irradiance level was approximately seven times that of the exposure of sunlight at sea level. After irradiation, 10 mg samples were dissolved in 4 mL ethanol / water solution (1:1 ratio), and the concentration of iodine was determined using UV spectrophotometry at 461 nm.Stability test for the present of polyphenol compounds.

[0208] FeCh salt (0.05 mmol) and NuMOF (0.05 mmol) were added to 5 mL polyphenolic compound solutions with a molar ratio of 1:5. The mixture was then incubated at room temperature for 2 hours. After incubation, the samples were subjected to RP-HPLC analysis to calculate the recovery of polyphenol compounds.

[0209] Additionally, photos of the iron-polyphenolic compound solutions were captured using an iPhone® 13 Pro Max, and RGB information was extracted from the photos for the calculation of color difference using the following formulation:Stability Test for Long-Term Storage Conditions.

[0210] NuMOFs and free iron salts loaded with iodine, iodide, and iodate were individually placed in microcentrifuge tubes and stored in a controlled environment at 40°C and 75% humidity. The storage conditions were regulated within a dedicated chamber equipped with a condensate recirculation system (Caron, Environmental Chamber and Condensate Recirculator). At predetermined intervals, the samples were retrieved from the storage chamber and subjected to analysis using inductively coupled plasma atomic emission spectroscopy (ICP-AES).In Vitro and In Vivo ModelsIron uptake and Intercellular uptake by Caco2 cell from NuMOFs.

[0211] Caco-2 cells (ATCC®) were cultured in Eagle's Minimum Essential Medium (EMEM) supplemented with 20% fetal bovine serum and 1% antibiotics. Approximately 500,000 cells were seeded in each well of a 12-well plate containing full growth medium and incubated at 37°C in a 5% CO2 atmosphere. After 24 hours, 100 pL of medium was aspirated from each well, and replaced with 100 pL of SGF-treated iron MOF solutions or iron salt solutions, with iron concentrations adjusted to 100 ppm, the concentration was confirmed by ICP MS. The cells were incubated for an additional 2 hours to facilitate iron uptake, followed by three washes with cold PBS (0-4 °C). Subsequently, 250 pL of coldlysis buffer (0-4 °C) was added to each well, and the plates were placed on ice for 5 minutes. The resulting lysate was transferred to tubes, treated with 2% nitric acid, and centrifuged to separate the supernatant for downstream ICP-MS analysis.

[0212] To visually evaluate cell uptake, confocal imaging was employed. Iron MOFs loaded with fluorescein were applied to the cells using the same protocol as above, but substituting a glass-bottom dish for the well plate. The concentration of iron ions in the sample solutions was maintained at 100 ppm. Imaging was performed using an Olympus FV 1200 Laser Scanning Confocal Microscope. Cells were stained with NucBlue™ Live ReadyProbes™ Reagent (Hoechst 33342) and CellTracker™ Fluorescent Probes, following the manufacturer's protocol.

[0213] Cell viability was assessed in the presence of 100 ppm SGF-treated iron MOF solutions or 100 ppm iron salt solutions using the CellTiter-Fluor™ Cell Viability Assay (PROMEGA®) in a 96-well plate format, according to the manufacturer's instructions.In Vivo Dual-Modal Imaging.

[0214] In vivo dual-modal imaging was performed utilizing a microSPECT / CT scanner (Milabs, Utrecht, The Netherlands) outfitted with a multi-pinhole focusing collimator. Each SPECT scan was conducted for a duration of 15 minutes, employing an energy window spanning from 20 to 40 keV. CT scanning parameters were set to precision mode, incorporating three-frame averaging, full angle acquisition, with a tube voltage of 55 kV, and a tube current of 615 mA.

[0215] All animal experiments adhered to the protocols approved by the Animal Care and Use Committee of Soochow University. Female specific pathogen-free BALB / c mice, aged 6 weeks and weighing between 20-23 g each, were obtained from Shanghai Slack Laboratory Animal Co., Ltd. The mice were orally administered Nal and MOF via gavage. Anesthesia was induced in the mice through inhalation of a 1.5% isoflurane / oxygen mixture (flow rate: 0.6 L / min) while positioned on the temperature-controlled animal bed of the microSPECT / CT scanner. Imaging scans were conducted at various time points (0, 4, 6, 8, 12, 24, and 48 hours). Subsequently, all microSPECT / CT data were processed utilizing POMD software (version 3.602).Blood circulation and biodistribution.

[0216] To elucidate the metabolic kinetics of iodine in vivo, Na125I was orally administered to mice in both free and MOF-encapsulated forms. Blood samples were collected from the retroorbital venous plexus of healthy BALB / c mice (n = 3) at 0, 1, 2, 4, 6, 8, 24, and 48 hours post-feeding. Subsequently, blood samples were weighed, and radioactivity was quantifiedusing a gamma counter (Multi Crystal LB 2111 gamma counter). Additionally, to examine the biodistribution of Na125!, major organs (heart, kidneys, liver, lungs, and spleen) were weighed, and radioactivity was measured.DFT calculation

[0217] All data in this study were calculated with the Gaussian 16 software package (53) and with the B3LYP level of density functional theory (DFT) (54-56). The basis set 6-31G (d) was selected for non-metal atoms. The effective core potentials (ECPs) basis set LanL2DZ (57, 58) was employed for the Fe atom. The relative free energies are used for discussion throughout the text.Statistical analysis.

[0218] All quantitative measurements were performed with at least three independent replicates. The values were expressed as the mean + / - SD. Statistical significance was evaluated using two-tailed Student’s t test. A P value of <0.05 was considered to be statistically significant.Table 1. The information summary of iron MOF.Table 2. The ChatGPT-gcncratcd summary of characterization results in classifying thermodynamically stable MOFs, including summary of water stability and ranking.Table 3. Criteria for MOF water stability classifications.Table 4. The smiles of ligands for high through put screening of water stability.Table 5. Chemical descriptors of ligands for ML models.Table 6. The predicted and experimental water stability of iron MOFs.Predicted Recovery ExperimentalNo Name ranking in water% ranking1 Fumaric acid 0.747253 95.51% High4 Trans, trans-muconic acid 0.648352 83.6% High3 Mesaconic acid 0.626374 82.14% High2 L-aspartic acid (AS) 0.648352 75.01% High5 2,3-Dimethylfumaric acid 0.560440 58.90% Middle6 Curcumin (Cu) 0.692308 N / A N / A7 Succinic acid (SA) 0.538462 N / A N / A8 Thiomalic acid 0.593407 N / A N / A9 Adipic acid (AD) 0.637363 N / A N / A10 Tartronic acid (TA) 0.417582 N / A N / AFor the experimental water stability based on the water recovery of samples in DI water, high: >60%, middle:30-60%, low: 0-30%.Table 7. EDX elemental analyses from FESEM experiment of NuMOF-1 molecules showing presence of C, O, Cl, Fe and I elements(a).Element Weight % Atomic % Error % Net Int. Z A FC K 49.2 64.64 6.2 36693.59 1.0788 0.5057 1O K 31.45 31.03 8.69 23533 1.0282 0.263 1Au M 5.76 0.46 4.86 4512.58 0.5837 1.3211 1.0152C1 K 0.77 0.34 2.98 1230.66 0.8619 0.9458 0.9992I L 0.62 0.08 7.2 252.27 0.6308 1.0824 1.0053Fe K 12.2 3.45 2.48 5265.16 0.7689 1.0078 1.0043Table 8. Estimated Manufacturing Cost of MIL-88A (NuMOF-1) - Water-Based Synthesis (Lab Scale, O.lmol scale).Starting Materials Fumaric Acid 116.07 g / mol H- g $147.95 / 2.5 kg $0.69Iron(III) Chloride 162.20 g / mol 16.2 g $10 / kg $0.16Sodium Hydroxide 2.0 M (optional) 1-6 g $15 / kg $0.02Deionized Water — 30 mL $0.10 / L $0.00Subtotal - Materials — — — — $0.88Manufacturing Costs Energy (Heating @ 90°C) 50 W x 9 h = 0.45 kWh — $0.10 / kWh $0.05Total Estimated Cost — -27.3 g product (70% yield) — — $0.93Estimated Cost per KG — — — — $34.07Synthesis batch size: 0.1 mol = -27.3 g final product (assuming 70% yield), All the price of chemical was from AMAZON® dated May 25th, 2025.Table 9. Comparison of NuMOF-1 with Conventional Dual Fortification TechnologiesEncapsulated Ferrous PotassiumParameter NuMOF-1 (This work) Fumarate lodide / IodateFe(II), coated (e.g., Iron form Fe(II) in MOF TiCF) NoneElemental LIodine form (encapsulated) Not compatible I" or ICECost (USD / kg, lab scale) ~34 -35-50 (with coatings) -5-10Heat / light / humidity Low (Iodine loss stability High (Fig. 2) Moderate common)Bioavailability High (Fig. 3-4) Moderate High (iodine only)Need for surface coating No Yes NoManufacturing Moderate (1-step MOF High (multi-layer complexity synthesis) encapsulation) LowCompatibility in Iron & Iodine co- Typically iodineDFS formulated Typically iron only onlyExample 2. Additional Biocompatible Metal Organic Frameworks

[0219] This example describes various biocompatiblc metals and biocompatiblc organic ligands that can be used for NuMOF synthesis. Biocompatible organic linkers for MOFs encompass molecules of plant or animal origin featuring carboxyl or alcohol groups, including, but not limited to, fumaric acid, cyclodextrin, muconic acid, mesaconic acid, aspartic acid, succinic acid, and citric acid. Additional biocompatible metals include, for example, zinc, calcium, iron, selenium, magnesium, and sodium. Formulations and reaction conditions for evaluation of MOF syntheses are provided in Table 10.Table 10. Formulations and reaction conditions for MOF synthesisMaterials and Methods for MOFsNuMOF-11 composed of calcium and cyclodextrin.

[0220] A solution containing 1 mmol of CaSC and 1 mmol of cyclodextrin dissolved in 3 mL of distilled water was prepared. Optionally, 0.5 mL of 2 M sodium hydroxide was added. This solution was subsequently transferred into a 12 mL reaction vessel and subjected to hydrothermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 3,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. The purified nanocrystals were subsequently dried at 40°C under vacuum conditions until reaching a constant weight.NuMOF-12, composed of magnesium and cyclodextrin.

[0221] A solution containing 1 mmol of MgSCL and 1 mmol of cyclodextrin dissolved in 3 mL of distilled water was prepared. Optionally, 0.5 mL of 2 M sodium hydroxide was added. This solution was subsequently transferred into a 12 mL reaction vessel and subjected to hydrothermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 3,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. The purified nanocrystals were subsequently dried at 40°C under vacuum conditions until reaching a constant weight.NuMOF-13, composed of selenium and cyclodextrin.

[0222] A solution containing 1 mmol of Na2SeO3 and 1 mmol of cyclodextrin dissolved in 3 mL of distilled water was prepared. Optionally, 0.5 mL of 2 M sodium hydroxide was added. This solution was subsequently transferred into a 12 mL reaction vessel and subjected to hydrothermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 3,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. The purified nanocrystals were subsequently dried at 40°C under vacuum conditions until reaching a constant weight.NuMOF-14, composed of zinc and cyclodextrin.

[0223] A solution containing 1 mmol of ZnC12 and 1 mmol of cyclodextrin dissolved in 3 mL of distilled water was prepared. Optionally, 0.5 mL of 2 M sodium hydroxide was added. Thissolution was subsequently transferred into a 12 mL reaction vessel and subjected to hydrothermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 3,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. The purified nanocrystals were subsequently dried at 40°C under vacuum conditions until reaching a constant weight.NuMOF-15, composed of calcium and vitamin C.

[0224] A solution containing 1 mmol of CaC12 and 1 mmol of vitamin C dissolved in 3 mL of distilled water was prepared. Optionally, 0.5 mL of 2 M sodium hydroxide was added. This solution was subsequently transferred into a 12 mL reaction vessel and subjected to hydrothermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 3,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. The purified nanocrystals were subsequently dried at 40°C under vacuum conditions until reaching a constant weight.NuMOF-16, composed of magnesium and vitamin C.

[0225] A solution containing 1 mmol of MgC12 and 1 mmol of vitamin C dissolved in 3 mL of distilled water was meticulously prepared. Optionally, 0.5 mL of 2 M sodium hydroxide was added. This solution was subsequently transferred into a 12 mL reaction vessel and subjected to hydrothermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 3,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. The purified nanocrystals were subsequently dried at 40°C under vacuum conditions until reaching a constant weight.NuMOF-17, composed of selenium and vitamin C.

[0226] A solution containing 1 mmol of Na2SeO3 and 1 mmol of vitamin C dissolved in 3 mL of distilled water was meticulously prepared. Optionally, 0.5 mL of 2 M sodium hydroxide was added. This solution was subsequently transferred into a 12 mL reaction vessel and subjected to hydrothermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 3,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. The purifiednanocrystals were subsequently dried at 40°C under vacuum conditions until reaching a constant weight.NuMOF-18, composed of zinc and vitamin C.

[0227] A solution containing 1 mmol of ZnC12 and 1 mmol of vitamin C dissolved in 3 mL of distilled water was prepared. Optionally, 0.5 mL of 2 M sodium hydroxide was added. This solution was subsequently transferred into a 12 mL reaction vessel and subjected to hydrothermal treatment at 90°C for a duration of 10 hours. Upon completion of the reaction, the resultant nanocrystals were isolated via centrifugation at 3,000 rpm for 3 minutes and then thoroughly washed with fresh ethanol three times to eliminate impurities. The purified nanocrystals were subsequently dried at 40°C under vacuum conditions until reaching a constant weight.Iron in vivo uptake experimentsIn Vivo Dual-Modal Imaging.

[0228] In vivo dual-modal imaging is performed utilizing a microSPECT / CT scanner (Milabs, Utrecht, The Netherlands) outfitted with a multi-pinhole focusing collimator. Each SPECT scan is conducted for a duration of 15 minutes, employing an energy window spanning from 20 to 40 keV. CT scanning parameters are set to precision mode, incorporating three-frame averaging, full angle acquisition, with a tube voltage of 55 kV, and a tube current of 615 mA.

[0229] Female specific pathogen-free BALB / c mice, aged 6 weeks and weighing between 20- 23 g each are orally administered59FeCh and MOF via gavage. Anesthesia is induced in the mice through inhalation of a 1.5% isoflurane / oxygen mixture (flow rate: 0.6 L / min) while positioned on the temperature-controlled animal bed of the microSPECT / CT scanner. Imaging scans are conducted at various time points (0, 4, 6, 8, 12, 24, and 48 hours). Subsequently, all microSPECT / CT data are processed utilizing POMD software (version 3.602).Blood circulation and biodistribution.

[0230] To elucidate the metabolic kinetics of iodine in vivo,59FeC12 is orally administered to mice in both free and MOF-encapsulated forms. Blood samples are collected from the retroorbital venous plexus of healthy BALB / c mice (n = 3) at 0, 1, 2, 4, 6, 8, 24, and 48 hours post-feeding. Subsequently, blood samples are weighed, and radioactivity is quantified using a gamma counter (Multi Crystal LB 2111 gamma counter). Additionally, to examine thebiodistribution of59FeCh, major organs (heart, kidneys, liver, lungs, and spleen) are weighed, and radioactivity is measured.Statistical analysis.

[0231] All quantitative measurements are performed with at least three independent replicates. The values are expressed as the mean + / - SD. Statistical significance is evaluated using two- tailed Student’s t test. A P value of <0.05 is considered to be statistically significant.Results

[0232] The release of iron from NuMOF is much slower compared to FeCh, while the iron intake is similar.Example 3. Enhanced Gastrointestinal Retention and Biodistribution of Metal Polyphenol Network (MPN)-Modified Cyclodextrin Metal-Organic Framework (CD-MOF) Oral Delivery Platform

[0233] Oral delivery of micronutrients remains a global challenge due to poor gastrointestinal (GI) retention, instability in harsh digestive environments, and limited bioavailability. Metalorganic frameworks (MOFs), including cyclodextrin-based MOFs (CD-MOFs), offer a promising platform for nutrient encapsulation, but their performance is often hindered by rapid transit and degradation in the GI tract. This example explored a modified cyclodextrin-based MOF (CD-MOF) functionalized with a metal polyphenol network (MPN) coating to further enhance mucosal adhesion and intestinal retention. Using in vivo fluorescence imaging, it was observed that MPN-modified CD-MOF exhibited prolonged GI retention and improved biodistribution compared to unmodified MOF and control formulations. Ex vivo imaging of major organs and intestinal tissues confirmed enhanced localization in the intestine and sustained presence over 24 hours. Furthermore, fecal fluorescence analysis revealed extended release and retention of MPN-modified particles. These findings underscore the importance of MPN- functionalized MOFs as a next-generation oral delivery platform for micronutrient fortification, offering improved bioavailability and sustained intestinal interaction.

[0234] Micronutrient deficiencies — especially of iron, iodine, and zinc — continue to affect over two billion individuals worldwide, posing a persistent challenge to global public health. Oral supplementation remains the most scalable intervention; however, many micronutrients suffer from poor stability in gastric environments, transient intestinal residence, and inefficientabsorption. These limitations severely constrain the efficacy of traditional supplementation approaches, particularly in low-rcsourcc settings where therapeutic compliance and absorption are already compromised.

[0235] Metal-organic frameworks (MOFs) have emerged as a class of hybrid porous materials with high surface area, tunable composition, and encapsulation versatility. CD-MOFs, formed from cyclodextrins (e.g., y-cyclodextrin) and alkali or alkaline earth metals, are promising due to their intrinsic biocompatibility and regulatory acceptance as food-grade materials. Despite their potential, the rapid disintegration and insufficient mucosal retention of CD-MOFs in the gastrointestinal environment significantly limit their utility for sustained oral delivery.

[0236] To address these limitations, the inventors engineered a novel MOF-based delivery system by coating CD-MOF particles with a metal-polyphenol network (MPN), comprising ferric ions and tannic acid. MPNs exhibit strong mucoadhesive and pH-responsive properties, and have demonstrated utility in drug delivery and biointerface engineering. The inventors posited that this MPN coating would enhance the intestinal retention and stability of CD-MOFs, thus facilitating prolonged nutrient release and absorption.

[0237] This example presents a comprehensive evaluation of the biodistribution, gastrointestinal transit, and excretion profile of MPN-coated CD-MOFs in vivo. Using non- invasive fluorescence imaging, ex vivo organ analysis, and fecal fluorescence tracking, it was observed that MPN-functionalization improved gastrointestinal retention and bioavailability compared to uncoated MOFs. These findings offer a transformative strategy for advancing nutrient delivery technologies using food-compatible, modular MOF platforms.MPN-Coated CD-MOFs Exhibit Sustained GI Localization and Altered Biodistribution

[0238] To evaluate the impact of MPN functionalization on in vivo retention, mice were orally administered fluorescently labeled CD-MOFs, MPN-CD-MOFs, or vehicle control, followed by whole-body fluorescence imaging over a 24-hour period.

[0239] FIG. 43A shows time-resolved in vivo fluorescence images, where both CD-MOF and MPN-CD-MOF groups demonstrated strong abdominal signals within 2-4 hours postadministration. However, while CD-MOF signals rapidly declined after 6 hours, MPN-coated particles showed sustained fluorescence in the abdominal region for up to 12 hours, indicating delayed transit and enhanced retention.

[0240] Quantitative ROT analysis of abdominal fluorescence (FIG. 43B) confirmed that MPN- CD-MOFs maintained significantly higher signal intensity over time (p < 0.01), with a slower decay slope compared to the unmodified MOF group. This suggests a potential shift in the mucosal interaction profile and longer residence in the absorptive region of the intestine.

[0241] To further investigate biodistribution, major organs were excised and imaged 24 hours post-dosing (FIG. 43C). Radiant efficiency analysis (FIG. 43D) revealed that both MOF groups accumulated predominantly in the intestine and liver, but MPN-CD-MOFs exhibited notably higher retention in the intestine (p < 0.05), consistent with enhanced mucoadhesion and reduced enzymatic degradation.

[0242] Fecal imaging over a 48-hour window (FIGs. 43E-43F) showed that MPN-CD-MOFs were retained longer in the GI tract, with delayed appearance and sustained fluorescence in fecal pellets, indicating prolonged GI residence and potentially improved release kinetics.MPN Functionalization Prolongs Intestinal Residence Time

[0243] To directly visualize intestinal localization, dissected intestines from treated mice were imaged ex vivo at multiple time points post-dosing (FIG. 44A). The control group exhibited minimal background signal, while both MOF groups demonstrated peak intestinal fluorescence at 2-4 hours. MPN-modified MOFs retained strong fluorescence through 8-12 hours, whereas signal from uncoated MOFs declined sharply after 4 hours.

[0244] Quantitative analysis (FIG. 44B) revealed that MPN-CD-MOFs retained >30% of peak fluorescence at 8 hours, in contrast to <15% for CD-MOF and <5% for the control group. This extended retention profile is attributed to the adhesive properties of the MPN layer, which likely enhances interactions with the intestinal mucosa and slows transit through the GI lumen.

[0245] These results support that MPN coatings improve the stability and adhesion of MOF- based delivery vehicles under physiologically relevant conditions. Enhanced retention not only prolongs the time window for nutrient absorption but may also enable targeted release in the distal small intestine — an advantage for nutrients with narrow absorption sites or pH-dependent uptake profiles.

[0246] This example validated the enhanced GI retention and biodistribution performance. This example demonstrated that MPN modification of biocompatiblc CD-MOFs significantly improved their performance as oral nutrient delivery vehicles. The advances include:• Prolonged GI residence: MPN coatings enhanced mucoadhesion and intestinal interaction, delaying transit and improving localization.• Favorable biodistribution: Enhanced accumulation in the intestine and liver suggested efficient interaction with nutrient absorption pathways.• Sustained fecal retention: Extended appearance in feces correlated with improved resistance to enzymatic degradation and slower release.

[0247] Together, these features offer a rational and food-compatible strategy for addressing limitations in micronutrient supplementation.Materials and Methods for MPN-CD-MOFsMaterials

[0248] P -Cyclodextrin ( -CD), ferric chloride hexahydrate (FcCE-blLO), tannic acid (TA), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and all other reagents were purchased from SIGMA- ALDRICH® (St. Louis, MO, USA) and used without further purification. Near-infrared fluorescent dye (e.g., Cy7-NHS ester or equivalent) was used for particle labeling. All solvents were analytical grade or higher.Synthesis of CD-MOF

[0249] CD-MOF was synthesized following previously reported procedures with minor modifications. Briefly, P-cyclodextrin (1 g) was dissolved in 20 mL deionized water and mixed with 0.5 g of potassium benzoate under stirring. After 4 hours at room temperature, the mixture was dialyzed against water for 24 hours and lyophilized to obtain CD-MOF crystals.MPN Modification

[0250] MPN (Metal-Polyphenol Network) coating was prepared by sequentially layering ferric ions (Fe3+) and tannic acid (TA) onto the surface of CD-MOF. CD-MOF particles (100 mg) were dispersed in water and treated with 0.1 mM FeCL for 10 minutes, followed by washing and subsequent addition of 0.1 mM tannic acid for another 10 minutes. This Fe3+ / TA layering step was repeated for a total of 3 cycles. MPN-modified CD-MOF (MPN / CD-MOF) was collected by centrifugation and washed thoroughly with water.Fluorescent Labeling

[0251] Both CD-MOF and MPN / CD-MOF were labeled with near-infrared (NIR) fluorescent dye by incubating 5 mg of particles in 2 mL of PBS containing 10 pM Cy7-NHS ester for 2 hours under gentle shaking. Excess dye was removed by centrifugation and triple washing with PBS until no free dye remained in the supernatant (as confirmed by absorbance at 750 nm).Animal Studies

[0252] All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of MIT and conducted in accordance with relevant ethical guidelines. Female BALB / c mice (6-8 weeks old) were randomly divided into three groups (n = 3 per group per time point): Control (saline), CD-MOF, and MPN / CD-MOF.In Vivo Imaging and Biodistribution

[0253] Mice were fasted for 4 hours prior to oral gavage of fluorescently labeled formulations (200 pL containing -100 pg particle mass). In vivo fluorescence imaging was performed using an IVIS Spectrum Imaging System (PERKINELMER®) at various time points postadministration (0, 2, 4, 8, 12, 24 hours). Regions of interest (ROI) were defined around the abdomen to quantify radiant efficiency.

[0254] At 24 hours post-administration, mice were euthanized, and major organs (heart, liver, spleen, lungs, kidneys, and intestines) were harvested for ex vivo imaging. Fluorescence was quantified using LIVING IMAGE® software.Ex Vivo Intestinal and Fecal Imaging

[0255] To assess gastrointestinal transit and fecal retention, mice were sacrificed at selected time points (2, 4, 8, 12, 24 hours), and intestines were carefully dissected, rinsed with PBS, and imaged ex vivo. Fecal pellets were collected from individual cages at 0-48 hours post-dosing and analyzed for fluorescence intensity.Data Analysis

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Check et al., Addition of polarization and diffuse functions to the LANL2DZ basis set for p-block elements. J. Phys. Chem. A 105, 8111-8116 (2001).58. P.I. Hay et al., Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals. J. Chem. Phys. 82, 299-310 (1985).EMBODIMENTS1. A metal-organic framework, comprising: a plurality of biocompatible metal cores comprising iron, calcium, magnesium, selenium, zinc, or a combination thereof; and a plurality of biocompatible organic ligands, each comprising at least two alkoxide or carboxylate moieties; wherein: each metal core is linked to at least one other metal core by at least one organic ligand.2. A metal-organic framework, comprising: a plurality of biocompatible metal cores; a plurality of biocompatible organic ligands; and a metal-polyphenolic network (MPN) coating; wherein: each metal core is linked to at least one other metal core by at least one organic ligand, forming a particle; and the MPN coating is deposited on the surface of the particle.3. The metal-organic framework of embodiment 1 or 2, wherein the plurality of organic ligands does not comprise terephthalic acid, 2,5- dihydroxyterephthalic acid, 4,4'-oxybis(benzoic acid), trimesic acid, 1,3,5-tri (4'-carboxy-4,4'-biphenyl) benzene, 4,4',4"-benzene-l,3,5-triyl-tri- benzoic acid, or biphenylcarboxylic acid.4. The metal-organic framework of any one of embodiments 1-3, wherein the plurality of organic ligands does not comprise a cyclodextrin.5. The metal-organic framework of any one of embodiments 1-4, wherein the plurality of organic ligands comprises fumaric acid, 2,3-dimethylfumaric acid, aspartic acid, mesaconic acid, muconic acid, succinic acid, citric acid, ascorbic acid, curcumin, thiomalic acid, adipic acid, tartronic acid, vitamin C, or a combination thereof.6. The metal-organic framework of any one of embodiments 1-3 or 5, wherein the plurality of organic ligands comprises a cyclodextrin.7. The metal-organic framework of any one of embodiments 1-6, wherein the plurality of organic ligands is homogenous.8. The metal-organic framework of any one of embodiments 1-7, wherein the plurality of biocompatible metal cores is homogenous.9. The metal-organic framework of any one of embodiments 1-8, wherein the plurality of biocompatible metal cores and the plurality of organic ligands are present at a ratio of about 1:100 to about 100:1.10. The metal-organic framework of any one of embodiments 1-9, wherein the plurality of biocompatible metal cores and the plurality of organic ligands are present at a ratio of about 1:10 to about 10:1.11. The metal-organic framework of any one of embodiments 1-10, wherein the plurality of biocompatible metal cores and the plurality of organic ligands are present at a ratio of about 1:10 to about 1:1.12. The metal-organic framework of any one of embodiments 1-11, wherein:(a) the plurality of biocompatible metal cores comprises calcium, and the plurality of organic ligands comprises vitamin C;(b) the plurality of biocompatible metal cores comprises magnesium, and the plurality of organic ligands comprises vitamin C;(c) the plurality of biocompatible metal cores comprises selenium, and the plurality of organic ligands comprises vitamin C;(d) the plurality of biocompatible metal cores comprises zinc, and the plurality of organic ligands comprises vitamin C;(e) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises vitamin C;(f) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises fumaric acid;(g) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises 2,3-dimethylfumaric acid;(h) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises L-aspartic acid;(i) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises mesaconic acid;(j) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises trans, trans-muconic acid;(k) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises curcumin;(l) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises succinic acid;(m) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises thiomalic acid;(n) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises adipic acid;(o) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises tartronic acid;(p) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises vitamin C;(q) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises fumaric acid;(r) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises 2,3-dimethyl fumaric acid;(s) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises L-aspartic acid;(t) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises mesaconic acid;(u) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises trans, trans-muconic acid;(v) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises curcumin;(w) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises succinic acid;(x) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises thiomalic acid;(y) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises adipic acid; or(z) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises tartronic acid.13. The metal-organic framework of any one of embodiments 1-3 or 5-12, wherein; the plurality of biocompatible metal cores comprises magnesium, selenium, or zinc; and the plurality of organic ligands comprises a cyclodextrin.14. The metal-organic framework of any one of embodiments 1-3 or 5-12, wherein: the plurality of biocompatible metal cores comprises iron or calcium; and the plurality of organic ligands comprises a cyclodextrin.15. The metal-organic framework of any of embodiments 5-14, wherein the cyclodextrin is a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, hydroxypropyl-P-cyclodextrin, hydroxypropyl-y- cyclodextrin, sulfobutylether-P-cyclodextrin (Captisol®), methyl-P-cyclodextrin, randomly methylated-P-cyclodextrin, carboxymethyl-P-cyclodextrin, ethyl-P-cyclodextrin, a cationic cyclodextrin, a branched cyclodextrin, or a polymeric cyclodextrin.16. The metal-organic framework of any of embodiments 5-15, wherein the cyclodextrin is P-cyclodextrin.17. The metal-organic framework of any of embodiments 5-15, wherein the cyclodextrin is y- cyclodextrin.18. The metal-organic framework of any one of embodiments 1-3 or 5-16, wherein: the plurality of biocompatible metal cores comprises iron; and the plurality of organic ligands comprises p-cyclodextrin.19. The metal-organic framework of any one of embodiments 1-18, wherein the metalorganic framework has an intcrplanar spacing of about 0.05 to about 0.5 nm.20. The metal-organic framework of any one of embodiments 1-19, wherein the metalorganic framework has an interplanar spacing of about 0.1 to about 0.3 nm.21. The metal-organic framework of any one of embodiments 1-20, further comprising a plurality of guest molecules.22. The metal-organic framework of embodiment 21, wherein each of the plurality of guest molecules has a molecular weight of less than 2 kDa.23. The metal-organic framework of embodiment 21 or 22, wherein each of the plurality of guest molecules has a molecular weight of less than 1 kDa.24. The metal-organic framework of any one of embodiments 21-23, wherein each of the plurality of guest molecules has a molecular weight of less than 500 Da.25. The metal-organic framework of any one of embodiments 21-24, wherein the plurality of guest molecules comprises cationic guest molecules.26. The metal-organic framework of any one of embodiments 21-25, wherein the plurality of guest molecules comprises neutral guest molecules.27. The metal-organic framework of any one of embodiments 21-26, wherein the plurality of guest molecules comprises anionic guest molecules.28. The metal-organic framework of any one of embodiments 21-27, wherein the plurality of guest molecules comprise guest molecules having a hydrophobicity of -2 to +5 logP.29. The metal-organic framework of any one of embodiments 21-28, wherein the plurality of guest molecules comprise guest molecules having a hydrophobicity of -1 to +3 logP.30. The metal-organic framework of any one of embodiments 21-29, wherein the plurality of guest molecules comprise guest molecules having a hydrophobicity of >0 logP.31. The metal-organic framework of any one of embodiments 21-30, wherein the plurality of guest molecules comprise guest molecules having a hydrophobicity of >+2 logP.32. The metal-organic framework of any one of embodiments 21-31, wherein the plurality of guest molecules comprises guest molecules that interact electrostatically with the metal-organic framework.33. The metal-organic framework of any one of embodiments 21-32, wherein the plurality of guest molecules comprises one or more micronutrients, probiotics, natural extracts, small molecule drugs, proteins, peptides, and nucleic acids.34. The metal-organic framework of any one of embodiments 21-33, wherein the plurality of guest molecules comprises one or more micronutrients selected from the group consisting of vitamin A, vitamin D, vitamin E, vitamin K, vitamin C, vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin, niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folate, folic acid), vitamin B12 (cobalamin), calcium, iron, magnesium, phosphorus, potassium, sodium, chloride, sulfur, iodine, zinc, copper, manganese, fluoride, selenium, chromium, molybdenum, choline, boron, silicon, nickel, and vanadium.35. The metal-organic framework of any one of embodiments 21-34, wherein the plurality of guest molecules comprises one or more micronutrients selected from the group consisting of iron, iodine, zinc, vitamin B12 (cobalamin), and vitamin B9 (folate, folic acid).36. The metal-organic framework of any one of embodiments 21-35, wherein the plurality of guest molecules comprises one or more probiotics selected from the group consisting of Lactobacillus casei, Lactobacillus salivarius, Bifidobacterium bifidum, and Bifidobacterium infantis.37. The metal-organic framework of any one of embodiments 21-36, wherein the plurality of guest molecules comprises one or more natural extracts selected from the group consisting of Curcumin, Quercetin, Epigallocatechin gallate (EGCG), Resveratrol, Berberine, and Coenzyme Q10.38. The metal-organic framework of any one of embodiments 21-37, wherein the plurality of guest molecules comprises one or more natural extracts selected from the group consisting of Resveratrol, Berberine, Linalool, and Menthol.39. The metal-organic framework of any one of embodiments 21-38, wherein the plurality of guest molecules comprises one or more small molecule drugs selected from the group consisting of Fluoxetine, Sertraline, Metformin, and Glipizide.40. The metal-organic framework of any one of embodiments 21-39, wherein the plurality of guest molecules comprises one or more proteins or peptides selected from the group consisting of Protease, Catalase, Glucagon-like peptide- 1 (GLP-1), and Growth hormone releasing hormone (GHRH).41. The metal-organic framework of any one of embodiments 21-40, wherein the plurality of guest molecules comprises one or more nucleic acids selected from the group consisting of DNA and RNA.42. The metal-organic framework of any one of embodiments 21-41, wherein the plurality of guest molecules comprises one or more nucleic acids selected from the group consisting of plasmids encoding CRISPR / Cas9 components and small interfering RNAs (siRNAs) targeting oncogenes.43. The metal-organic framework of any one of embodiments 21-42, wherein the plurality of guest molecules comprises one or more of iodine, caffeine, resveratrol, curcumin, lycopene, quercetin, beta-carotene, or lutein.44. The metal-organic framework of any one of embodiments 21-43, wherein the plurality of guest molecules is loaded in the metal-organic framework at about 0 g / g to about 2 g / g.45. The metal-organic framework of any one of embodiments 21-44, wherein the plurality of guest molecules is loaded in the metal-organic framework at about 0.01 g / g to about 2 g / g.46. The metal-organic framework of any one of embodiments 21-45, wherein the plurality of guest molecules is loaded in the metal-organic framework at about 0.1 g / g to about 2 g / g.47. The metal-organic framework of any one of embodiments 21-46, wherein the plurality of guest molecules is loaded in the metal-organic framework at about 1 g / g to about 1.5 g / g.48. The metal-organic framework of any one of embodiments 21-47, wherein the plurality of guest molecules is loaded in the metal-organic framework at about 1.00 g / g to about 1.20 g / g.49. The metal-organic framework of any one of embodiments 21-48, wherein the metalorganic framework improves the thermal stability, hydrolytic stability, light stability, and / or oxidative stability of the guest molecules.50. The metal-organic framework of any one of embodiments 1-49, wherein the metalorganic framework is stable at about 22 °C to about 50 °C.51. The metal-organic framework of any one of embodiments 1-50, wherein the metalorganic framework is stable at about 0% to about 80% relative humidity.52. The metal-organic framework of any one of embodiments I -51 , wherein the metalorganic framework is stable for at least 8 weeks.53. The metal-organic framework of any one of embodiments 21-52, wherein stability of the metal-organic framework is assessed by percent recovery of the guest molecule.54. The metal-organic framework of any one of embodiments 21-53, wherein the metalorganic framework releases the guest molecule or degrades under physiological conditions.55. The metal-organic framework of any one of embodiments 21-54, wherein the metalorganic framework releases the guest molecule or degrades under acidic conditions.56. The metal-organic framework of any one of embodiments 1-55, wherein the metalorganic framework releases the guest molecule or degrades upon treatment with simulated gastric fluid (SGF).57. The metal-organic framework of any one of embodiments 1-56, wherein the metalorganic framework is in the form of a particle.58. The metal-organic framework of any one of embodiments 1-57, wherein the metalorganic framework has a particle size of about 0.1 pm to about 50 pm.59. The metal-organic framework of any one of embodiments 1-58, wherein the metalorganic framework has a particle size of about 0.5 pm to about 20 pm.60. The metal-organic framework of any one of embodiments 1-59, wherein the metalorganic framework has a particle size of about 1 pm to about 10 pm.61. The metal-organic framework of any one of embodiments 1-60, wherein the metalorganic framework has a BET surface area of about 50 m2 / g to about 2,000 m2 / g.62. The metal-organic framework of any one of embodiments I -61 , wherein the metalorganic framework has a BET surface area of about 100 m2 / g to about 1,000 m2 / g.63. The metal-organic framework of any one of embodiments 1-62, wherein the metalorganic framework has a BET surface area of about 300 m2 / g to about 700 m2 / g.64. The metal-organic framework of any one of embodiments 1-63, wherein the metalorganic framework further comprises a metal-polyphenol network (MPN) coating.65. The metal-organic framework of embodiment 2 or 64, wherein the MPN comprises a plurality of biocompatible metal ions and a plurality of biocompatible polyphenols.66. The metal-organic framework of embodiment 65, wherein the plurality of biocompatible polyphenols comprises one or more of tannic acid, gallic acid, a catechin, quercetin, ellagic acid, or ferulic acid.67. The metal-organic framework of embodiment 65 or 66, wherein the plurality of biocompatible polyphenols comprises tannic acid.68. The metal-organic framework of any one of embodiments 65-67, wherein the plurality of biocompatible metal ions comprises biocompatible alkali metal ions, alkaline earth metal ions, and / or transition metal ions.69. The metal-organic framework of any one of embodiments 65-68, wherein the plurality of biocompatible metal ions comprises one or more of calcium, magnesium, zinc, iron, copper, and manganese.70. The metal-organic framework of any one of embodiments 65-69, wherein the plurality of biocompatible metal ions comprises one or more of Ca2+, Mg2+, Zn2+, Fe2+, Fe3+, Cu2+, and Mn2+.71 . The metal-organic framework of any one of embodiments 65-70, wherein the plurality of biocompatiblc metal ions comprises Fc3+.72. The metal-organic framework of any one of embodiments 2 or 64-71, wherein the MPN coating comprises Fe3+ions and tannic acid.73. The metal-organic framework of any one of embodiments 2 or 64-72, wherein the MPN coating is layered on the surface of the particle.74. The metal-organic framework of any one of embodiments 2 or 64-73, wherein the MPN coating is about 10 nm to about 1 pm thick.75. The metal-organic framework of any one of embodiments 2 or 64-74, wherein the MPN coating is about 10 nm to about 20 nm thick.76. The metal-organic framework of any one of embodiments 2 or 64-74, wherein the MPN coating is about 20 nm to about 100 nm thick.77. The metal-organic framework of any one of embodiments 2 or 64-74, wherein the MPN coating is about 100 nm to about 500 nm thick.78. The metal-organic framework of any one of embodiments 2 or 64-74, wherein the MPN coating is about 500 nm to about 1 pm thick.79. The metal-organic framework of any one of embodiments 2 or 64-78, wherein the MPN comprises a plurality of biocompatible metal ions and a plurality of biocompatible polyphenols, and the biocompatible polyphenols coordinate to the biocompatible metal cores of the metalorganic framework.80. The metal-organic framework of any one of embodiments 2 or 64-79, wherein the MPN coating improves the mucosal adhesion, prolongs gastrointestinal retention, enhances intestinalinteraction, and / or extends fecal retention of the metal-organic framework relative to an uncoated metal-organic framework.81. The metal-organic framework of any one of embodiments 1-80, wherein gastrointestinal retention of the metal-organic framework is about 2 to about 6 hours.82. The metal-organic framework of any one of embodiments 1-81, wherein gastrointestinal retention of the metal-organic framework is about 2 to about 4 hours.83. The metal-organic framework of any one of embodiments 1-80, wherein gastrointestinal retention of the metal-organic framework is about 6 to about 12 hours.84. The metal-organic framework of any one of embodiments 1-80 or 83, wherein gastrointestinal retention of the metal-organic framework is about 8 to about 12 hours.85. The metal-organic framework of any one of embodiments 2 or 64-84, wherein the MPN coating enhances localization in the intestine and / or improves biodistribution of the metalorganic framework relative to an uncoated metal-organic framework.86. The metal-organic framework of any one of embodiments 1-85, wherein the metalorganic framework accumulates in the intestine and liver.87. The metal-organic framework of any one of embodiments 1-86, wherein the metalorganic framework does not significantly accumulate in the heart, spleen, lung, and / or kidneys.88. The metal-organic framework of any one of embodiments 2 or 64-87, wherein the MPN coating enhances interaction with nutrient absorption pathways relative to an uncoated metalorganic framework.89. The metal-organic framework of any one of embodiments 2 o 64-88, wherein the MPN coating improves resistance to enzymatic degradation.90. The metal-organic framework of any one of embodiments 2 or 64-89, wherein the MPN coating increases the stability of the metal-organic framework relative to an uncoated metalorganic framework.91. The metal-organic framework of any one of embodiments 2 or 64-90, wherein the MPN coating slows degradation of the metal-organic framework relative to an uncoated metal-organic framework.92. The metal-organic framework of any one of embodiments 2 or 64-91, wherein the MPN coating extends release of a guest molecule in the metal-organic framework relative to an uncoated metal-organic framework.93. The metal-organic framework of any one of embodiments 1-92, wherein the metalorganic framework further comprises a near-infrared (NIR) fluorescent dye.94. A composition comprising a metal-organic framework of any one of embodiments 1-93 and an excipient.95. The composition of embodiment 94, wherein the composition is a pharmaceutical composition.96. The composition of embodiment 94 or 95, wherein the composition is a nutraceutical composition.97. A food product comprising a metal-organic framework of any one of embodiments 1-93 and an excipient.98. The food product of embodiment 97, wherein the food product further comprises one or more of a sweetener, colorant, flavoring agent, cooling agent, or preservative.99. The food product of embodiment 97 or 98, wherein the excipient is a foodstuff.100. The food product of any one of embodiments 97-99, wherein the foodstuff comprises one or more of a fruit, vegetable, carbohydrate, grain, or starch, protein, fat or oil, and dairy or nondairy alternative.101. A beverage comprising a metal-organic framework of any one of embodiments 1-93 and water.102. The beverage of embodiment 101, wherein the beverage further comprises one or more of a sweetener, colorant, flavoring agent, cooling agent, or preservative.103. A nutritional supplement comprising a metal-organic framework of any one of embodiments 1-93 and an excipient.104. The composition, food product, beverage, or nutritional supplement of any one of embodiments 94-103, further comprising one or more micronutrients, probiotics, natural extracts, small molecule drugs, proteins, peptides, and nucleic acids.105. The composition, food product, beverage, or nutritional supplement of any one of embodiments 94-104, further comprising one or more micronutrients selected from the group consisting of iron, iodine, zinc, vitamin B12 (cobalamin), and vitamin B9 (folate, folic acid).106. The composition, food product, beverage, or nutritional supplement of any one of embodiments 94-105, further comprising one or more natural extracts selected from the group consisting of Curcumin, Quercetin, Epigallocatechin gallate (EGCG), Resveratrol, Berberine, and Coenzyme Q10.107. The composition, food product, beverage, or nutritional supplement of any one of embodiments 94-106, wherein the composition, food product, beverage, or nutritional supplement is non-perishable.108. The composition, food product, beverage, or nutritional supplement of any one of embodiments 94-107, wherein the composition, food product, beverage, or nutritional supplement is stable at room temperature.109. The composition, food product, beverage, or nutritional supplement of any one of embodiments 94-108, wherein the composition, food product, beverage, or nutritional supplement is stable at up to about 85 °F.110. The composition, food product, beverage, or nutritional supplement of any one of embodiments 94-109, wherein the composition, food product, beverage, or nutritional supplement is stable for at least 6 weeks.111. A kit comprising: a metal-organic framework of any one of embodiments 1-93, or a composition, food product, beverage, or nutritional supplement of any one of embodiments 94-110; and instructions for using the metal-organic framework, composition, food product, beverage, or nutritional supplement.112. A method of delivering an agent to a subject, comprising administering to the subject a metal-organic framework of any one of embodiments 1-93, or a composition, food product, beverage, or nutritional supplement of any one of embodiments 94-110.113. The method of embodiment 112, wherein the agent is one or more components of the metal-organic framework.114. The method of embodiment 112 or 113, wherein the agent is one or more components of the metal-organic framework selected from the plurality of biocompatiblc metal core, biocompatible organic ligands, and guest molecules.115. The method of any one of embodiments 112-114, wherein the subject has a micronutrient deficiency.116. A method of treating or preventing a disease, disorder, or condition in a subject, comprising administering to the subject a metal-organic framework of any one of embodiments 1-93, or a composition, food product, beverage, or nutritional supplement of any one of embodiments 94-110.117. The method of any one of embodiments 112-116, wherein the metal-organic framework, composition, food product, beverage, or nutritional supplement is orally administered to the subject.118. The method of embodiment 116 or 117, wherein the disease, disorder, or condition is a micronutrient deficiency, genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, metabolic disorder, inflammatory disease, or autoimmune disease.119. The method of any one of embodiments 116-118, wherein the disease, disorder, or condition is a micronutrient deficiency.120. The method of embodiment 115, 118, or 119, wherein the micronutrient deficiency is a vitamin or mineral deficiency.121. The method of any one of embodiments 115 or 118-120, wherein the micronutrient deficiency is vitamin A deficiency, vitamin D deficiency, vitamin E deficiency, iron deficiency, or zinc deficiency.122. The method of any one of embodiments 115 or 118-121, wherein the micronutrient deficiency is iron deficiency, iodine deficiency, or zinc deficiency.EQUIVALENTS AND SCOPE

[0257] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process .

[0258] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the ait, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0259] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMSWhat is claimed is:

1. A metal-organic framework, comprising: a plurality of biocompatible metal cores comprising iron, calcium, magnesium, selenium, zinc, or a combination thereof; and a plurality of biocompatiblc organic ligands, each comprising at least two alkoxide or carboxylate moieties; wherein: each metal core is linked to at least one other metal core by at least one organic ligand.

2. A metal-organic framework, comprising: a plurality of biocompatible metal cores; a plurality of biocompatible organic ligands; and a metal-polyphenolic network (MPN) coating; wherein: each metal core is linked to at least one other metal core by at least one organic ligand, forming a particle; and the MPN coating is deposited on the surface of the particle.

3. The metal-organic framework of claim 1 or 2, wherein the plurality of organic ligands comprises fumaric acid, 2, 3 -dimethylfumaric acid, aspartic acid, mesaconic acid, muconic acid, succinic acid, citric acid, ascorbic acid, curcumin, thiomalic acid, adipic acid, tartronic acid, vitamin C, or a combination thereof.

4. The metal-organic framework of any one of claims 1-3, wherein the plurality of organic ligands comprises a cyclodextrin.

5. The metal-organic framework of any one of claims 1 -4, wherein:(a) the plurality of biocompatiblc metal cores comprises calcium, and the plurality of organic ligands comprises vitamin C;(b) the plurality of biocompatible metal cores comprises magnesium, and the plurality of organic ligands comprises vitamin C;(c) the plurality of biocompatible metal cores comprises selenium, and the plurality of organic ligands comprises vitamin C;(d) the plurality of biocompatible metal cores comprises zinc, and the plurality of organic ligands comprises vitamin C;(e) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises vitamin C;(f) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises fumaric acid;(g) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises 2,3-dimethylfumaric acid;(h) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises L-aspartic acid;(i) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises mesaconic acid;(j) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises trans, trans-muconic acid;(k) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises curcumin;(l) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises succinic acid;(m) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises thiomalic acid;(n) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises adipic acid;(o) the plurality of biocompatible metal cores comprises iron, and the plurality of organic ligands comprises tartronic acid;(p) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises vitamin C;(q) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises fumaric acid;(r) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises 2,3-dimethyl fumaric acid;(s) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises L-aspariic acid;(t) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises mesaconic acid;(u) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises trans, trans-muconic acid;(v) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises curcumin;(w) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises succinic acid;(x) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises thiomalic acid;(y) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises adipic acid; or(z) the plurality of biocompatible metal cores comprises sodium, and the plurality of organic ligands comprises tartronic acid.

6. The metal-organic framework of any one of claims 1-5, wherein: the plurality of biocompatible metal cores comprises iron; and the plurality of organic ligands comprises P-cyclodextrin.

7. The metal-organic framework of any one of claims 1-6, further comprising a plurality of guest molecules.

8. The metal-organic framework of claim 7, wherein the plurality of guest molecules comprises one or more micronutrients, probiotics, natural extracts, small molecule drugs, proteins, peptides, and nucleic acids.

9. The metal-organic framework of claim 7 or 8, wherein the plurality of guest molecules comprises one or more micronutrients selected from the group consisting of vitamin A, vitamin D, vitamin E, vitamin K, vitamin C, vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin, niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folate, folic acid), vitamin B12 (cobalamin), calcium, iron, magnesium, phosphorus, potassium, sodium, chloride, sulfur, iodine, zinc, copper, manganese, fluoride, selenium, chromium, molybdenum, choline, boron, silicon, nickel, and vanadium.

10. The metal-organic framework of any one of claims 7-9, wherein the plurality of guest molecules is loaded in the metal-organic framework at about 0 g / g to about 2 g / g.

11. The metal-organic framework of any one of claims 1-10, wherein the metal-organic framework is in the form of a particle.

12. The metal-organic framework of any one of claims 1-11, wherein the metal-organic framework further comprises a metal-polyphenol network (MPN) coating.

13. The metal-organic framework of claim 2 or 12, wherein the MPN comprises a plurality of biocompatible metal ions and a plurality of biocompatible polyphenols.

14. The metal-organic framework of any one of claims 2, 12, or 13, wherein the MPN comprises a plurality of biocompatible metal ions and a plurality of biocompatible polyphenols, and the biocompatible polyphenols coordinate to the biocompatible metal cores of the metalorganic framework.

15. A composition comprising a metal-organic framework of any one of claims 1- 14 and an excipient.

16. A food product comprising a metal-organic framework of any one of claims 1-14 and an excipient.

17. A beverage comprising a metal-organic framework of any one of claims 1-14 and water.

18. A nutritional supplement comprising a metal-organic framework of any one of claims 1- 14 and an excipient.

19. A method of delivering an agent to a subject, comprising administering to the subject a metal-organic framework of any one of claims 1-14, or a composition, food product, beverage, or nutritional supplement of any one of claims 15-18.

20. A method of treating or preventing a disease, disorder, or condition in a subject, comprising administering to the subject a metal-organic framework of any one of claims 1-14, or a composition, food product, beverage, or nutritional supplement of any one of claims 15-18.

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