Targeted and degrader-encapsulated nanogels for protein degradation, and compositions and methods thereof

Abstract

The invention provides novel antibody-nanogel conjugates with encapsulated protein degraders and related methods for controlled and targeted delivery of degrader molecules as therapeutic agents.

Description

TARGETED AND DEGRADER-ENCAPSULATED NANOGELS FOR PROTEINDEGRADATION, AND COMPOSITIONS AND METHODS THEREOFStatement Regarding Federally Sponsored Research

[0001] This invention was made with government support under Grant no. GM-136395, awarded by the National Institutes of Health. The Government has certain rights in the invention.Priority Claims and Related Patent Applications

[0002] This application claims the benefit of priority to U.S. Provisional Application Serial No. 63 / 573,580, filed on April 3, 2024, the entire content of which is incorporated herein by reference in its entirety.Technical Fields of the Invention

[0003] The invention generally relates to polymer nano-structures and delivery of therapeutic agents. More particularly, the invention relates to novel antibody-nanogel conjugates with encapsulated protein degraders and related methods for controlled and targeted delivery of degrader molecules as therapeutic agents.Background of the Invention

[0004] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. Targeted protein degraders have attracted significant attention in the past decade due to their potential advantages in efficacy over traditional inhibitors. The selective identification and removal of damaged, misfolded or excess proteins is achieved via the ubiquitin-proteasome pathway. Proteolysis targeting chimera (PROTAC) molecules have attracted particular interest as a promising platform for drug discovery against difficult to address protein targets. (See, e.g., W02020041331A1; W02017197051A1; WO2017197055A1; Troup, et al. 2020 Target Antitumor Ther. 1 :273-312.)

[0005] One disadvantage of PROTAC is the high molecular weight due to the combination of heterobifunctional ligands required for their functionality: a ligand to the protein of interest, an E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase. The resulting conjugate molecule typically is poor in terms of bioavailability as typical PROTAC molecules are twice the molecular weight of commonly seen drug molecules.

[0006] Antibody-drug conjugate (ADC) represents another fast-growing class of highly potent pharmaceutical drugs combining the powers of chemotherapy and immunotherapy. This technology attaches highly specific mAbs to cytotoxic agents with the help of various linkers, allowing selective delivery of highly potent drugs to tumor cells while sparing healthy cells, attenuating the main clinical obstacle of traditional chemotherapy, thus providing a broad therapeutic window. To date, thirteen ADCs have received market approval by the US FDA. (See, e.g., Bross et al. 2001 Clin. Cancer Res. 7 , 1490-1496; Hamann et al. 2002 Bioconjug. Chem. 13, 47-58; Drago et al. 2021 Nature Reviews 18, 327-344; Khongorzui et al. 2020 Molecular Cancer Res. 18:3-19.)

[0007] The ADC platform, however, is not without major limitations. For example, covalent conjugation of therapeutic molecules to an antibody requires the existence of chemical handles on the drug molecule which may not be readily available or difficult to introduce. In addition, there is a structural drawback in regard to the drug-antibody ratio. Furthermore, ADC stability has been a consistent challenge in development of ADCs.

[0008] Novel technology platforms that retain the advantages of PROTAC and ADC technologies while addressing their shortcomings are needed.Summary of the Invention

[0009] The invention provides novel antibody-nanogel conjugates with encapsulated protein degraders such as PROTAC molecules, and related methods for controlled and targeted delivery of the PROTAC molecules and similar targeted protein degraders.

[0010] In one aspect, the invention generally relates to an antibody -nanoassembly conjugate, comprising: a nanoassembly comprising: a water-soluble polymer host comprising a crosslinked polymer network and one or more PROTAC molecules non-covalently encapsulated in the polymer host; and a targeting moiety covalently linked to the nanoassembly, wherein each of the one or more PROTAC molecules comprises: a ligand having a binding affinity to a protein ofinterest covalently linked to an E3 ubiquitin ligase binding moiety that targets an E3 ubiquitin ligase via a bond or a chemical linking moiety; and the PROTAC molecules are releasable in their intact form upon partial or complete de-crosslinking of the crosslinked polymer network in response to a chemical or biological trigger.

[0011] In another aspect, the invention generally relates to a nanoassembly conjugate, comprising: a water-soluble polymer host comprising a crosslinked polymer network; and one or more PROTAC molecules non-covalently encapsulated in the polymer host, wherein each of the one or more PROTAC molecules comprises: a ligand having a binding affinity to a protein of interest covalently linked to an E3 ubiquitin ligase binding moiety that targets an E3 ubiquitin ligase via a bond or a chemical linking moiety; and the PROTAC molecules are releasable in their intact form upon partial or complete de-crosslinking of the crosslinked polymer network in response to a chemical or biological trigger.

[0012] In yet another aspect, the invention generally relates to a composition comprising the nanoassembly with encapsulated PROTAC molecules.

[0013] In yet another aspect, the invention generally relates to a composition comprising the antibody-nanoassembly conjugates with encapsulated PROTAC molecules.

[0014] In yet another aspect, the invention generally relates to a method for delivering a PROTAC molecule to a biological site, comprising: transporting an antibody-nanoassembly conjugate to a biological site of interest; and causing at least a partial de-crosslinking of the crosslinked polymer network, thereby releasing the PROTAC molecules at or near the biological site of interest.

[0015] In yet another aspect, the invention generally relates to a method for treating a disease or condition, comprising administering to a subject in need thereof an antibody-nanoassembly conjugate.

[0016] In yet another aspect, the invention generally relates to a method for making a nanoassembly disclosed herein.

[0017] In yet another aspect, the invention generally relates to a method for making an antibody-nanoassembly conjugate disclosed herein.Brief Description of the Drawings

[0018] FIG. 1. A schematic illustration of dANC induced cell-selective protein degradation.

[0019] FIG. 2. An exemplary scheme for preparing an dANC.

[0020] FIG. 3. An exemplary procedure for preparing an dANC.

[0021] FIG. 4. Exemplary data of Trop2-dBETl ANC degradation study in Trop2+ cell lines.

[0022] FIG. 5. Exemplary data of Trop2-dBETl ANC degradation study in Trop2+ cell lines.

[0023] FIG. 6. Exemplary data of Trop2-dBET6 ANC degradation study in Trop2+ cell lines.

[0024] FIG. 7. Exemplary data of EGFR-dBET6 ANC degradation study in EGFR+ cell lines.Detailed Description of the Invention

[0025] The invention provides novel antibody-nanogel conjugates with encapsulated protein degraders such as PROTAC molecules, and related methods for controlled and targeted delivery of the PROTAC molecules and similar targeted protein degraders.

[0026] As disclosed herein, encapsulation of PROTAC molecules in triggerable polymeric nanogels render them much more bioavailable for targeted protein degradation. Moreover, when decorated with ligands (e.g., antibodies) on the surface of the nanogels that are complementary to the receptors on the surface of the cells, the bioavailability of PROTAC molecules become even better.

[0027] The invention builds on the ANC technology developed by the present inventors and significantly expanding its reach to PROTAC. (See, e.g., US9,592,302B2; US10,358,531B2; US9,795,689B2; US9,868,821B2, US10,131,745B2 & US10,494,479B2; US9,999,599B2; Wu et al. 2023 Bioconjugate Chem. 34: 707-718; Huynh, et al. 2023 Biomacromolecules 24: 849- 857.)

[0028] Encapsulation of PROTAC molecules in ANCs make them more bioavailable already offers a great advantage over the naked PROTAC molecules. With the ability to introduce antibody on the surface of the nanogels, the resultant degrader ANCs (dANCs) enable PROTAC molecules to be available as ADC-equivalents.

[0029] In one aspect, the invention generally relates to an antibody-nanoassembly conjugate, comprising: a nanoassembly comprising: a water-soluble polymer host comprising a crosslinked polymer network and one or more PROTAC molecules non-covalently encapsulated in the polymer host; and a targeting moiety covalently linked to the nanoassembly, wherein each of the one or more PROTAC molecules comprises: a ligand having a binding affinity to a protein of interest covalently linked to an E3 ubiquitin ligase binding moiety that targets an E3 ubiquitinligase via a bond or a chemical linking moiety; and the PROTAC molecules are releasable in their intact form upon partial or complete de-crosslinking of the crosslinked polymer network in response to a chemical or biological trigger.

[0030] In certain embodiments, the targeting moiety is an antibody. In certain embodiments, the targeting moiety is a biosimilar, such as an aptamer or an antibody fragment nanobody or camelid antibody. In certain embodiments, the targeting moiety is a peptide. In certain embodiments, the targeting moiety is a small molecule ligand.

[0031] In certain embodiments, the E3 ubiquitin ligase is selected from the group consisting of von Hippel Lindau (VHL) E3 ubiquitin ligase, b-Transducin Repeat Containing (b-TRCP) E3 Ubiquitin Protein Ligase, Mouse Double Minute 2 (Mdm2) E3 Ubiquitin Protein Ligase, and a Cereblon (CRBN) E3 Ubiquitin ligase.

[0032] In certain embodiments, the antibody-nanoassembly conjugate is characterized by a PROTAC loading from about 1 wt% to about 30 wt%.

[0033]

[0019] In certain embodiments, the crosslinked polymer network has a crosslinking density from about 2% to about 70%, relative to the total number of structural units in the polymer.

[0034] In certain embodiments, de-crosslinking of the crosslinked polymer network in the antibody-nanoassembly conjugate is due to a biological, chemical or physical stimulus in a microenvironment.

[0035] In certain embodiments, the biological, chemical or physical stimuli is a change of redox potential.

[0036] In certain embodiments, the biological, chemical or physical stimuli is a change in pH value.

[0037] In certain embodiments, the biological, chemical or physical stimuli is an external light signal.

[0038] In certain embodiments, the microenvironment wherein the de-crosslinking occurs is an in vivo biological site.

[0039] In another aspect, the invention generally relates to a nanoassembly conjugate, comprising: a water-soluble polymer host comprising a crosslinked polymer network; and one or more PROTAC molecules non-covalently encapsulated in the polymer host, wherein each of the one or more PROTAC molecules comprises: a ligand having a binding affinity to a protein ofinterest covalently linked to an E3 ubiquitin ligase binding moiety that targets an E3 ubiquitin ligase via a bond or a chemical linking moiety; and the PROTAC molecules are releasable in their intact form upon partial or complete de-crosslinking of the crosslinked polymer network in response to a chemical or biological trigger.

[0040] In certain embodiments, the water-soluble polymer host comprises a crosslinked copolymer network.

[0041] In certain embodiments, the crosslinked co-polymer network is a random co-polymer network.

[0042] In certain embodiments, the crosslinked co-polymer network is an amphiphilic block co-polymer network.

[0043] In certain embodiments, the loading weight percentage of the PROTAC molecules is from about 1% to about 30% (e.g., from about 1% to about 20%, from about 1% to about 10%, from about 5% to about 30%, from about 10% to about 30%, from about 2% to about 20%).

[0044] In certain embodiments, the crosslinked polymer network has a crosslinking density from about 2% to about 70% (e.g., from about 2% to about 50%, from about 2% to about 25%, from about 2% to about 25%, from about 5% to about 70%, from about 10% to about 70%, from about 20% to about 70%, from about 40% to about 70%), relative to the total number of structural units in the polymer.

[0045] In certain embodiments, the co-polymer network comprises a co-polymer represented by the structural formula (I):wherein i is an integer selected from about 10 to about 100 (e.g., from about 10 to about 75, from about 10 to about 50, from about 10 to about 30, from about 10 to about 20, from about 20 to about 100, from about 50 to about 100); and is a number selected from about 0 to about 100 (e.g., from about 5 to about 100, from about 10 to about 100, from about 20 to about 100, from about 50 to about 100, from about 0 to about 50, from about 0 to about 25, from about 0 to about 10).

[0046] In certain embodiments, the co-polymer network comprises a co-polymer represented by the structural formula (IA):whereinJ is an integer selected from about 5 to about 250 (e.g., from about 5 to about 200, from about 5 to about 150, from about 25 to about 250, from about 50 to about 250, from about 50 to about 200, from about 100 to about 150); andR comprises a group selected from:Ci-3 alkyl,N3, dibenzcyclooctyne (DBCO), tetrazine, trans-cyclooctene (TCO), andalkyne.

[0047] In certain embodiments, R is

[0048] In yet another aspect, the invention generally relates to a composition comprising the nanoassembly with encapsulated PROTAC molecules.

[0049] In yet another aspect, the invention generally relates to a composition comprising the antibody-nanoassembly conjugates with encapsulated PROTAC molecules.

[0050] In yet another aspect, the invention generally relates to a method for delivering a PROTAC molecule to a biological site, comprising: transporting an antibody-nanoassembly conjugate to a biological site of interest; and causing at least a partial de-crosslinking of the crosslinked polymer network, thereby releasing the PROTAC molecules at or near the biological site of interest.

[0051] In yet another aspect, the invention generally relates to a method for treating a disease or condition, comprising administering to a subject in need thereof an antibody-nanoassembly conjugate.

[0052] In yet another aspect, the invention generally relates to a method for making a nanoassembly disclosed herein.

[0053] In yet another aspect, the invention generally relates to a method for making an antibody-nanoassembly conjugate disclosed herein.

[0054] FIG. l is a schematic illustration of dANC induced cell -selective protein degradation.

[0055] FIG. 2 shows an exemplary scheme for preparing an dANC.

[0056] FIG. 3 depicts an exemplary procedure for preparing an dANC.

[0057] FIG. 4 shows certain exemplary data of Trop2-dBETl ANC degradation study in Trop2+ cell lines. At 30 minutes incubation dANCs (degrader ANCs) were substantially better than free drug PROTAC. PROTAC-encapsulated nanogel (NG) was better than free drug PROTAC at 30 minutes, but not better than dANC, showing receptor-mediated selective uptake and drug release by ANCs. Free drug showed comparable degradation only at 24 hours incubation, showing the enhanced bioavailability because of the encapsulation.

[0058] FIG. 5 shows certain exemplary data of Trop2-dBETl ANC degradation study in Trop2+ cell lines. Both dANC and NG behaved similarly when the antibody was not complementary to the cell surface receptor.

[0059] FIG. 6 shows certain exemplary data of Trop2-dBET6 ANC degradation study in Trop2+ cell lines. At 30 minutes incubation dANCs (degrader ANCs) were substantially better than free drug PROTAC. PROTAC-encapsulated NG was better than free drug PROTAC at 30 minutes, but not better than dANC, showing receptor-mediated selective uptake and drug release by ANCs. Free drug showed comparable degradation only at 24 hours incubation, showing the enhanced bioavailability because of the encapsulation.

[0060] FIG. 7 shows certain exemplary data of EGFR-dBET6 ANC degradation study in EGFR+ cell lines. dBET6 itself did not work efficiently in MDA-MB-468 cell line. Still the following selectivity results were evident. At 30 minutes incubation dANCs were substantially better than free drug PROTAC. PROTAC-encapsulated NG was better than free drug PROTAC at 30 minutes, but not better than dANC, showing receptor-mediated selective uptake and drug release by ANCs. Free drug showed comparable degradation only at 24 hours incubation, showing the enhanced bioavailability because of the encapsulation.

[0061] Overall, dANCs showed better bioavailability than PROTAC-encapsulated nanogel (NG), which are better that free drug PROTACs in o Trop2+ MDA-MB-468 cell line using dBETl PROTAC o Trop2+ HCC 1937 cell line using dBET6 PROTAC

[0062] Similar trends were observed with EGFR targeting antibodies as well, although the inherent efficacy of dBET6 was much poorer in the MDA-MB-468 cell line.

[0001] Definitions of specific functional groups and chemical terms are described in more detail below. General principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2006. It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties.

[0002] As used herein, “Cx-Cy” refers in general to groups that have from x to y (inclusive) carbon atoms. Therefore, for example, Ci-Ce refers to groups that have 1, 2, 3, 4, 5, or 6 carbon atoms, which encompass C1-C2, C1-C3, C1-C4, C1-C5, C2-C3, C2-C4, C2-C5, C2-C6, and all likecombinations. “C1-C20” and the likes similarly encompass the various combinations between 1 and 20 (inclusive) carbon atoms, such as Ci-Ce, C1-C12 and C3-C12.

[0003] As used herein, the term “alkyl”, refers to a hydrocarbyl group, which is a saturated hydrocarbon radical having the number of carbon atoms designated and includes straight, branched chain, cyclic and polycyclic groups. The term “hydrocarbyl” refers to any moiety comprising only hydrogen and carbon atoms. Hydrocarbyl groups include saturated (e.g., alkyl groups), unsaturated groups (e.g., alkenes and alkynes), aromatic groups (e.g., phenyl and naphthyl) and mixtures thereof.

[0004] As used herein, the term “Cx-Cy” alkyl refers to a saturated linear or branched free radical consisting essentially of x to y carbon atoms, wherein x is an integer from 1 to about 10 and y is an integer from about 2 to about 20. Exemplary Cx-Cyalkyl groups include “C1-C20 alkyl,” which refers to a saturated linear or branched free radical consisting essentially of 1 to 20 carbon atoms and a corresponding number of hydrogen atoms. Exemplary C1-C20 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dodecanyl, etc.

[0005] As used herein, the term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0006] As used herein, the term “chemical, biological, or physical stimuli” includes a change in redox potential, redox reagent, pH, ionic strength, enzymatic activity, protein concentration, light (e.g., UVA, UVB or UVC), heat, or mechanical stress.

[0007] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

[0008] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0009] Materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed anddiscussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.

[0010] The below Examples describe certain exemplary embodiments of compounds prepared according to the disclosed invention. It will be appreciated that the following general methods, and other methods known to one of ordinary skill in the art, can be applied to compounds and subclasses and species thereof, as disclosed herein.Examples

[0063] Applicant’s disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment,” “in an embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0064] The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and / or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

[0065] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

[0066] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.Incorporation by Reference

[0067] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.Equivalents

[0068] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

What is Claimed is:CLAIMS1 . A nanoassembly, comprising: a water-soluble polymer host comprising a crosslinked polymer network; and one or more PROTAC molecules non-covalently encapsulated in the polymer host, wherein each of the one or more PROTAC molecules comprises: a ligand having a binding affinity to a protein of interest covalently linked to an E3 ubiquitin ligase binding moiety that targets an E3 ubiquitin ligase via a bond or a chemical linking moiety; and the PROTAC molecules are releasable in their intact form upon partial or complete de-crosslinking of the crosslinked polymer network in response to a chemical or biological trigger.

2. The nanoassembly of claim 1, wherein the water-soluble polymer host comprises a crosslinked co-polymer network.

3. The nanoassembly of claim 2, wherein the crosslinked co-polymer network is a random co-polymer network.

4. The nanoassembly of claim 2, wherein the crosslinked co-polymer network is a block copolymer network.

5. The nanoassembly of any one of claims 1-4, wherein the loading weight percentage of the PROTAC molecules is from about 1% to about 30%.

6. The nanoassembly of any one of claims 1-5, wherein the crosslinked polymer network has a crosslinking density from about 2% to about 70%, relative to the total number of structural units in the polymer.

7. An antibody-nanoassembly conjugate, comprising: a nanoassembly comprising: a water-soluble polymer host comprising a crosslinked polymer network and one or more PROTAC molecules non-covalently encapsulated in the polymer host; and a targeting moiety covalently linked to the nanoassembly, whereineach of the one or more PROTAC molecules comprises: a ligand having a binding affinity to a protein of interest covalently linked to an E3 ubiquitin ligase binding moiety that targets an E3 ubiquitin ligase via a bond or a chemical linking moiety; and the PROTAC molecules are releasable in their intact form upon partial or complete de-crosslinking of the crosslinked polymer network in response to a chemical or biological trigger.

8. The antibody-nanoassembly conjugate of claim 7, wherein the targeting moiety is selected from an antibody, a biosimilar, a nanobody, an antibody fragment, an aptamer, a peptide, and a small molecule ligand.

9. The antibody-nanoassembly conjugate of claim 7, wherein the E3 ubiquitin ligase is selected from the group consisting of von Hippel Lindau (VHL) E3 ubiquitin ligase, b- Transducin Repeat Containing (b-TRCP) E3 Ubiquitin Protein Ligase, Mouse Double Minute 2 (Mdm2) E3 Ubiquitin Protein Ligase, and a Cereblon (CRBN) E3 Ubiquitin ligase.

10. The antibody-nanoassembly conjugate of any one of claims 7-9, wherein the decrosslinking of the crosslinked polymer network is due to a biological, chemical or physical stimulus in a microenvironment.

11. The antibody-nanoassembly conjugate of claim 10, wherein the biological, chemical or physical stimuli is a change of redox potential.

12. The antibody-nanoassembly conjugate of claim 10, wherein the biological, chemical or physical stimuli is a change in pH value.

13. The antibody-nanoassembly conjugate of claim 10, wherein the biological, chemical or physical stimuli is an external light signal.

14. The antibody-nanoassembly conjugate of any one of claims 10-13, wherein the microenvironment is an in vivo biological site.

15. The antibody-nanoassembly conjugate of any one of claims 7-14, wherein the water- soluble polymer host comprises a crosslinked co-polymer network.

16. The antibody-nanoassembly conjugate of claim 15, wherein the crosslinked co-polymer network is a random co-polymer network.

17. The antibody-nanoassembly conjugate of claim 15, wherein the crosslinked co-polymer network is an amphiphilic block co-polymer network.

18. The antibody-nanoassembly conjugate of any one of claims 7-17, wherein the loading weight percentage of the PROTAC molecules is from about 1% to about 30%.

19. The antibody-nanoassembly conjugate of any one of claims 7-18, wherein the crosslinked polymer network has a crosslinking density from about 2% to about 70%, relative to the total number of structural units in the polymer.

20. A composition comprising the nanoassembly of any one of claims 1-6.

21. A composition comprising the antibody-nanoassembly conjugate of any one of claims 7- 19.

22. A method for delivering a PROTAC molecule to a biological site, comprising: transporting an antibody-nanoassembly conjugate of any one of claims 7-19 to a biological site of interest; and causing at least a partial de-crosslinking of the crosslinked polymer network, thereby releasing the PROTAC molecules at or near the biological site of interest.

23. A method for treating a disease or condition, comprising administering to a subject in need thereof an antibody-nanoassembly conjugate of any one of claims 7-19.

24. A method for making a nanoassembly of any one of claims 1-6.

25. A method for making an antibody-nanoassembly conjugate of any one of claims 7-19.

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