Compositions and methods relating to particle-attached cells - Patents.com

Abstract

Provided herein are polymeric particles and compositions (ie, "backpacks") that can attach to cells and deliver payload agents to the cells and / or direct therapeutic activity of these cells. TIFF2024529341000012.tif97170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 222,120, filed July 15, 2021. The contents of U.S. Provisional Application No. 63 / 222,120 are incorporated herein by reference in their entirety.

[0002] government support This invention was made with Government support under W81XWH-19-2-0011 awarded by the United States Army. The United States Government has certain rights in this invention.

[0003] Technical Field The technology described herein relates to methods and compositions relating to cells having particles attached to their surface. [Background technology]

[0004] background Cell-attached particles have shown promise for the targeted delivery of therapeutic and diagnostic agents in patients, but existing technologies for such particles have been limited in both binding efficacy and the cell types to which they can attach. Summary of the Invention

[0005] overview Described herein are improved polymer particles that provide improved binding efficiency, for example, provide strong enough binding efficiency to allow direct injection of polymer particles that attach in vivo, as well as polymer particles that can effectively bind to a wider range of cell types.Furthermore, described herein are polymer particles that can successfully deliver imaging agents, for example MRI contrast agents.

[0006] In one aspect of any of the above-mentioned embodiments, the polymer particle described herein comprises at least one imaging reagent.In some embodiments of any of the above-mentioned aspects, the at least one imaging reagent is at least one MRI contrast reagent.In some embodiments of any of the above-mentioned aspects, the polymer particle further comprises at least one binding reagent selected from the group consisting of CD11b binding reagent; CD3 binding reagent; CD19 binding reagent; CD49b binding reagent; CD56 binding reagent; CD11a binding reagent; CD27 binding reagent; CD44 binding reagent; CD45 binding reagent; NKG2D binding reagent; NKp30 binding reagent; NKp46 binding reagent; and ICAM1 binding reagent.In some embodiments of any of the above-mentioned aspects, the polymer particle further comprises at least one binding reagent selected from the group consisting of CD11b binding reagent; CD3 binding reagent; CD19 binding reagent; CD49b binding reagent; and CD56 binding reagent.

[0007] In one aspect of any of the above-mentioned embodiments, the polymer particle described herein comprises at least one binding reagent selected from the group consisting of CD11b binding reagent, CD3 binding reagent, CD19 binding reagent, CD49b binding reagent, and CD56 binding reagent.In some embodiments of any of the above-mentioned embodiments, the binding reagent is CD11b binding reagent, CD3 binding reagent, or CD19 binding reagent.In one aspect of any of the above-mentioned embodiments, the polymer particle described herein comprises at least one binding reagent selected from the group consisting of CD11b binding reagent, CD3 binding reagent, CD19 binding reagent, CD49b binding reagent, CD56 binding reagent, CD11a binding reagent, CD27 binding reagent, CD44 binding reagent, CD45 binding reagent, NKG2D binding reagent, NKp30 binding reagent, NKp46 binding reagent, and ICAM1 binding reagent.

[0008] In some embodiments of any of the preceding aspects, the binding reagent is a CD11b binding reagent.In some embodiments of any of the preceding aspects, the binding reagent is a CD45 binding reagent.

[0009] In some embodiments of any of the preceding aspects, the binding reagent is an antibody or antibody reagent. In some embodiments of any of the preceding aspects, the antibody or antibody reagent is an anti-CD11b antibody or anti-CD11b antibody reagent. In some embodiments of any of the preceding aspects, the antibody or antibody reagent is an anti-CD45 antibody or anti-CD45 antibody reagent. In some embodiments of any of the preceding aspects, the antibody or antibody reagent comprises one or more CDRs of an antibody or antibody reagent selected from Table 2. In some embodiments of any of the preceding aspects, the antibody or antibody reagent comprises six CDRs of an antibody or antibody reagent selected from Table 2. In some embodiments of any of the preceding aspects, the binding reagent further comprises a streptavidin or biotin molecule.

[0010] In one aspect of any of the above embodiments, described herein are polymer particles further comprising ICAM, NKp30, and / or NKp46. In one aspect of any of the above embodiments, described herein are polymer particles comprising ICAM, NKp30, and / or NKp46. In some embodiments of any of the above aspects, the polymer particles comprise ICAM and NKp30.

[0011] In some embodiments of any of the above aspects, the polymer particle further comprises one or more cell adhesion molecules (e.g., polyelectrolytes). In some embodiments of any of the above aspects, the polymer particle comprises a single region comprising a hydrogel of one or more cell adhesion molecules (e.g., polyelectrolytes). In some embodiments of any of the above aspects, the polymer particle further comprises one or more structural polymers. In some embodiments of any of the above aspects, the polymer particle comprises a single region comprising a hydrogel of one or more structural polymers.

[0012] In some embodiments of any of the above aspects, the polymer particles include a. a first region comprising a first selected cell adhesion molecule or molecules (e.g., polyelectrolytes) and, optionally, one or more binding reagents; b. a second region comprising a second selected type or types of cell adhesion molecules (e.g., polyelectrolytes); and c. a third region comprising one or more structural polymers and, optionally, one or more binding reagents; In some embodiments of any of the above aspects, the first selected cell adhesion molecule or molecules comprise one or more of hyaluronic acid (HA) and bovine serum albumin (BSA), the second selected cell adhesion molecule or molecules are poly(allylamine) hydrochloride (PAH), and the one or more structural polymers are one or more of poly(lactic-co-glycolic acid) (PLGA), PLGA-PEG, PLGA-PEG-maleimide, and PLGA-PEG-biotin.

[0013] In some embodiments of any of the above aspects, the polymer particles include a. a first region comprising a first selected structural polymer or polymers and, optionally, one or more binding reagents; and b. a second region comprising a second selected structural polymer or polymers; Includes.

[0014] In some embodiments of any of the above aspects, the polymer particles include a. a first region comprising a first selected structural polymer or polymers and, optionally, one or more binding reagents; b. a second region comprising a second selected structural polymer or polymers; and c. a third region comprising a third selected structural polymer or polymers and, optionally, one or more binding reagents; Includes.

[0015] In some embodiments of any of the above aspects, the second region is disposed between the first region and the third region, and / or the second region separates the first region and the third region from one another.

[0016] In some embodiments of any of the above aspects, the cell adhesion molecule comprises one or more of a cell adhesion polyelectrolyte, an immunoglobulin, or a ligand for a cell surface receptor. In some embodiments of any of the above aspects, the cell adhesion polyelectrolyte comprises one or more of hyaluronic acid (HA), methylacrylated HA, hyaluronic acid-aldehyde, bovine serum albumin (BSA), PEG, PEG dimethylacrylate, and / or poly(allylamine) hydrochloride (PAH). In some embodiments of any of the above aspects, the cell adhesion polyelectrolyte comprises one or more of hyaluronic acid (HA), methylacrylated HA, and hyaluronic acid-aldehyde; and one or more of PEG and PEG dimethylacrylate.

[0017] In some embodiments of any of the foregoing aspects, the structural polymer comprises one or more of poly(lactic-co-glycolic acid) (PLGA); a combination of PLGA and poly(D,L-lactide-co-glycolide); a combination of PLGA and acid-terminated poly(D,L-lactide-co-glycolide); a 50:50 molar ratio combination of PLGA and poly(D,L-lactide-co-glycolide); -polyvinyl alcohol (PVA); hyaluronic acid (HA); gelatin; collagen; PLGA-PEG; or poly(glycerol sebacate) (PGS).

[0018] In some embodiments of any of the above aspects, the second region further comprises poly(lactic acid-co-caprolactone) (PLCL). In some embodiments of any of the above aspects, the second region comprises, or further comprises, a near-infrared degradable polymer or polymer linker.

[0019] In some embodiments of any of the preceding aspects, the polymer particle comprises a binding reagent comprising a streptavidin molecule conjugated to a structural polymer further comprising biotin. In some embodiments of any of the preceding aspects, the polymer particle comprises a binding reagent comprising a streptavidin molecule conjugated to a PLGA-PEG-biotin. In some embodiments of any of the preceding aspects, the polymer particle comprises a binding reagent conjugated to a PLGA-PEG-maleimide via a DTT catalyzed reaction. In some embodiments of any of the preceding aspects, the polymer particle comprises a binding reagent comprising a biotin molecule conjugated to a structural polymer further comprising streptavidin.

[0020] In some embodiments of any of the above aspects, the polymer particles further comprise one or more imaging agents.In some embodiments of any of the above aspects, the one or more imaging agents are selected from the group consisting of one or more contrast agents, one or more MRI contrast agents, one or more microbubbles, one or more metal ions, one or more radioisotopes, one or more optical imaging agents, one or more SPECT imaging agents, and one or more PET imaging agents.In some embodiments of any of the above aspects, the one or more MRI contrast agents comprise one or more of gadolinium-based contrast agents, superparamagnetic iron oxide, ultrasmall superparamagnetic iron oxide, superparamagnetic iron-platinum, manganese chelate, iron salt, and perflubron. In some embodiments of any of the preceding aspects, the gadolinium-based imaging agent comprises one or more of gadolinium, gadoxetate, gadobutrol, gadoterate, gadoteridol, gadopentetate, gadobenate, gadopentetic acid dimegulmine, gadoxentate, gadoversetamide, gadodiamide, gadofosveset, gadocholetic acid, gadomeritol, gadomer 17, gadoxetic acid. In some embodiments of any of the preceding aspects, the one or more imaging agents further comprise a methylacrylate. In some embodiments of any of the above aspects, the one or more imaging agents are methylacrylate cross-linked to or more of one or more of methylacrylated HA and dimethylacrylate PEG.

[0021] In some embodiments of any of the above aspects, the polymer particles are substantially discoid in shape. In some embodiments of any of the above aspects, the polymer particles are discoid in shape. In some embodiments of any of the above aspects, the polymer particles have a diameter of about 100 nm to about 10 μm. In some embodiments of any of the above aspects, the polymer particles have a diameter of about 100 nm to about 1 μm. In some embodiments of any of the above aspects, the polymer particles have a size of about 6 μm×500 nm. In some embodiments of any of the above aspects, the polymer particles have a size of about 6 μm×250 nm. In some embodiments of any of the above aspects, the polymer particles have a size of 1-2 μm×7-9 μm. In some embodiments of any of the above aspects, the polymer particles have a size of 0.5×10 -11 cm 3 ~10×10 -11 cm 3 In some embodiments of any of the above aspects, the polymer particles have a volume of 1.25×10 -11 cm 3 ~5×10 -11 cm 3 In some embodiments of any of the above aspects, the polymer particles have a shape of a rod, a cylinder, a cube, a rectangular prism, a hexahedron, or a pyramid. In some embodiments of any of the above aspects, the domains are layers.

[0022] In some embodiments of any of the above aspects, the polymer particles further comprise one or more cell targeting ligands. In some embodiments of any of the above aspects, the cell targeting ligands are located in the region that comprises the cell adhesion molecule (e.g., polyelectrolyte). In some embodiments of any of the above aspects, the cell targeting ligand is an IgG, an antibody, a polypeptide, or an aptamer.

[0023] In some embodiments of any of the preceding aspects, the polymer particle further comprises one or more payload reagents. In some embodiments of any of the preceding aspects, the payload reagent is a therapeutic molecule. In some embodiments of any of the preceding aspects, the payload reagent is a small molecule or a polypeptide. In some embodiments of any of the preceding aspects, the payload reagent is present in admixture with the structural polymer. In some embodiments of any of the preceding aspects, the payload reagent is present in a second region.

[0024] In some embodiments of any of the above aspects, the polymer particle further comprises an echogenic liposome.In some embodiments of any of the above aspects, the polymer particle further comprises a magnetic nanoparticle.In some embodiments of any of the above aspects, the polymer particle further comprises a gold nanoparticle.

[0025] In some embodiments of any of the above aspects, the polymer particle further comprises at least one polarization inducer. In some embodiments of any of the above aspects, the polarization inducer is an N1 / M1 polarization inducer. In some embodiments of any of the above aspects, the polarization inducer is an N1 / M2 polarization inducer. In some embodiments of any of the above aspects, the N1 / M1 polarization inducer (an agent that polarizes to N1 / M1) is selected from the group consisting of IFN-γ; TNF; TNF-α; Toll-like receptor agonists (e.g., LPS, muramyl dipeptide, or lipoteichoic acid); GM-CSF; IL-1β; IL-6; IL-12; IL-23, and CD11b. In some embodiments of any of the preceding aspects, the N2 / M2 polarization inducer (an agent that polarizes towards N2 / M2) is selected from the group consisting of IL-4; IL-10; a glucocortoid (e.g., cortisol, cortisone, prednisone, prednisolone, methylprednisonolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, and deoxycorticosterone acetate); M-CSF, TGF-β, IL-6; and IL-13. In some embodiments of any of the preceding aspects, release of one or more of the polarization inducers is triggered by contacting the particle with a small molecule or a nucleic acid. In some embodiments of any of the preceding aspects, the phenotype of the macrophage is modulated by release of one or more polarization inducers.

[0026] In one aspect of any of the preceding embodiments, a. cells; b. The polymer particles according to any one of the preceding claims, which are disposed on the cell surface of a cell. Described herein is an engineered cell composition comprising: In some embodiments of any of the preceding aspects, the cell is a monocyte, macrophage, natural killer cell, or neutrophil. In some embodiments of any of the preceding aspects, the macrophage is an M0 macrophage. In some embodiments of any of the preceding aspects, the macrophage is an M1 polarized macrophage. In some embodiments of any of the preceding aspects, the macrophage is an M2 polarized macrophage. In some embodiments of any of the preceding aspects, the macrophage is substantially induced to an M1 or M2 phenotype.

[0027] In one aspect of any of the above embodiments, described herein is a method of obtaining an image of a subject, comprising administering to a subject a polymer particle or engineered cell composition described herein, wherein the polymer particle comprises an imaging agent, and then subjecting the subject to an imaging scan capable of detecting the imaging agent. In one aspect of any of the above embodiments, the cell is a macrophage, monocyte, or T cell.

[0028] In one aspect of any of the above embodiments, described herein is a method of treating cancer and / or tumors in a subject in need of such treatment, comprising administering to the subject a polymer particle or engineered cell composition as described herein. In some embodiments of any of the above aspects, the polymer particle comprises a payload reagent that is a chemotherapeutic agent. In some embodiments of any of the above aspects, the method further comprises subjecting the subject to radiation or at least one chemotherapy. In some embodiments of any of the above aspects, the cell is a macrophage, a NK cell, or a T cell.

[0029] In one aspect of any of the above embodiments, described herein is a method of treating a fracture, wound, injury (e.g., TBI), or infection in a subject in need thereof, comprising administering to the subject a polymer particle or engineered cell composition described herein. In some embodiments of any of the above aspects, the polymer particle comprises a payload reagent that is an antibiotic, antiviral, antibacterial, hemostatic, anti-inflammatory, or analgesic.

[0030] In one aspect of any of the above embodiments, described herein is a method of treating inflammation in a subject in need thereof, comprising administering to the subject a polymer particle or engineered cell composition as described herein. In some embodiments of any of the above aspects, the polymer particle comprises a payload reagent that is an anti-inflammatory agent. In some embodiments of any of the above aspects, the inflammation is in the lung, joint, or skin. In some embodiments of any of the above aspects, the polymer particle comprises IL-4. In some embodiments of any of the above aspects, the cell is a neutrophil.

[0031] In one aspect of any of the above embodiments, described herein is a method of treating an autoimmune condition in a subject in need thereof, comprising administering to the subject a polymer particle or engineered cell composition as described herein. In some embodiments of any of the above aspects, the polymer particle comprises a payload reagent that is an immunosuppressant. In some embodiments of any of the above aspects, the autoimmune condition is multiple sclerosis, diabetes, or arthritis. In some embodiments of any of the above aspects, the cell is a macrophage or a T cell.

[0032] In one aspect of any of the above embodiments, described herein is a method of providing hemostatic therapy to a subject in need thereof, comprising administering to the subject a polymer particle or an engineered cell composition described herein. In some embodiments of any of the above aspects, the polymer particle comprises a payload reagent that is a hemostatic agent.

[0033] In one aspect of any of the above embodiments, described herein is a method of treating a neurodegenerative disorder, a central nervous system disorder, or a peripheral nervous system disorder in a subject in need thereof, comprising administering to the subject a polymer particle or an engineered cell composition as described herein. In some embodiments of any of the above aspects, the polymer particle comprises a payload reagent that is a therapeutic agent for the neurodegenerative disorder, a central nervous system disorder, or a peripheral nervous system disorder.

[0034] In one aspect of any of the above embodiments, described herein is a method of delivering a payload reagent to the central nervous system of a subject in need thereof, comprising administering to the subject a polymer particle or engineered cell composition described herein, wherein the cells are monocytes and / or the binding reagent is an anti-CD11b binding reagent.

[0035] In one aspect of any of the above embodiments, described herein is a method of providing a gene therapy vector to a subject in need thereof, comprising administering to the subject a polymer particle or engineered cell composition as described herein, wherein the polymer particle comprises a payload reagent that is a gene therapy vector. In some embodiments of any of the above aspects, the gene therapy vector is AAV.

[0036] In one aspect of any of the above embodiments, described herein is a method of vaccinating a subject or inducing an immune response in a subject in need thereof, comprising administering to a subject a polymer particle or engineered cell composition as described herein, wherein the polymer particle comprises a payload reagent that is an antigen. In some embodiments of any of the above aspects, the cell is a B cell.

[0037] In some embodiments of any of the above aspects, the cells are autologous to the subject. In some embodiments of any of the above aspects, the cells are xenogeneic to the subject. In some embodiments of any of the above aspects, the method further comprises a first step of obtaining cells from a donor and / or subject and contacting the cells with polymer particles ex vivo. In some embodiments of any of the above aspects, a therapeutically effective dose of the polymer particles or engineered cell composition is administered.

[0038] In one aspect of any of the above embodiments, described herein are polymer particles or engineered cell compositions described herein for use in the methods described herein. [Brief description of the drawings]

[0039] [Figure 1] FIG. 1 illustrates the attachment of an exemplary anti-CD11b backpack design to monocytes. [Diagram 2] FIG. 2 illustrates the design and assembly of an exemplary backpack design. [Diagram 3] FIG. 3 illustrates the release kinetics of an exemplary backpack. [Figure 4] FIG. 4 illustrates the design and assembly of an exemplary backpack design. [Diagram 5] FIG. 5 illustrates the design and assembly of an exemplary backpack design. [Figure 6] FIG. 6 illustrates flow cytometry measurements of backpack attachment. [Figure 7] FIG. 7 illustrates the attachment of anti-CD11b backpack to neutrophils. [Figure 8] FIG. 8 illustrates the attachment of the BSA-PAH backpack to NK cells. [Figure 9] FIG. 9 illustrates backpack attachment rates under different conditions. [Figure 10] FIG. 10 illustrates the design and assembly of several exemplary backpack designs. [Figure 11] FIG. 11 illustrates neutrophil adhesion rates for several exemplary backpack designs. [Figure 12] FIG. 12 illustrates the attachment rates of several exemplary backpack designs. [Figure 13] FIG. 13 demonstrates the biodistribution of the backpack. [Figure 14] FIG. 14 demonstrates the biodistribution of neutrophils. [Figure 15] FIG. 15 demonstrates the loading and release profiles of several backpack designs. [Figure 16] FIG. 16 demonstrates the loading and release profiles of several backpack designs. [Figure 17] FIG. 17 illustrates an exemplary protocol for preparing a gadolinium-filled backpack. [Figure 18] FIG. 18 illustrates an exemplary protocol for preparing a gadolinium-filled backpack. [Figure 19] FIG. 19 demonstrates the relaxivity of the gadolinium-filled backpack. [Figure 20] FIG. 20 demonstrates the stability of gadolinium-loaded backpack attachment to macrophages. [Figure 21] FIG. 21 illustrates MRI imaging of a gadolinium-filled backpack injected into ex vivo rat brain tissue. [Figure 22] FIG. 22 illustrates an exemplary backpack design. [Figure 23] FIG. 23 illustrates an exemplary procedure for printing a backpack. [Figure 24] FIG. 24 illustrates an exemplary procedure for printing a backpack. [Diagram 25] FIG. 25 illustrates the binding of HA backpack to macrophages. [Figure 26] FIG. 26 illustrates the stability of HA backpack attached to macrophages. [Figure 27] FIG. 27 illustrates the release kinetics of IFN-γ from the backpack. [Figure 28] FIG. 28 illustrates the stability of IFN-γ in the backpack. [Figure 29] FIG. 29 illustrates IL-4 release from the backpack. [Figure 30A] FIG. 30A demonstrates the relaxivity of the gadolinium-filled backpack. [Figure 30B] FIG. 30B demonstrates the relaxivity of the gadolinium-filled backpack. [Figure 30C] FIG. 30C demonstrates the relaxivity of the gadolinium-filled backpack. [Diagram 31] FIG. 31 illustrates the attachment of an exemplary backpack design. [Diagram 32] FIG. 32 illustrates the effect of an IFN-γ-loaded backpack on macrophage phenotype. [Diagram 33] FIG. 33 illustrates the effect of administering an IFN-γ-loaded backpack to cancer-bearing mice. [Diagram 34] FIG. 34 illustrates a schematic of an exemplary polymer particle configuration. [Figure 35A] FIG. 35A illustrates an exemplary method of modifying a backpack. [Figure 35B] FIG. 35B illustrates an exemplary method of modifying a backpack. [Figure 36A] Figures 36A-36B illustrate the adhesion rate of neutrophils to unmodified backpacks. Figure 36A shows a schematic of the backpack structure used. [Figure 36B] FIG. 36B illustrates a graph of the attachment rate of backpacks with different types of PLGA based on termini (acid or ester) or L:G ratio (50:50 or 65:35). [Figure 36C] FIG. 36C illustrates a graph of backpack attachment rates with different cell:BP ratios and cell concentrations. [Figure 37-1] Figures 37A-37D demonstrate that an antibody-modified backpack increases neutrophil adhesion. Figure 37A shows a schematic diagram of a method for preparing an antibody reagent for use in the backpack. Figure 37B illustrates a schematic diagram of the modified backpack used in Figures 37C-37D. [Figure 37-2] Figure 37C illustrates a graph of the attachment rate of backpacks modified with a combination of BSA, PAH, and HA. Figure 37D illustrates a graph of the attachment rate of backpacks modified with anti-CD11b. [Figure 38A] FIG. 38A is from Miralda et al. 2017 and illustrates a list of priming agents. [Figure 38B] FIG. 38B depicts a graph of backpack attachment rates in the presence or absence of IFNg and GMCSF. [Figure 38C] Figure 38C illustrates the effect of GCSF concentration on backpack adhesion. Figure 38D illustrates the effect of GMCSF concentration on backpack adhesion. For Figures 38C-38D, cells were treated with each concentration of cytokine for about 30 minutes before addition of the backpack. In general, higher cytokine concentrations increase adhesion to neutrophils up to a certain threshold concentration (highlighted in the box). [Figure 38D] See legend to Figure 38C. [Figure 39-1]Figures 39A-39E illustrate the scale-up of backpack adhesion to neutrophils. Figure 39A illustrates the adhesion rate of 1 million (M) cells + 1 million (M) backpacks in a 96-well plate. Figure 39B illustrates the adhesion rate in a 15 mL centrifuge tuble. Changing the reactor vessel has a large effect on adhesion, probably due to the lower area for settling in the 15 mL tube. [Figure 39-2] 39C-39D illustrate adhesion rates in the indicated volumes and reactors. [Figure 39-3] FIG. 39E illustrates the rate of adhesion upon incubation in a 96-well plate followed by collection in a 15 mL tube. [Diagram 40] FIG. 40 illustrates microscopic images showing that the backpack is retained on the surface of neutrophils. [Figure 41-1] Figures 41A-41G illustrate neutrophil viability under different conditions: Figure 41A illustrates the effect of media formulations on neutrophil viability. [Figure 41-2] 41B-41E illustrate the attachment and survival rates over time. [Figure 41-3] Description of Figure 41-2. [Figure 41-4] 41F-41G illustrate the amount of neutrophil degranulation upon backpack adhesion. [Diagram 42] FIG. 42 illustrates a graph of N1 polarization marker levels following backpack attachment. [Diagram 43] 43A-43B illustrate the levels of neutrophil activation markers following backpack adhesion. [Figure 44-1] 44A-44B illustrate the levels of neutrophil polarization markers following backpack adhesion. [Figure 44-2] Figure 44C illustrates the in vitro toxicity of neutrophils against 4T1 cells, and Figure 44D illustrates the levels of MPO release after treatment of neutrophils with nanoparticles. [Figure 44-3] FIG. 44E illustrates the levels of MPO release after adhesion to different surfaces. [Figure 45-1] Figures 45A-45K demonstrate that backpack-bearing neutrophils reach the tumor within 4 hours. Figure 45A illustrates a schematic of the experiment. Figure 45B illustrates a graph of the amount of neutrophils in the tumor over time. [Figure 45-2] FIG. 45C illustrates images of the amount of neutrophils in the tumor over time. [Figure 45-3] Figures 45D-45E illustrate the accumulation of cells and backpacks in organs. In Figure 45D, cells were stained with VivoTrack680. In Figure 45E, backpacks were stained with Rhodamine B. Organs were excised at 4 and 24 hours and imaged using IVIS. [Figure 45-4] Description of Figure 45-3. [Figure 45-5] Figures 45F-45H depict graphs of neutrophil accumulation in 4T1 tumors and other tissues over time. [Figure 45-6] Figures 4I-45K illustrate graphs of backpack accumulation in 4T1 tumors and other tissues over time. [Figure 46-1] Figures 46A-46G illustrate the immune response to neutrophils + backpack following intratumoral injection. Figure 46A illustrates a schematic of the experiment. [Figure 46-2] Figures 46B-46G illustrate graphs demonstrating that neutrophil backpack alters the tumor microenvironment (TME). [Figure 46-3] See description of Figure 46-2. [Figure 47A] FIG. 47A illustrates the efficacy of the neutrophil backpack in vivo. [Figure 47B] FIG. 47B illustrates the efficacy of the neutrophil backpack in vivo. [Figure 48-1] FIG. 48A illustrates a schematic of antibody-mediated coupling of the backpack to cells. [Figure 48-2] FIG. 48B illustrates images of the backpack on mouse and human NK cells. [Figure 48-3]Figure 48C illustrates the effect of media composition upon backpack attachment to C57BL / 6 spleen-derived murine NK cells with a 2 hour incubation. Figure 48D illustrates the effect of backpack:cell ratio upon backpack attachment to C57BL / 6 spleen-derived murine NK cells with a 2 hour incubation. [Figure 48-4] Figure 48E illustrates the attachment rate using different ligands and complete media at a backpack:cell ratio of 2:1. Figure 48F illustrates the attachment rate using different ligands and time and complete media at a backpack:cell ratio of 2:1. [Figure 48-5] Figures 48G-H illustrate backpack attachment to primary NK cells and NK-92 cells using ICAM1 as a ligand. [Figure 49-1] FIG. 49A illustrates the levels of degranulation surface markers expressed on NK-92 cells after attachment of the indicated backpacks. [Figure 49-2] Figure 49B illustrates the levels of IFN-γ secretion in NK-92 cells after attachment of the indicated backpacks at a 2:1 backpack:cell ratio. Figure 49C illustrates the levels of IFN-γ secretion in NK-92 cells after attachment of the indicated backpacks at a 2:1 backpack:cell ratio. [Figure 49-3] Figures 49D-49I depict graphs of gene expression measured by RT-PCR in human primary NK cells after backpack attachment. [Figure 49-4] See description of Figure 49-3. [Figure 49-5] Figure 49J illustrates a graph of IFN-γ secretion in mouse NK cells after backpack attachment. Figure 49K illustrates a graph of IFN-γ secretion in mouse NK cells expanded with IL-15 after backpack attachment. [Figure 50-1] Figures 50A-50B illustrate IFN-γ production on NK-92 cells after attachment of the indicated backpack. A BP:cell ratio of 2:1 was used, and free cytokines were used at a concentration of 100 ng / ml. Cells were washed three times after incubation with cytokines. [Figure 50-2] Figures 50C-50D illustrate degranulation and surface marker expression on NK-92 cells after attachment of the indicated backpacks. A BP:cell ratio of 2:1 was used, and free cytokines were used at a concentration of 100 ng / ml. Cells were washed three times after incubation with cytokines. [Figure 51-1] 51A-51B illustrate the biodistribution of NK-92 in A375 melanoma-bearing mice. The mice were J:Nu nude mice with subcutaneous A375 tumors in the flank. [Figure 51-2] Figures 51C-51E illustrate the biodistribution of NK-92-conjugated BP in A375 melanoma-bearing mice. Mice were J:Nu nude mice with subcutaneous A375 tumors in the flank. BP (rhodamine signal) overlaps with organ autofluorescence, but BP is detectable in single cell suspensions. [Figure 51-3] See description of Figure 51-2. [Figure 52-1] FIG. 52A illustrates a schematic overview of the monocyte / backpack adhesion method. [Figure 52-2] Figure 52B illustrates a graph of monocyte adhesion for a number of backpack formulations. Figure 52C illustrates a graph of primary human monocyte adhesion for the indicated backpack formulations. Figure 52D illustrates a graph of primary mouse monocyte adhesion for the indicated backpack formulations. [Figure 52-3] Figures 52E-52F illustrate images of backpacks attached to monocytes. [Figure 52-4] FIG. 52G depicts a graph of antibody-mediated backpack adhesion to monocytes under different shear conditions. [Figure 53A] FIG. 53A illustrates a schematic of a backpack loaded with cytokines or small molecules. [Figure 53B] FIG. 53B illustrates a graph showing IL-4 loading into the backpack. [Figure 53C] FIG. 53C illustrates a graph showing dex loading into the backpack. [Figure 54A]FIG. 54A illustrates the viability of monocytes after backpack attachment. [Figure 54B] FIG. 54B illustrates CD11b expression levels on monocytes 1 hour after backpack attachment. [Fig. 54C] FIG. 54C illustrates Ly6C expression levels in monocytes 1 hour after backpack attachment. [Fig. 54D] FIG. 54D illustrates CCR2 expression levels in monocytes 1 hour after backpack attachment. [Figure 54E] FIG. 54E illustrates CX3CR1 expression levels in monocytes 1 hour after backpack attachment. [Fig. 54F] FIG. 54F illustrates the viability of monocytes after backpack attachment. [Figure 54G] Figures 54G-54H illustrate CD11b expression 1 hour and 24 hours after backpack attachment. [Fig. 54H] See legend to Figure 54G. [Fig. 54I] Figures 54I-54J illustrate Ly6C expression 1 hour and 24 hours after backpack attachment. [Fig. 54J] See legend to Figure 54I. [Figure 54K] Figures 54K-54L illustrate CCR2 expression 1 hour and 24 hours after backpack attachment. [Figure 54L] See legend to Figure 54K. [Figure 54M] Figures 54M-54N illustrate CX3CR1 expression 1 hour and 24 hours after backpack attachment. [Fig. 54N] See legend to Figure 54M. [Figure 55-1] Figure 55A illustrates the levels of M1 marker gene expression 72 hours after attachment of the indicated backpack to monocytes. Figure 55B illustrates the levels of M2 marker gene expression 72 hours after attachment of the indicated backpack to monocytes. [Figure 55-2]Figures 55C-55H illustrate the levels of phenotypic markers upon attachment of different backpacks compared to monocytes alone. [Figure 55-3] See description of Figure 55-2. [Figure 55-4] See description of Figure 55-2. [Figure 55-5] FIG. 55I shows a graph demonstrating that the drug-loaded backpack can maintain carrier monocyte viability after 72 hours. [Figure 56-1] FIG. 56A illustrates a single dose regimen treatment of chronic EAE in vivo. [Figure 56-2] FIG. 56B illustrates a two-dose regimen treatment of chronic EAE in vivo. [Figure 56-3] Figures 56C-56D illustrate EAE biodistribution studies. [Figure 56-4] Figures 56E-56H illustrate levels of immune cells / markers in blood after two dose regimens after acute EAE treatment. Figures 56I-56K illustrate levels of indicated cell types in brain after two dose regimens after acute EAE treatment. Figures 56L-56M illustrate levels of indicated cell types in spinal cord after two dose regimens after acute EAE treatment. Figure 56N illustrates levels of indicated cell types in spinal cord after two dose regimens after acute EAE treatment. Figures 56O-56P illustrate levels of IFN-γ production in CNS after two dose regimens after acute EAE treatment. Figure 56Q illustrates levels of IL-17A production in serum after two dose regimens after acute EAE treatment. In Figures 56E-56Q, "drug" or "drug loading" refers to IL-4 and dexamethasone. [Figure 56-5] See description of Figure 56-4. [Figure 56-6] See description of Figure 56-4. [Figure 56-7] See description of Figure 56-4. [Figure 56-8] See description of Figure 56-4. [Figure 56-9] See description of Figure 56-4. [Figure 57A] FIG. 57A illustrates a schematic of TBI backpack therapy. [Figure 57B] FIG. 57B illustrates the attachment of these backpacks to macrophages. [Figure 58-1] Figures 58A-58D illustrate the attachment of backpacks to different cells. Attachment was performed ex vivo in whole blood under static conditions for 1 hour. [Figure 58-2] Figures 58E-58I illustrate binding to different cell types in vivo over time. [Figure 58-3] See description of Figure 58-2. [Figure 58-4] 58J-58N illustrate the biodistribution of backpacks with and without CD11b over time. [Figure 58-5] See description of Figure 58-4. [Figure 58-6] Figures 58O-58P illustrate the binding of backpack to liver-associated immune cells in vivo. [Figure 58-7] Figures 58Q-58R illustrate the binding of backpack to lung-associated immune cells in vivo. [Figure 59-1] Figures 59A-59H illustrate the organ distribution of different backpack types. Backpacks were injected intravenously into healthy mice at a dose of 2 million backpacks per mouse. [Figure 59-2] See description of Figure 59-1. [Figure 59-3] See description of Figure 59-1. [Figure 59-4] See description of Figure 59-1. [Figure 60A] FIG. 60A illustrates a schematic diagram of the structure of the Gd backpack. [Figure 60B] FIG. 60B illustrates the preparation of a Gd-loaded hydrogel backpack. [Figure 60C] FIG. 60C illustrates the preparation of a Gd-loaded hydrogel backpack. [Figure 60D] FIG. 60D illustrates a graph of backpack yield. [Figure 61-1] FIG. 61A illustrates a summary of the paramagnetic properties of Gd BP. [Figure 61-2] 61B-E illustrate the analysis of the paramagnetic properties of GdBP and free gadovist. [Figure 61-3] See description for Figure 61-3. [Figure 62-1] Figures 62A-62E illustrate the preparation of a cell backpack system. Figures 62A-62B illustrate images of a cell backpack attached to cells. [Figure 62-2] Figure 62C illustrates a schematic of this process. [Figure 62-3] 62D and 62E illustrate the adhesion rate. [Figure 63A] FIG. 63A illustrates different methods of antibody modification of the backpack. [Figure 63B] 63B-63C illustrate cBP stability under shear stress (FIG. 63B) and freezing (FIG. 63C). [Figure 63C] See legend to Figure 63B. [Fig. 63D] 63D-63E illustrate MR images of Gd BP in rat brain tissue. [Figure 63E] See legend to Figure 63D. [Fig.63F] 63F-63G depict graphs of the biodistribution of Gd BP in healthy mice. [Figure 63G] See legend to Figure 63F. [Fig. 63H] Figures 63H-63J illustrate the biodistribution of GdBP in mice with lung metastases. [Fig.63I] See legend to Figure 63H. [Fig. 63J] See legend to Figure 63H. [Figure 63K] Figures 63K-63L illustrate graphs of lung:liver accumulation ratios. [Figure 63L] See legend to Figure 63K. [Figure 63M] Figures 63M-63N illustrate the brain distribution of BP and cBP. [Figure 63N] See legend to Figure 63N. [Fig. 64A]Figures 64A-64C illustrate M1 and M2 macrophage marker levels in macrophages with BP and in total macrophages. [Fig. 64B] See legend to Figure 64A. [Fig. 64C] See legend to Figure 64A. [Fig.64D] Figures 64D-64G illustrate cytokine release levels in macrophages with BP and in total macrophages. Macrophages are porcine macrophages. LPS was used at 100 ng / mL and IL4 was used at 20 ng / mL. [Figure 64E] See legend to Figure 64D. [Fig.64F] See legend to Figure 64D. [Figure 64G] See legend to Figure 64D. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] Detailed Description The methods and compositions described herein relate to polymer particles that can attach to cell surfaces, such as the surface of monocytes or macrophages. The polymer particles described herein are resistant to phagocytosis when attached to cell surfaces. These polymer particles are referred to herein as "backpacks."

[0041] It is particularly difficult for such polymer particles to attach to certain cell types, such as natural killer cells, monocytes, and neutrophils. The inventors have demonstrated herein that the inclusion of a binding reagent specific for a certain cell surface target surprisingly increases the ability of the polymer particles to attach to cells, particularly natural killer cells, monocytes, and neutrophils. The increase in binding efficiency is large enough that the polymer particles can be directly injected into a subject (where they can then attach to cells in vivo), instead of having to perform the attachment ex vivo and then inject the cells to which the polymer particles are attached.

[0042] Thus, in one aspect of any of the above-mentioned embodiments, the polymer particle described herein comprises at least one binding reagent selected from the group consisting of CD11b binding reagent; CD3 binding reagent; CD19 binding reagent; CD49b binding reagent; and CD56 binding reagent.In one aspect of any of the above-mentioned embodiments, the polymer particle described herein comprises at least one binding reagent selected from the group consisting of CD11b binding reagent; CD3 binding reagent; CD19 binding reagent; CD49b binding reagent; CD56 binding reagent; CD11a binding reagent; CD27 binding reagent; CD44 binding reagent; CD45 binding reagent; NKG2D binding reagent; NKp30 binding reagent; NKp46 binding reagent; and ICAM1 binding reagent.In some embodiments of any of the above-mentioned aspects, the binding reagent is CD11b binding reagent; CD3 binding reagent; or CD19 binding reagent.In some embodiments of any of the above-mentioned aspects, the binding reagent is CD11b binding reagent.

[0043] As used herein, "binding reagent" refers to an agent that specifically binds to a target molecule. Exemplary binding reagents can include antibodies, antibody reagents, aptamers, ligands, intrabodies, and the like.

[0044] As used herein, "integrin subunit αM", "ITGAM", "cluster of differentiation 11b", or "CD11b" refers to the integrin chain that combines with ITGB2 to form the CR3 or Mac-1 leukocyte-specific receptor. The sequences of the CD11b gene and polypeptide of many species are known, for example, the mRNA (e.g., NCBI Ref Seq:NM_000632.4 and NM_001145808.2) and polypeptide (e.g., NCBI Ref Seq:NP_001139280.1 and NP_000623.2) of human CD11b (NCBI Gene ID No:3684).

[0045] As used herein, "CD3" or "cluster of differentiation 3" is a protein complex that functions as a T cell coreceptor. As used herein, binding to CD3 can refer to binding to the entire complex or to any one or more of the four chains that make up CD3. The four chains of CD3 are one CD3γ, one CD3δ, and two CD3ε. The sequences of the CD3γ gene and polypeptide of many species are known, for example, the mRNA (e.g., NCBI Ref Seq:NM_000073.3) and polypeptide (e.g., NCBI Ref Seq:NP_00064.1) of human CD3γ (NCBI Gene ID No:917). The sequences of the CD3δ gene and polypeptides of many species are known, for example the mRNA (e.g., NCBI Ref Seq: NM_000732.6 and NM_001040651.2) and polypeptide (e.g., NCBI Ref Seq: NP_000723.1 and NP_001035741.1) of human CD3δ (NCBI Gene ID No: 915). The sequences of the CD3ε gene and polypeptides of many species are known, for example the mRNA (e.g., NCBI Ref Seq: NM_000733.4) and polypeptide (e.g., NCBI Ref Seq: NP_000724.1) of human CD3ε (NCBI Gene ID No: 916).

[0046] As used herein, "cluster of differentiation 19" or "CD19" refers to a transmembrane protein typically found on B cells. The sequences of CD19 genes and polypeptides of many species are known, for example, the mRNA (e.g., NCBI Ref Seq:NM_001178098.2, NM_001385732.1, and NM_001770.6) and polypeptide (e.g., NCBI Ref Seq:NP_001171569.1, NP_001372661.1, and NP_001761.3) of human CD19 (NCBI Gene ID No:930).

[0047] As used herein, "cluster of differentiation 49b" or "CD49" refers to the integrin alpha subunit protein. The sequences of the CD49b gene and polypeptide of many species are known, for example, the mRNA (e.g., NCBI Ref Seq:NM_002203.4) and polypeptide (e.g., NCBI Ref Seq:NP_002194.2) of human CD49b (NCBI Gene ID No:3673).

[0048] As used herein, "cluster of differentiation 56," or "CD56," refers to a glycoprotein commonly found on NK cells. The sequences of the CD56 gene and polypeptide of multiple species are known, for example, the mRNA (e.g., NCBI Ref Seq:NM_000615.7) and polypeptide (e.g., NCBI Ref Seq:NP_000606.3) of human CD56 (NCBI Gene ID No:4684).

[0049] In some embodiments of any of the above aspects, the binding reagent is an antibody or an antibody reagent.

[0050] In some embodiments of any of the preceding aspects, the antibody or antibody reagent is an anti-CD11b antibody or an anti-CD11b antibody reagent. In some embodiments of any of the preceding aspects, the antibody or antibody reagent is an anti-CD3 antibody or an anti-CD3 antibody reagent. In some embodiments of any of the preceding aspects, the antibody or antibody reagent is an anti-CD19 antibody or an anti-CD19 antibody reagent.

[0051] In some embodiments of any of the preceding aspects, the antibody or antibody reagent is an anti-CD49b antibody or anti-CD49b antibody reagent. In some embodiments of any of the preceding aspects, the antibody or antibody reagent is an anti-CD56 antibody or anti-CD56 antibody reagent.

[0052] The antibody and antibody reagent specific to the target / antigen provided herein are known in the art and are commercially available.For example, Table 2 shows the exemplary commercially available antibody species specific to the target / antigen described herein.Additional species are known to those skilled in the art, and are, for example, published and available in scientific literature.

[0053] (Table 2) TIFF2024529341000002.tif20170TIFF2024529341000003.tif232170TIFF2024529341000004.tif232170TIFF2024529341000005.tif168170

[0054] In some embodiments of any of the preceding aspects, the antibody or antibody reagent comprises one or more CDRs of an antibody or antibody reagent selected from Table 2. In some embodiments of any of the preceding aspects, the antibody or antibody reagent comprises six CDRs of an antibody or antibody reagent selected from Table 2.

[0055] In one aspect of any of the above embodiments, described herein are polymer particles as described herein and further comprising ICAM1, NKp30, and / or NKp46. In one aspect of any of the above embodiments, described herein are polymer particles comprising ICAM1, NKp30, and / or NKp46. Sequences of ICAM1, NKp30, and NKp46 are known in the art, for example, human ICAM1 (NCBI Gene ID 3383), human NKp46 (NCBI Gene ID: 9437), and human NKp30 (NCBI Gene ID: 259197). In some embodiments of any of the above aspects, ICAM1, NKp46, or NKp30 is a polypeptide associated with the aforementioned NCBI gene identification number as of the filing date of this application. In some embodiments of any of the above aspects, the polymer particle comprises ICAM and NKp30.

[0056] Several polymer particle configurations are provided herein. These configurations are referred to herein as: 1) hydrogel backpack; 2) uncoated sandwich backpack or layer-by-layer (LbL) backpack; and 3) coated sandwich backpack or layer-by-layer (LbL) backpack. Exemplary embodiments of each are illustrated in FIG. 34.

[0057] A hydrogel backpack, for example, includes a single layer or region of a structural polymer or cell attachment molecule present as a hydrogel.

[0058] In some embodiments of any of the above aspects, the polymer particles described herein further comprise one or more structural polymers. In some embodiments of any of the above aspects, the polymer particles described herein further comprise a single polymer region, which region comprises one or more structural polymers. In some embodiments of any of the above aspects, the polymer particles described herein further comprise a single polymer region or layer, which region or layer comprises a hydrogel comprising one or more structural polymers.

[0059] The term "gel" as used herein refers to a state of matter between a liquid and a solid. Thus, a "gel" has some of the properties of a liquid (i.e., it is shape-resilient and deformable) and some of the properties of a solid (i.e., the shape is composed of enough separate parts to maintain three dimensions on a two-dimensional surface). Gels may be provided in a pharma- ceutically acceptable carrier known to those skilled in the art, such as saline or phosphate-buffered saline. Such carriers may routinely contain pharma-ceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, and optionally other therapeutic agents. A non-limiting example of a gel is a hydrogel. A hydrogel is a material formed when organic polymers (natural or synthetic) are crosslinked via covalent, ionic, or hydrogen bonds to create a three-dimensional open-lattice structure that traps water molecules to form a gel.

[0060] A structural polymer is a polymer suitable for being formed into a thin disk. Exemplary structural polymers include, by way of non-limiting example, polylactic acid (PLA); polyglycolide (PGA); poly-(ε-caprolactone) (PCL); polyphosphazenes; polyorthoesters; polyanhydrides; poly(α-hydroxyesters); poly(ether esters); copolymers of glycolide with lactide and ε-caprolactone or trimethylene carbonate; poly(sebacic acid polyol) elastomers; elastomers; poly(polyol citrate); polyesters; poly(glycolic acid); poly(lactic acid); poly(caprolactone); poly(lactic acid-co-glycolic acid); poly(butylene succinate); poly(trimethylene carbonate); poly(p-dioxanone); poly(butylene terephthalate); poly(ester amides); Hybrane™ S1200; DegraPol™; polyurethanes; polyanhydrides; Poly[(carboxyphenoxy)propane-sebacic acid]; polyphosphoesters; poly[bis(hydroxyethyl)terephthalate-ethyl orthophosphorylate / terephthaloyl chloride]; poly(orthoesters); poly(alkyl cyanoacrylates); poly(butyl cyanoacrylate); polyethers; poly(ethylene glycol); poly(amino acids); tyrosine-derived polycarbonates; microbial polyesters; poly(β-hydroxyalkanoates); poly(hydroxybutyrate); poly(hydroxybutyrate-co-hydroxyvalerate); collagen; albumin; gluten; chitosan; hyaluronate; cellulose; alginates as well as starch. Suitable structural polymers are discussed in further detail, for example, in Bat et al. Regen. Med. 9:385-398 (2014), and Marin et al. Int. J. Nanomedicine 8:3071-3091 (2013), which are incorporated herein by reference in their entireties.In some embodiments of any of the above aspects, the structural polymer comprises poly(lactic-co-glycolic acid) (PLGA), polyvinyl alcohol (PVA), hyaluronic acid (HA), gelatin, collagen, and / or poly(glycerol sebacate) (PGS).

[0061] In some embodiments of any of the above aspects, the region comprising one or more structural polymers comprises one structural polymer. In some embodiments of any of the above aspects, the region comprising one or more structural polymers comprises two or more structural polymers.

[0062] In some embodiments of any of the above aspects, the region comprising a structural polymer comprises poly(lactic acid-co-caprolactone) (PLCL). In some embodiments of any of the above aspects, the region comprising a structural polymer comprises a) poly(lactic acid-co-glycolic acid) (PLGA) and / or poly(glycerol sebacate) (PGS), and b) poly(lactic acid-co-caprolactone) (PLCL).

[0063] In some embodiments of any of the above aspects, the one or more structural polymers comprise poly(lactic-co-glycolic acid) (PLGA); a combination of PLGA and poly(D,L-lactide-co-glycolide); a combination of PLGA and acid-terminated poly(D,L-lactide-co-glycolide); a 50:50 molar ratio combination of PLGA and poly(D,L-lactide-co-glycolide); -polyvinyl alcohol (PVA); hyaluronic acid (HA); gelatin; collagen; PLGA-PEG; or poly(glycerol sebacate) (PGS). In some embodiments of any of the above aspects, the one or more structural polymers comprise poly(lactic-co-glycolic acid) (PLGA); a combination of PLGA and poly(D,L-lactide-co-glycolide); a combination of PLGA and acid-terminated poly(D,L-lactide-co-glycolide); a 50:50 molar ratio combination of PLGA and poly(D,L-lactide-co-glycolide); -polyvinyl alcohol (PVA); gelatin; collagen; PLGA-PEG; or poly(glycerol sebacate) (PGS). In some embodiments of any of the preceding aspects, the one or more structural polymers comprise poly(lactic-co-glycolic acid) (PLGA); a combination of PLGA and poly(D,L-lactide-co-glycolide); a combination of PLGA and poly(D,L-lactide-co-glycolide) with acid ends; a 50:50 molar ratio combination of PLGA and poly(D,L-lactide-co-glycolide); or PLGA-PEG. In some embodiments of any of the preceding aspects, the one or more structural polymers comprise, consist of, or consist essentially of PLGA. In some embodiments of any of the preceding aspects, the one or more structural polymers comprise, consist of, or consist essentially of PLGA-PEG. In some embodiments of any of the preceding aspects, the one or more structural polymers comprise, consist of, or consist essentially of a combination of PLGA and PLGA-PEG. In some embodiments of any of the preceding aspects, the one or more structural polymers comprise polyvinyl alcohol (PVA).

[0064] In some embodiments of any of the above aspects, the hydrogel backpack comprises a single polymer region or layer, where the region or layer comprises one or more biotinylated structural polymers. In some embodiments of any of the above aspects, the hydrogel backpack comprises a single polymer region or layer, where the region or layer comprises one or more biotinylated structural polymers bound to one or more binding reagents, including streptavidin molecules.

[0065] In some embodiments of any of the above aspects, the hydrogel backpack comprises a single polymer region or layer, the region or layer comprising one or more structural polymers that comprise maleimide molecules. In some embodiments of any of the above aspects, the hydrogel backpack comprises a single polymer region or layer, the region or layer comprising one or more structural polymers that are covalently conjugated to one or more binding reagents.

[0066] In some embodiments of any of the above aspects, the hydrogel backpack includes a single polymer region or layer, where the region or layer comprises a hydrogel comprising PLGA; a combination of PLGA and poly(D,L-lactide-co-glycolide); a combination of PLGA and acid-terminated poly(D,L-lactide-co-glycolide); or a 50:50 molar ratio of PLGA and poly(D,L-lactide-co-glycolide).

[0067] In some embodiments of any of the preceding aspects, the hydrogel backpack comprises, consists of, or consists essentially of a single polymer region or layer, the region or layer comprising a hydrogel of one or more structural polymers. In some embodiments of any of the preceding aspects, the hydrogel backpack comprises, consists of, or consists essentially of a single polymer region or layer, the region or layer comprising a) a hydrogel of one or more structural polymers, and b) one or more binding reagents. In some embodiments of any of the preceding aspects, the hydrogel backpack comprises, consists of, or consists essentially of a single polymer region or layer, the region or layer comprising a) a hydrogel of one or more structural polymers, b) one or more binding reagents, and c) one or more polarization inducers. In some embodiments of any of the preceding aspects, the hydrogel backpack comprises, consists of, or consists essentially of a single polymer region or layer, the region or layer comprising a) a hydrogel of one or more structural polymers, and b) one or more polarization inducers.

[0068] In some embodiments of any of the above aspects, the one or more structural polymers comprise, consist essentially of, or consist of one or more of the following: poly(lactic-co-glycolic acid) (PLGA), PLGA-PEG, PLGA-PEG-maleimide, PLGA-PEG-biotin; a combination of PLGA and poly(D,L-lactide-co-glycolide); a combination of PLGA and poly(D,L-lactide-co-glycolide) with acid ends; or a 50:50 molar ratio combination of PLGA and poly(D,L-lactide-co-glycolide). In some embodiments of any of the above aspects, the one or more structural polymers comprise, consist essentially of, or consist of PLGA-PEG. In some embodiments of any of the above aspects, the one or more structural polymers comprise, consist essentially of, or consist of PLGA. In some embodiments of any of the above aspects, the one or more structural polymers comprise, consist essentially of, or consist of a combination of PLGA and PLGA-PEG.

[0069] In some embodiments of any of the above aspects, the polymer particles described herein further comprise one or more cell adhesion molecules. In some embodiments of any of the above aspects, the polymer particles described herein further comprise a single polymer region, which region comprises one or more types of one or more cell adhesion molecules. In some embodiments of any of the above aspects, the polymer particles described herein further comprise a single polymer region or layer, which region or layer comprises a hydrogel comprising one or more types of one or more cell adhesion molecules.

[0070] Cell adhesion molecules can be any molecule that adheres to the surface of cells, such as monocytes, macrophages, natural killer cells, T cells, or neutrophils.Non-limiting examples of suitable cell adhesion molecules include polyelectrolytes, immunoglobulins, ligands for cell surface receptors, and / or monocyte targeting ligands and / or macrophage targeting ligands.Characteristics that can enhance cell adhesion include, for example, high surface free energy, hydrophilic protein content, low surface hydration, and low surface charge density. Exemplary non-limiting cell adhesion molecules may include poly(glycidyl methacrylate) (PGMA); polycaprolactone (PCL); polydimethylsiloxane (PDMS); poly(hexamethyldisiloxane) (PHMDSO); superhydrophobic perfluorinated PEDOT (PEDOT-F); superhydrophobic polystyrene (PS); plasma-treated poly(methyl methacrylate) (PMMA); plasma-treated poly-3-hydroxybutyrate (P3HB); phosphatidylethanolamine (PE); and carboxymethylchitin (CMCH). Cell adhesion molecules may also include or comprise, for example, RGD peptides, collagen, fibronectin, gelatin, and collagen. Further discussion of cell adhesion molecules can be found, for example, in Lih et al. Progress in Polymer Science 44:28-61 (2015) and Chen et al. Materials Today (2017). These are incorporated herein by reference in their entirety.

[0071] In some embodiments of any of the above aspects, the cell-adherent polyelectrolyte comprises hyaluronic acid, poly(allylamine) hydrochloride, and / or hyaluronic acid modified to include aldehyde groups.

[0072] Ligands for certain cell surface receptors and / or for targeting monocytes or macrophages are known in the art and may include natural or synthetic ligands. Exemplary ligands for macrophages and / or monocytes may include, by way of non-limiting example, IL-4; CX3CL1; IL-17A; IL-17F; M-CSF; GM-CSF; LDL; ApoE; IL-2; IFN-γ; Hsp60; Hsp70; complement C5A; leukotriene B4; CCL2; CCL4; CCL3; CCL5; CCL7; CCL8; CXCL8; CXCL9; CXCL10; and / or CXCL11. In some embodiments of any of the above aspects, the monocyte targeting ligand and / or macrophage targeting ligand is an IgG, an antibody (e.g., an antibody specific for a molecule (e.g., a receptor) on the cell surface of a monocyte or macrophage), a polypeptide, or an aptamer.

[0073] In some embodiments of any of the above aspects, the cell adhesion molecule may be specific to one or more cell types, such as macrophages and / or monocytes. However, the particles can adhere to isolated cell populations in vitro, and therefore such specificity is not required in all embodiments. In some embodiments of any of the above aspects, the cell adhesion molecule is not specific to a particular cell type.

[0074] In some embodiments of any of the above aspects, the region comprising at least one cell adhesion molecule comprises one type of cell adhesion molecule. In some embodiments of any of the above aspects, the region comprising at least one cell adhesion molecule comprises two or more types of cell adhesion molecules, e.g., two cell adhesion polyelectrolytes and / or one cell adhesion polyelectrolyte and one immunoglobulin.

[0075] In some embodiments of any of the above aspects, the cell adhesion molecule comprises one or more of a cell adhesion polyelectrolyte, an immunoglobulin, or a ligand for a receptor on the cell surface.

[0076] In some embodiments of any of the preceding aspects, the cell-attaching polyelectrolyte comprises one or more of hyaluronic acid (HA), methylacrylated HA, hyaluronic acid-aldehyde, bovine serum albumin (BSA), PEG, PEG dimethylacrylate, and / or poly(allylamine) hydrochloride (PAH). In some embodiments of any of the preceding aspects, the hyaluronic acid is modified to include an aldehyde group. In some embodiments of any of the preceding aspects, the cell-attaching polyelectrolyte comprises one or more of hyaluronic acid (HA), methylacrylated HA, and hyaluronic acid-aldehyde; and one or more of PEG and PEG dimethylacrylate. In some embodiments of any of the preceding aspects, the cell-attaching polyelectrolyte comprises one or more of hyaluronic acid (HA) and methylacrylated HA; and one or more of PEG and PEG dimethylacrylate. In some embodiments of any of the preceding aspects, the cell-attaching polyelectrolyte comprises HA and PEG. In some embodiments of any of the above aspects, the cell adhesion polyelectrolyte comprises methyl acrylated HA and dimethyl acrylated PEG.

[0077] In some embodiments of any of the preceding aspects, the hydrogel backpack comprises, consists of, or consists essentially of a single polymer region or layer, the region or layer comprising a) one or more hydrogels of one or more cell adhesion molecules, b) one or more binding reagents, and c) one or more MRI contrast reagents. In some embodiments of any of the preceding aspects, the hydrogel backpack comprises, consists of, or consists essentially of a single polymer region or layer, the region or layer comprising a) one or more hydrogels of one or more cell adhesion molecules, and b) one or more MRI contrast reagents. In some embodiments of any of the preceding aspects, the one or more cell adhesion molecules comprise, consist essentially of, or consist of hyaluronic acid (HA), methyl acrylated HA, PEG, dimethyl PEG acrylate, and combinations thereof. In some embodiments of any of the preceding aspects, the one or more cell adhesion molecules comprise, consist essentially of, or consist of methyl acrylated HA and dimethyl PEG acrylate. In some embodiments of any of the above aspects, the hydrogel backpack comprises, consists of, or consists essentially of a single polymeric region or layer, the region or layer comprising: a) a hydrogel of methylacrylated HA and dimethylacrylate PEG, and b) one or more methacrylated MRI contrast agents.

[0078] A two-layer backpack includes at least two distinct regions or layers. In an uncoated two-layer backpack, the layers are stacked and substantially parallel to each other. An uncoated two-layer backpack can be created, for example, by stamping each layer in succession. In a coated two-layer backpack, the second layer (applied last) wraps around the side of the backpack so that only one side of the first layer is exposed to the outside environment. In a coated two-layer backpack, the side of the first or bottom layer can be partially or completely coated, but the side of the first or bottom layer that is most distal from the other layer is not coated. A coated two-layer backpack can be created, for example, by stamping the first layer and then spin-coating the second layer.

[0079] In some embodiments of any of the above aspects, the polymer particle comprises a) a first region comprising one or more binding reagents and one or more cell adhesion molecules (e.g., polyelectrolytes), and b) a second region comprising one or more structural polymers and, optionally, one or more binding reagents. In some embodiments of any of the above aspects, the polymer particle comprises a) a first region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) and, optionally, one or more binding reagents, and b) a second region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) and, optionally, one or more binding reagents. In some embodiments of any of the above aspects, the polymer particle comprises a) a first region comprising a hydrogel of one or more structural polymers; and b) a second region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) and, optionally, one or more binding reagents. In some embodiments of any of the above aspects, the polymer particle comprises: a) a first region comprising a hydrogel of one or more structural polymers; and b) a second region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) and one or more binding reagents.

[0080] In some embodiments of any of the above aspects, the first cell adhesion molecule is hyaluronic acid (HA), methyl acrylated HA, hyaluronic acid-aldehyde, or bovine serum albumin (BSA), the second cell adhesion molecule is poly(allylamine) hydrochloride (PAH), and the structural polymer is one or more of poly(lactic-co-glycolic acid) (PLGA), PLGA-PEG, PLGA-PEG-maleimide, or PLGA-PEG-biotin. In some embodiments of any of the above aspects, the cell adhesion molecule is hyaluronic acid (HA), methyl acrylated HA, hyaluronic acid-aldehyde, or bovine serum albumin (BSA), the second cell adhesion molecule is poly(allylamine) hydrochloride (PAH), and the structural polymer is one or more of poly(lactic-co-glycolic acid) (PLGA), PLGA-PEG, PLGA-PEG-maleimide, or PLGA-PEG-biotin. In some embodiments of any of the above aspects, the PLGA structural polymer is a combination of PLGA and poly(D,L-lactide-co-glycolide); a combination of PLGA and acid terminated poly(D,L-lactide-co-glycolide); or a 50:50 molar ratio combination of PLGA and poly(D,L-lactide-co-glycolide).

[0081] In some embodiments of any of the preceding aspects, the bi-layer backpack comprises a first layer of HA and a second layer of PAH. In some embodiments of any of the preceding aspects, the bi-layer backpack comprises a first layer of HA and a second layer of PLGA hydrogel. In some embodiments of any of the preceding aspects, the bi-layer backpack comprises a first layer of BSA and a second layer of PAH. In some embodiments of any of the preceding aspects, the bi-layer backpack comprises a first layer of BSA and a second layer of PLGA hydrogel.

[0082] A sandwich backpack includes at least three distinct regions or layers. In an uncoated sandwich backpack, the layers are stacked and substantially parallel to each other such that the first and third layers do not contact each other. An uncoated sandwich backpack can be created, for example, by stamping each layer in succession. In a coated sandwich backpack, the third layer (applied last) wraps around the side of the backpack such that in the cross section of the backpack, the furthest edge of the third layer (applied last) at least partially contacts the edge of the first layer. In a coated sandwich backpack, the second, or middle, layer may be partially coated or completely coated. In a coated sandwich backpack, the side of the first, or bottom layer may be partially coated or completely coated, but the face of the first, or bottom layer that is most distal from the other layers is not coated. A coated sandwich backpack can be created, for example, by stamping the first and second layers in succession and then spin coating the third layer.

[0083] In some embodiments of any of the above aspects, the second region is disposed between the first region and the third region, and / or the second region separates the first region and the third region from one another.

[0084] In some embodiments of any of the above aspects, the polymer particle comprises a) a first region comprising one or more binding reagents and one or more cell adhesion molecules (e.g., polyelectrolytes), and b) a second region comprising one or more structural polymers.

[0085] In some embodiments of any of the above aspects, the polymer particle comprises: a) a first region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) and, optionally, one or more binding reagents; b) a second region comprising one or more structural polymers; and c) a third region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) and, optionally, one or more binding reagents.

[0086] In some embodiments of any of the above aspects, the polymer particle comprises a) a first region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) and, optionally, one or more binding reagents; b) a second region comprising one or more cell adhesion molecules (e.g., polyelectrolytes); and b) a third region comprising one or more structural polymers and, optionally, one or more binding reagents. In some embodiments of any of the above aspects, the polymer particle comprises a) a first region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) and one or more binding reagents; b) a second region comprising one or more cell adhesion molecules (e.g., polyelectrolytes); and b) a third region comprising one or more structural polymers and one or more binding reagents. In some embodiments of any of the above aspects, the polymer particle comprises a) a first region comprising one or more cell adhesion molecules (e.g., polyelectrolytes); b) a second region comprising one or more cell adhesion molecules (e.g., polyelectrolytes); and b) a third region comprising one or more structural polymers and one or more binding reagents. In some embodiments of any of the above aspects, the polymer particle comprises a) a first region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) and one or more binding reagents; b) a second region comprising one or more cell adhesion molecules (e.g., polyelectrolytes); and b) a third region comprising one or more structural polymers.

[0087] In some embodiments of any of the above aspects, the polymer particle comprises a) a first region comprising a first cell adhesion molecule (e.g., polyelectrolyte); b) a second region comprising a second cell adhesion molecule (e.g., polyelectrolyte); and c) a third region comprising one or more structural polymers and, optionally, one or more binding reagents. In some embodiments of any of the above aspects, the polymer particle comprises a) a first region comprising a first cell adhesion molecule (e.g., polyelectrolyte); b) a second region comprising a second cell adhesion molecule (e.g., polyelectrolyte); and c) a third region comprising one or more structural polymers and one or more binding reagents.

[0088] In some embodiments of any of the above aspects, the third region comprises one or more binding reagents and the first region does not comprise one or more binding reagents.

[0089] When the polymer particle comprises two or more regions / layers, each of which comprises a cell adhesion molecule, these regions / layers may comprise the same or different cell adhesion molecules.

[0090] In some embodiments of any of the preceding aspects, the sandwich backpack comprises a first layer of HA, a second layer of PAH, and a third layer of PLGA (e.g., the LbL HA-PAH design of Example 2). In some embodiments of any of the preceding aspects, the sandwich backpack comprises a first layer of HA, a second layer of PAH, and a third layer of PLGA hydrogel. In some embodiments of any of the preceding aspects, the sandwich backpack comprises a first layer of BSA, a second layer of PAH, and a third layer of PLGA hydrogel (e.g., the LbL BSA-PAH design of Example 2). In some embodiments of any of the preceding aspects, the sandwich backpack comprises a first layer of BSA, a second layer of PAH, and a third layer of PLGA hydrogel.

[0091] In some embodiments of any of the above aspects, the polymer particle comprises: a) a first region comprising one or more cell adhesion molecules (e.g., polyelectrolytes); b) a second region comprising one or more cell adhesion molecules (e.g., polyelectrolytes); and b) a third region comprising one or more structural polymers, wherein the first cell adhesion molecule is hyaluronic acid (HA), methylacrylated HA, hyaluronic acid-aldehyde, or bovine serum albumin (BSA), the second cell adhesion molecule is poly(allylamine) hydrochloride (PAH), and the structural polymer is one or more of poly(lactic-co-glycolic acid) (PLGA), PLGA-PEG, PLGA-PEG-maleimide, or PLGA-PEG-biotin.

[0092] In some embodiments of any of the above aspects, the polymer particle comprises: a) a first region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) comprising streptavidin molecules; b) a second region comprising one or more cell adhesion molecules (e.g., polyelectrolytes); and b) a third region comprising one or more structural polymers, wherein the first cell adhesion molecule is hyaluronic acid (HA), methylacrylated HA, hyaluronic acid-aldehyde, or bovine serum albumin (BSA), the second cell adhesion molecule is poly(allylamine) hydrochloride (PAH), and the structural polymer is one or more of poly(lactic-co-glycolic acid) (PLGA), PLGA-PEG, PLGA-PEG-maleimide, or PLGA-PEG-biotin. In some embodiments of any of the above aspects, the polymer particle comprises: a) a first region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) comprising streptavidin molecules conjugated to a biotinylated binding reagent; b) a second region comprising one or more cell adhesion molecules (e.g., polyelectrolytes); and b) a third region comprising one or more structural polymers, wherein the first cell adhesion molecule is hyaluronic acid (HA), methylacrylated HA, hyaluronic acid-aldehyde, or bovine serum albumin (BSA), the second cell adhesion molecule is poly(allylamine) hydrochloride (PAH), and the structural polymer is one or more of poly(lactic-co-glycolic acid) (PLGA), PLGA-PEG, PLGA-PEG-maleimide, or PLGA-PEG-biotin. In some embodiments of any of the above aspects, the PLGA structural polymer is a combination of PLGA and poly(D,L-lactide-co-glycolide); a combination of PLGA and acid terminated poly(D,L-lactide-co-glycolide); or a 50:50 molar ratio combination of PLGA and poly(D,L-lactide-co-glycolide).

[0093] In some embodiments of any of the above aspects, the polymer particle comprises: a) a first region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) covalently conjugated to one or more binding reagents; b) a second region comprising one or more cell adhesion molecules (e.g., polyelectrolytes); and b) a third region comprising one or more structural polymers, wherein the first cell adhesion molecule is hyaluronic acid (HA), methylacrylated HA, hyaluronic acid-aldehyde, or bovine serum albumin (BSA), the second cell adhesion molecule is poly(allylamine) hydrochloride (PAH), and the structural polymer is one or more of poly(lactic-co-glycolic acid) (PLGA), PLGA-PEG, PLGA-PEG-maleimide, or PLGA-PEG-biotin. In some embodiments of any of the above aspects, the PLGA structural polymer is a combination of PLGA and poly(D,L-lactide-co-glycolide); a combination of PLGA and acid terminated poly(D,L-lactide-co-glycolide); or a 50:50 molar ratio combination of PLGA and poly(D,L-lactide-co-glycolide).

[0094] In some embodiments of any of the above aspects, the polymer particle comprises: a) a first region comprising one or more structural polymers and, optionally, one or more binding reagents; b) a second region comprising one or more structural polymers; and c) a third region comprising one or more structural polymers and, optionally, one or more binding reagents. In some embodiments of any of the above aspects, the polymer particle comprises: a) a first region comprising PLGA and, optionally, one or more binding reagents; b) a second region comprising PVA; and c) a third region comprising PLGA and, optionally, one or more binding reagents.

[0095] In some embodiments of any of the preceding aspects, the second region comprises PVA. In some embodiments of any of the preceding aspects, the second region consists essentially of PVA and a payload reagent. In some embodiments of any of the preceding aspects, the PVA is present at a concentration of less than 1% by weight. In some embodiments of any of the preceding aspects, the PVA is present at a concentration of 0.5% by weight or less.

[0096] In some embodiments of any of the preceding aspects, the first selected structural polymer(s) comprise PLGA, the second selected structural polymer(s) comprise PVA, and the third selected structural polymer(s) comprise PLGA. In some embodiments of any of the preceding aspects, the first selected structural polymer(s) consist of PLGA, the second selected structural polymer(s) consist of PVA, and the third selected structural polymer(s) consist of PLGA.

[0097] In some embodiments of any of the preceding aspects, the region comprising the structural polymer is, or is formed using, an approximately 5-20% by weight solution of the structural polymer. In some embodiments of any of the preceding aspects, the region comprising the structural polymer is, or is formed using, a 5-20% by weight solution of the structural polymer. In some embodiments of any of the preceding aspects, the region comprising the structural polymer is, or is formed using, an approximately 1-20% by weight solution of the structural polymer. In some embodiments of any of the preceding aspects, the region comprising the structural polymer is, or is formed using, a 1-20% by weight solution of the structural polymer. In some embodiments of any of the preceding aspects, the region comprising the structural polymer is, or is formed using, an approximately 8-12% by weight solution of the structural polymer. In some embodiments of any of the preceding aspects, the region comprising the structural polymer is, or is formed using, an 8-12% by weight solution of the structural polymer.

[0098] In some embodiments of any of the above aspects, the region comprising the structural polymer is, or is formed with, about a 10% by weight solution of the structural polymer. In some embodiments of any of the above aspects, the region comprising the structural polymer is, or is formed with, a 10% by weight solution of the structural polymer.

[0099] The discoid particles exhibited favorable characteristics, e.g., favorable characteristics for retention on the cell surface without altering cell behavior. In some embodiments of any of the above aspects, the polymer particles are substantially discoid in shape. In some embodiments of any of the above aspects, the polymer particles are substantially discoid in shape. As used herein, "discoid" refers to particles having a disk-like shape with substantially flat, concave, or convex faces.

[0100] In some embodiments of any of the above aspects, the polymer particles described herein have a disk-like shape, and the diameter of the circular surface is about 4 to about 35 times the size of the particle height (e.g., or depth). In some embodiments of any of the above aspects, the polymer particles described herein have a disk-like shape, and the diameter of the circular surface is about 4 to about 35 times the size of the particle height. In some embodiments of any of the above aspects, the polymer particles described herein have a disk-like shape, and the diameter of the circular surface is about 10 to about 35 times the size of the particle height (e.g., or depth). In some embodiments of any of the above aspects, the polymer particles described herein have a disk-like shape, and the diameter of the circular surface is about 10 to 35 times the size of the particle height. In some embodiments of any of the above aspects, the polymer particles described herein have a disk-like shape, and the diameter of the circular surface is about 18 to about 26 times the size of the particle height. In some embodiments of any of the above aspects, the polymer particles described herein have a disk-like shape, and the diameter of the circular surface is about 18 to 26 times the size of the particle height.

[0101] In some embodiments of any of the above aspects, the substantially disc-shaped particle has two substantially opposed and circular faces, each of which has a diameter at least 10 times the height (e.g., depth) of the particle. In some embodiments of any of the above aspects, the widest diameter of the substantially circular face is no more than 150% of the shortest diameter of that face.

[0102] In some embodiments of any of the above aspects, the polymer particles have the shape of a rod, a cylinder, a cube, a rectangular prism, a hexahedron, or a pyramid.

[0103] In some embodiments of any of the above aspects, the diameter of the polymer particles is about 50 nm to about 20 μm. In some embodiments of any of the above aspects, the diameter of the polymer particles is 50 nm to 20 μm. In some embodiments of any of the above aspects, the diameter of the polymer particles is about 100 nm to about 10 μm. In some embodiments of any of the above aspects, the diameter of the polymer particles is 100 nm to 10 μm. In some embodiments of any of the above aspects, the diameter of the polymer particles is about 1 μm to about 10 μm. In some embodiments of any of the above aspects, the diameter of the polymer particles is 1 μm to 10 μm.

[0104] In some embodiments of any of the above aspects, the polymer particles are about 3 μm×150 nm in size to about 12 μm×500 nm in size. In some embodiments of any of the above aspects, the polymer particles are about 3 μm×150 nm in size to about 12 μm×500 nm in size. In some embodiments of any of the above aspects, the polymer particles are about 6 μm×500 nm in size. In some embodiments of any of the above aspects, the polymer particles are 6 μm×500 nm in size. In some embodiments of any of the above aspects, the polymer particles are about 6 μm×250 nm in size. In some embodiments of any of the above aspects, the polymer particles are 6 μm×250 nm in size.

[0105] In some embodiments of any of the above aspects, the polymer particles are about 0.5-5 μm×5-15 μm in size. In some embodiments of any of the above aspects, the polymer particles are about 0.5-5 μm×5-15 μm in size. In some embodiments of any of the above aspects, the polymer particles are about 1-2 μm×7-9 μm in size. In some embodiments of any of the above aspects, the polymer particles are about 1-2 μm×7-9 μm in size. In some embodiments of any of the above aspects, the polymer particles are about 1.5 μm×8 μm in size.

[0106] In some embodiments of any of the above aspects, the region can be a layer. In some embodiments of any of the above aspects, the region can be a surface of the disk-shaped form of the particle. In some embodiments of any of the above aspects, the region can be an interior space (or a portion thereof) of the disk-shaped form of the particle.

[0107] The binding reagents described herein may be attached or conjugated to one or more components of the polymer particle by any method known in the art, for example, by direct chemical bonding or via a linker molecule. The term "conjugate" refers to two or more molecular structures linked by direct or indirect covalent or non-covalent bonds. Non-covalent interactions include, but are not limited to, electrostatic interactions, hydrogen bonding interactions, van der Waals interactions, dipole-dipole interactions, π-π stacking, magnetic interactions, and metal coordination. Preferably, the conjugate is a covalent conjugate.

[0108] The linker may be homobifunctional or heterobifunctional. In some cases, a combination of homobifunctional and heterobifunctional linkers is used. Examples of homobifunctional linkers include adipic acid dihydrazide, amino acids such as glycine, aldehydes such as ethanedial, pyruvaldehyde, 2-formyl-malonaldehyde, glutaraldehyde, adipaldehyde, heptanedial, octadialdehyde; Diglycidyl ethers, diols such as 1,2-ethanediol, 1,3-propanediol, 1,4-butanediol, 2,3-butanediol, 1,5-pentanediol, benzene-1,4-diol, 1,6-hexanediol, tetra(ethylene glycol)diol), PEG, dithiols such as 1,2-ethanedithiol, 1,3-propanedithiol, 1,4-butanedithiol, 2,3-butanedithiol, 1,5-pentanedithiol, benzene-1,4-dithiol, 1,6-hexanedithiol Examples of linkers include, but are not limited to, tetra(ethylene glycol)dithiol, diamines such as ethylenediamine, propane-1,2-diamine, propane-1,3-diamine, N-methylethylenediamine, N,N'-dimethylethylenediamine, pentane-1,5-diamine, hexane-1,6-diamine, spermine and spermidine, divinyl adipate, divinyl sebacate, diamine-terminated PEG, double ester PEG-N-hydroxysuccinimide, and diisocyanate-terminated PEG. In a preferred embodiment, the homobifunctional linker is adipic acid dihydrazide.Examples of heterobifunctional linkers include, but are not limited to, epichlorohydrin, S-acetylthioglycolic acid N-hydroxysuccinimide ester, 5-azido-2-nitrobenzoic acid N-hydroxysuccinimide ester, 4-azidophenacyl bromide, bromoacetic acid N-hydroxysuccinimide ester, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, iodoacetic acid N-hydroxysuccinimide ester, 4-(Nmmaleimido)benzophenone 3-(2-pyridyldithio)propionic acid N-hydroxysuccinimide ester 3-maleimidobenzoic acid N-hydroxysuccinimide ester, N,N′-cystamine-bis-acrylamide, N,N′-methylene-bis-acrylamide, and N,N′-ethylene-bis-acrylamide.

[0109] One way of attaching or conjugating the binding reagent is via streptavidin-biotin linkage. In some embodiments of any of the above aspects, the binding reagent further comprises a streptavidin molecule. In some embodiments of any of the above aspects, the binding reagent further comprises a streptavidin molecule and one or more other components of the polymer particle comprise a biotin molecule. In some embodiments of any of the above aspects, the binding reagent further comprises a biotin molecule. In some embodiments of any of the above aspects, the binding reagent further comprises a biotin molecule and one or more other components of the polymer particle comprise a streptavidin molecule.

[0110] In some embodiments of any of the preceding aspects, the biotin and / or streptavidin-containing polymer particle component may be one or more structural polymers. In some embodiments of any of the preceding aspects, the biotin-containing polymer particle component may be one or more structural polymers. In some embodiments of any of the preceding aspects, the biotin and / or streptavidin-containing polymer particle structural polymer may be PLGA-PEG. In some embodiments of any of the preceding aspects, the biotin-containing polymer particle structural polymer may be PLGA-PEG-biotin. In some embodiments of any of the preceding aspects, the polymer particle comprises a binding reagent coupled to the structural polymer via a streptavidin-biotin linkage. In some embodiments of any of the preceding aspects, the polymer particle comprises a binding reagent coupled to the PLGA-PEG via a streptavidin-biotin linkage.

[0111] One way to attach or conjugate the binding reagent is via linkage to a maleimide via DTT catalysis. In some embodiments of any of the above aspects, the binding reagent further comprises a maleimide molecule. In some embodiments of any of the above aspects, one or more other components of the polymer particle other than the binding reagent comprise a maleimide molecule. In some embodiments of any of the above aspects, the component of the polymer particle that comprises the maleimide molecule may be one or more structural polymers. In some embodiments of any of the above aspects, the structural polymer of the polymer particle that comprises the maleimide may be PLGA-PEG. In some embodiments of any of the above aspects, the polymer particle comprises a binding reagent that is coupled to a structural polymer that comprises a maleimide molecule via DTT catalysis. In some embodiments of any of the above aspects, the polymer particle comprises a binding reagent that is coupled to a PLGA-PEG-maleimide via DTT catalysis.

[0112] In some embodiments of any of the above aspects, the polymer particles described herein may further comprise one or more imaging agents. As used herein, "imaging agent" refers to an element, functional group, or molecule that allows for its detection and / or imaging. The imaging agent may be an echogenic substance (either liquid or gaseous), a non-metallic isotope, an optical reporter, a boron neutron absorber, a paramagnetic metal ion, a ferromagnetic metal, a gamma-emitting radioisotope, a positron-emitting radioisotope, or an X-ray absorber. In some embodiments of any of the above aspects, the imaging agent may be a contrast agent. As used herein, the term "contrast agent" refers to any molecule that alters the optical properties of a tissue or organ that contains the molecule. Optical properties that can be altered include, but are not limited to, absorbance, reflectance, fluorescence, birefringence, optical scattering, and the like. In some embodiments, a detectable label also includes any imaging agent that can facilitate imaging or visualization of a tissue or organ in a subject, such as, but not limited to, bubbles, liposomes, spheres, contrast agents, or any of the detectable labels described herein.

[0113] Suitable optical reporters include, but are not limited to, fluorescent reporters and chemiluminescent groups.A wide variety of fluorescent reporter dyes are known in the art.Typically, fluorophores are aromatic or heteroaromatic compounds, and can be pyrene, anthracene, naphthalene, acridine, stilbene, indole, benzindole, oxazole, thiazole, benzothiazole, cyanine, carbocyanine, salicylate, anthranilate, coumarin, fluorescein, rhodamine, or other similar compounds.

[0114] Exemplary fluorophores include 1,5 IAEDANS; 1,8-ANS; 4-methylumbelliferone; 5-carboxy-2,7-dichlorofluorescein; 5-carboxyfluorescein (5-FAM); 5-carboxynaphthofluorescein (pH10); 5-carboxytetramethylrhodamine (5-TAMRA); 5-FAM (5-carboxyfluorescein); 5-hydroxytryptamine (HAT); 5-ROX (carboxy-X-rhodamine); 5-TAMRA (5-carboxytetramethylrhodamine); 6-carboxyrhodamine 6G; 6-CR 6G; 6-JOE; 7-amino-4-methylcoumarin; 7-aminoactimycin D (7-AAD); 7-hydroxy-4-methylcoumarin; 9-amino-6-chloro-2-methoxyacridine; ABQ; acid fuchsin; ACMA (9-amino-6-chloro-2-methoxyacridine); Acridine Orange; Acridine Red; Acridine Yellow; Acriflavine; Acriflavine Feulgen SITSA; Aequorin (photoprotein); Alexa Fluor 350 (trademark); Alexa Fluor 430 (trademark); Alexa Fluor 488 (trademark); Alexa Fluor 532 (trademark); Alexa Fluor 546 (trademark); Alexa Fluor 568 (trademark); Alexa Fluor 594 (trademark); Alexa Fluor 633 (trademark); Alexa Fluor 647 (trademark); Alexa Fluor 660 (trademark); Alexa Fluor 680 (trademark); Alizarin Complexone; Alizarin Red; Allophycocyanin (APC); AMC, AMCA-S; AMCA (aminomethylcoumarin); AMCA-X; Aminoactimycin D; Aminocoumarin; Aniline Blue; Anthrocyl stearate; APC-Cy7; APTS; Astrazon Brilliant Red 4G; Astrazon Orange R; Astrazon Red 6B; Astrazon Yellow 7 GLL; Atabrine; ATTO-TAG(TM) CBQCA; ATTO-TAG(TM) FQ; Auramine;Aurophosphine G; Aurophosphine; BAO 9 (Bisaminophenyloxadiazole); BCECF (high pH); BCECF (low pH); Berberine sulfate; β-lactamase; BFP blue-shifted GFP (Y66H); BG-647; Bimane; Bisbenzamide; Blancophor FFG; Blancophor SV; BOBO™-1; BOBO™-3; Bodipy 492 / 515; Bodipy 493 / 503; Bodipy 500 / 510; Bodipy 505 / 515; Bodipy 530 / 550; Bodipy 542 / 563; Bodipy 558 / 568; Bodipy 564 / 570; Bodipy 576 / 589; Bodipy 581 / 591; Bodipy 630 / 650-X; Bodipy 650 / 665-X; Bodipy 665 / 676; Bodipy Fl; Bodipy FL ATP; Bodipy Fl-Ceramide; Bodipy R6G SE; Bodipy TMR; Bodipy TMR-X Conjugate; Bodipy TMR-X, SE; Bodipy TR; Bodipy TR ATP; Bodipy TR-X SE; BO-PRO™-1; BO-PRO™-3; Brilliant Sulphoflavin FF; Calcein; Calcein Blue; Calcium Crimson™; Calcium Green; Calcium Green-1 Ca; 2+ Dye; Calcium Green-2 Ca 2+ Calcium Green-5N Ca 2+ Calcium Green-C18 Ca 2+; Calcium Orange; Calcofluor White; Carboxy-X-Rhodamine (5-ROX); Cascade Blue™; Cascade Yellow; Catecholamine; CFDA; CFP-Cyan Fluorescent Protein; Chlorophyll; Chromomycin A; Chromomycin A; CMFDA; Coelenterazine; Coelenterazine cp; Coelenterazine f; Coelenterazine fcp; Coelenterazine h; Coelenterazine hcp; Coelenterazine ip; Coelenterazine O; Coumarin phalloidin; CPM methylcoumarin; CTC; Cy2™; Cy3.1 8; Cy3.5™; Cy3™; Cy5.1 8; Cy5.5™; Cy5™; Cy7™; Cyan GFP; cyclic AMP Fluorosensor (FiCRhR); d2; Dabsyl; Dansyl; Dansylamine; Dansylcadaverine; Dansyl chloride; Dansyl DHPE; Dansyl fluoride; DAPI; Dapoxyl; Dapoxyl 2; Dapoxyl 3; DCFDA; DCFH (dichlorodihydrofluorescein diacetate); DDAO; DHR (dihydrorhodamine 123); Di-4-ANEPPS; Di-8-ANEPPS (non-ratio); DiA (4-Di-16-ASP); DIDS; dihydrorhodamine 123 (DHR); DiO (DiOC18 (3)); DiR; DiR (DiIC18 (7)); dopamine; DsRed; DTAF; DY-630-NHS; DY-635-NHS; EBFP; ECFP; EGFP; ELF97; Eosin; Erythrosine; Erythrosine ITC; Ethidium homodimer-1 (EthD-1); Euchrysin; Europium(III) chloride; Europium; EYFP; Fast Blue; FDA; Feulgen (pararosaniline); FITC; FL-645; Flazo Orange; Fluo-3; Fluo-4; Fluorescein diacetate; Fluoro-Emerald; Fluoro-gold (hydroxystilbamidine); Fluor-Ruby;FluorX; FM 1-43™; FM 4-46; Fura Red™ (high pH); Fura-2, high calcium; Fura-2, low calcium; Genacryl Brilliant Red B; Genacryl Brilliant Yellow 10GF; Genacryl Pink 3G; Genacryl Yellow 5GF; GFP (S65T); GFP redshift (rsGFP); GFP wild type, non-UV excited (wtGFP); GFP wild type, UV excited (wtGFP); GFPuv; Gloxalic Acid; Granular Blue; Hematoporphyrin; Hoechst 33258; Hoechst 33342; Hoechst 34580; HPTS; Hydroxycoumarin; Hydroxystilbamidine (FluoroGold); Hydroxytryptamine; Indodicarbocyanine (DiD); Indotricarbocyanine (DiR); Intrawhite Cf; JC-1; JO-JO-1; JO-PRO-1; LaserPro; Laurodan; LDS 751; Leucophor PAF; Leucophor SF; Leucophor WS; Lissamine Rhodamine; Lissamine Rhodamine B; LOLO-1; LO-PRO-1; Lucifer Yellow; Mag Green; Magdala Red (Phloxine B); Magnesium Green; Magnesium Orange; Malachite Green; Marina Blue; Maxilon Brilliant Flavin 10 GFF; Maxillon Brilliant Flavin 8 GFF; Merocyanine; Methoxycoumarin; Mitotracker Green FM; Mitotracker Orange; Mitotracker Red;Mithramycin; Monobromobimane; Monobromobimane (mBBr-GSH); Monochlorobimane; MPS (Methyl Green Pyronine Stilbene); NBD; NBD-amine; Nile Red; Nitrobenzoxadidole; Noradrenaline; Nuclear Fast Red; Nuclear Yellow; Nylosan Brilliant Iavin E8G; Oregon Green (trademark); Oregon Green 488-X; Oregon Green (trademark) 488; Oregon Green (trademark) 500; Oregon Green (trademark) 514; Pacific Blue; Pararosaniline (Feulgen); PE-Cy5; PE-Cy7; PerCP; PerCP-Cy5.5; PE-Texas Red (Red 613); Phloxine B (Magdala Red); Phorwite AR; Phorwite BKL; Phorwite Rev; Phorwite RPA; Phosphine 3R; Photoresist; Phycoerythrin B [PE]; Phycoerythrin R [PE]; PKH26; PKH67; PMIA; Pontochrome Blue Black; POPO-1; POPO-3; PO-PRO-1; PO-PRO-3; Primulin; Procion Yellow; Propidium Iodid (PI); PyMPO; Pyrene; Pyronine; Pyronine B; Pyrozal Brilliant Flavin 7GF; QSY7; Quinacrine Mustard; Resorufin; RH414; Rhod-2; Rhodamine; Rhodamine 110; Rhodamine 123; Rhodamine 5 GLD; Rhodamine 6G; Rhodamine B 540; Rhodamine B 200; Rhodamine B extra; Rhodamine BB; Rhodamine BG; Rhodamine Green; Rhodamine Phallicidine; Rhodamine Phalloidin; Rhodamine Red; Rhodamine WT; Rose Bengal;R-Phycoerythrin (PE); Redshifted GFP (rsGFP, S65T); S65A; S65C; S65L; S65T; Sapphire GFP; Serotonin; Sevron Brilliant Red 2B; Sevron Brilliant Red 4G; Sevron Brilliant Red B; Sevron Orange; Sevron Yellow L; sgBFP™; sgBFP™ (Superglow BFP); sgGFP™; sgGFP™ (Superglow GFP); SITS; SITS (Primulin); SITS (Stilbene Isothiosulphonic Acid); SPQ (6-Methoxy-N-(3-Sulfopropyl)-quinolinium); Stilbene; Sulphorhodamine B can C; Sulphorhodamine G Extra; Tetracycline; Tetramethylrhodamine; Texas Red™; Texas Red-X™ conjugate; Thiadicarbocyanine (DiSC3); Thiazine Red R; Thiazole Orange; Thioflavin 5; Thioflavin S; Thioflavin TCN; Thiolyte; Thiozole Orange; Tinopol CBS (calcofluor white); TMR; TO-PRO-1; TO-PRO-3; TO-PRO-5; TOTO-1; TOTO-3; TriColor (PE-Cy5); TRITC (tetramethylrhodamine isothiocyanate); True Blue; TruRed; Ultralite; Uranine B; Ubitex SFC; wtGFP; WW781; XL665; X-Rhodamine; XRITC; Xylene Orange; Y66F; Y66H; Y66W; Yellow GFP; YFP; YO-PRO-1; YO-PRO-3; YOYO-1;and YOYO-3. Many suitable forms of these fluorescent compounds are available and can be used.

[0115] Other exemplary detectable labels include luminescent and bioluminescent markers (e.g., biotin, luciferases (e.g., bacterial, firefly, click beetle, etc.), luciferin, and aequorin), radiolabels (e.g., 3H, 125I, 35S, 14C, or 32P), enzymes (e.g., galactosidase, glucorinidase, phosphatases (e.g., alkaline phosphatase), peroxidases (e.g., horseradish peroxidase), and cholinesterase), and calorimetric labels, such as colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, and latex) beads. Patents disclosing the use of such labels include U.S. Pat. Nos. 3,817,837, 3,850,752, 3,939,350, 3,996,345, 4,277,437, 4,275,149, and 4,366,241, each of which is incorporated herein by reference.

[0116] Suitable echogenic gases include, but are not limited to, sulfur hexafluoride or perfluorocarbon gases, such as perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluropentane, or perfluorohexane. Suitable non-metallic isotopes include: 11 C. 14 C. 13 N, 18 F, 123 I, 124 I, and 125 Suitable radioisotopes include, but are not limited to, I. 99 mTc, 95 Tc, 111 In, 62 Cu, 64 Cu, Ga, 68Ga, and 153 Suitable paramagnetic metal ions include, but are not limited to, Gd. Suitable paramagnetic metal ions include, but are not limited to, Gd(III), Dy(III), Fe(III), and Mn(II). Suitable X-ray absorbers include, but are not limited to, Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag, and Ir.

[0117] In some embodiments, the radionuclide is conjugated to a chelator or chelator-linker attached to the heme-binding molecule and / or composition. Radionuclides suitable for direct conjugation include: 18 F, 124 I, 125 I, 131 Suitable radionuclides for use with the chelating agent include, but are not limited to, I, I, and mixtures thereof. 47 Sc, 64 Cu, 67 Cu, 89 Sr, 86 Y, 87 Y, 90 Y, 105 Rh, 111 Ag, 111 In, 117 mSn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, 212 Suitable chelators include, but are not limited to, DOTA, BAD, TETA, DTPA, EDTA, NTA, HDTA, phosphonate analogs thereof, and mixtures thereof. Those skilled in the art are familiar with methods for attaching radionuclides, chelators, and chelator-linkers to molecules such as heme-binding molecules and / or compositions and carrier scaffolds disclosed herein.

[0118] Means for detecting such labels are well known to those of skill in the art. Thus, for example, radiolabels can be detected using photographic film or scintillation counters, fluorescent markers can be detected using photodetectors that detect emitted light, enzymatic labels are typically detected by providing the enzyme with an enzyme substrate and detecting the reaction product produced by the action of the enzyme on the enzyme substrate, and calorimetric labels can be detected by visualizing a colored label. Exemplary methods for in vivo detection or imaging of a detectable label include, but are not limited to, x-radiography, magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT, or less commonly, SPET), scintigraphy, ultrasound, CAT scan, photoacoustic imaging, thermography, linear tomography, poly tomography, sonography, orthopantomography (OPT or OPG), and computed tomography (CT) or computed axial tomography (CAT scan).

[0119] The imaging agents may include one or more contrast agents, one or more MRI contrast agents, one or more microbubbles, one or more metal ions, one or more radioisotopes, one or more optical imaging agents, one or more SPECT imaging agents, and one or more PET imaging agents.

[0120] Targeted delivery of MRI contrast agents has proven tricky, as conjugation, encapsulation, or other means for attaching or binding contrast agents to carriers, or targeting moieties often remove or reduce their ability to be detected by MRI.In particular, MRI contrast agents, especially gadolinium-based agents, must remain in contact with water to function as MRI contrast agents, but at the same time must be attached with carriers or targeting moieties.It is demonstrated herein that attaching MRI contrast agents to the present polymer particles can avoid such adverse effects.Therefore, in one aspect of the above embodiment, polymer particles are provided herein that contain at least one MRI contrast agent.

[0121] In some embodiments of any of the above aspects, described herein is a polymer particle that comprises, consists of, or consists essentially of a single polymer region or layer, the region or layer comprising a) one or more hydrogels of one or more cell adhesion molecules, b) one or more binding reagents, c) and one or more MRI contrast reagents.In some embodiments of any of the above aspects, described herein is a polymer particle that comprises, consists of, or consists essentially of a single polymer region or layer, the region or layer comprising a) one or more hydrogels of one or more cell adhesion molecules, and b) one or more MRI contrast reagents.In some embodiments of any of the above aspects, the one or more cell adhesion molecules comprise, consist essentially of, or consist of hyaluronic acid (HA), methyl acrylated HA, PEG, dimethyl PEG acrylate, and combinations thereof. In some embodiments of any of the above aspects, the one or more cell adhesion molecules comprise, consist essentially of, or consist of methylacrylated HA and PEG dimethylacrylate.Described herein, in some embodiments of any of the above aspects, are polymer particles that comprise, consist of, or consist essentially of a single polymer region or layer, the region or layer comprising a) a hydrogel of methylacrylated HA and PEG dimethylacrylate, and b) one or more methacrylated MRI contrast agents.

[0122] The MRI contrast agent may include one or more of gadolinium-based contrast agents, superparamagnetic iron oxide, ultrasmall superparamagnetic iron oxide, superparamagnetic iron-platinum, manganese chelate, iron salts, and perflubron. In some embodiments of any of the above aspects, the gadolinium-based contrast agent may include one or more of gadolinium, gadoxetate, gadobutrol, gadoterate, gadoteridol, gadopentetate, gadobenate, gadopentetate dimeglumine, gadoxetate, gadoversetamide, gadodiamide, gadofosveset, gadocholetic acid, gadomeritol, gadomer 17, and gadoxetic acid.

[0123] Imaging agent can be conjugated or attached to the polymer particle described herein by any method described herein, for example, by any method described herein for conjugating or attaching binding agent.In some embodiments of any of the above aspects, one or more imaging agents further comprise methyl acrylate.In some embodiments of any of the above aspects, one or more imaging agents are methyl acrylate crosslinked with one or more of methyl acrylated HA and dimethyl PEG acrylate.

[0124] In some embodiments of any of the above aspects, the polymer particles described herein may further comprise at least one polarization inducer, e.g., the particles are disposed on the cell surface of a monocyte or macrophage. In some embodiments of any of the above aspects, the cell is a monocytic cell. In some embodiments of any of the above aspects, the cell is a monocytic cell when the polymer particles are attached to the cell (e.g., the cell may differentiate into a macrophage after attachment, either under the influence of the particles or independently of the particles). In some embodiments of any of the above aspects, the cell is a macrophage cell, e.g., an M0, M1, M2, M1 polarized, or M2 polarized macrophage.

[0125] The presence of the polymer particles on the cell surface can direct or modulate the phenotype of the cell, e.g., increase the likelihood, duration, magnitude, or rate of development of N1 / M1 or N2 / M2 phenotypic characteristics, upon contact of the cell with the polarization-inducing agent. In some embodiments of any of the above aspects, macrophages are substantially induced toward an N1 / M1 or N2 / M2 phenotype by attachment of the polymer particles. In some embodiments of any of the above aspects, the phenotype of the macrophages is modulated by release of one or more polarization-inducing agents from the polymer particles, e.g., by induced or uninduced release of cytokines and / or induced or uninduced degradation of the polymer particles.

[0126] M1 or M1 polarized macrophages are also called "killer" macrophages, which promote inflammation and have antitumor activity. M1 or M1 polarized macrophages secrete high levels of IL-12 and low levels of IL-10. M1 macrophages can be characterized, for example, by the expression of CCL3, CCL5, CD80, CCR7, iNOS, and INF-γ. M2 or M2 polarized macrophages are also called "repair" macrophages, which contribute to wound healing and tissue repair. M2 macrophages can suppress the immune system and / or inflammation, for example, by producing high levels of IL-10. M2 polarized macrophages can be characterized, for example, by the expression of CCL22, CD206, CD163, YM1, Fizz1, and arginase 1. Similar phenotypes (N1 and N2) are known for neutrophils.

[0127] A "polarization inducer" as described herein is an agent that, upon contact with macrophages and / or monocytes, alters the likelihood, persistence, magnitude, or rate of development of a particular macrophage phenotype (e.g., either the N1 / M1 phenotype or the N2 / M2 phenotype) compared to the absence of the polarization inducer. A polarization inducer can be an N1 / M1 polarization inducer or an N2 / M2 polarization inducer, e.g., an N1 / M1 polarization inducer increases the likelihood, persistence, or rate of development of the N1 / M1 phenotype, and an N2 / M2 polarization inducer increases the likelihood, persistence, or rate of development of the N2 / M2 phenotype. Exemplary N1 / M1 and N2 / M2 phenotypes are described herein and are well known in the art. Further details can be found, for example, in Mills et al. "M1 / M2 macrophages" Frontiers Media SA (2015) and Kloc "Macrophages: Origin, Function, and Biointervention" Spring (2017), each of which is incorporated herein by reference in its entirety.

[0128] Polarizing inducers for the N1 / M1 and N2 / M2 macrophage phenotypes are known in the art, and non-limiting examples include N1 / M1 polarizing Toll-like receptor (TLR) agonists (e.g., LPS, muramyl dipeptide, or lipoteichoic acid); N1 / M1 polarizing cytokines IFN-γ (e.g., NCBI Gene ID: 3458); TNF (e.g., NCBI Gene ID: 7124); IL-12 (e.g., NCBI Gene IDs: 3592 and 3593); GM-CSF (e.g., NCBI Gene ID: 1438); IL-1β (e.g., NCBI Gene ID: 3553); IL-6 (e.g., NCBI Gene ID: 3569); CD11b (e.g., NCBI Gene ID: 3684) and IL-23 (e.g., NCBI Gene ID: 3696); ID:51561), as well as N2 / M2 polarizing cytokines IL-4 (e.g., NCBI Gene ID:3565); IL-10 (e.g., NCBI Gene ID:3586); glucocorticoids (e.g., cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, and deoxycorticosterone acetate); M-CSF (e.g., NCBI Gene ID:1435), TGF-β (e.g., NCBI Gene ID:7040); IL-6 (e.g., NCBI Gene ID:3569); and IL-13 (e.g., NCBI Gene ID:3596).TLR agonists are known in the art, and may include, by way of non-limiting example, LPS, dsRNA; flagella; bacterial lipoprotein; ssRNA; cpG DNA; bacterial peptidoglycan; profillin; rRNA; imiquimod; resiquimod; IMO-2055; picibanil; monophsophoryl lipid A (MPL); polyribocytidylic acid (poly I:C); CpG-28; MGN1703; glucopyranosyl lipid A; entolimod; and ODN2006. Further details about TLR agonists can be found, for example, in Kaczanowska et al. 2013 J. Leukoc. Biol. 93:847-863, the entire contents of which are incorporated herein by reference. TLR agonists are also commercially available, for example, the TLR1-9 Agonist Kit (catalog no. tlrl-kit1hw; Invitrogen; San Diego, Calif.).

[0129] The polarization inducer may be present in the first region, the second region, a third region forming a layer between the first and second regions, the interior space of the polymer particle, or any combination thereof. In some embodiments of any of the above aspects, the third region may comprise a different structural polymer or mixture of structural polymers than the first and second regions.

[0130] The placement of the polarization inducer may be influenced by whether the polarization inducer effect is to be exerted immediately after particle attachment, or whether it is desirable to induce the polarization inducer effect by controlled degradation of the polymer particles as described herein below. In some embodiments of any of the above aspects, the polarization inducer may be present in the first region. In some embodiments of any of the above aspects, the first region includes the polarization inducer. In some embodiments of any of the above aspects, only the first region includes the polarization inducer.

[0131] In one aspect of any of the above embodiments, described herein is a method of providing or preparing N1 neutrophils and / or M1 macrophages, comprising contacting neutrophils and / or macrophages with a polymer particle described herein. In some embodiments of any of the above aspects, described herein is a method of inducing an N1 / M1 immune response in a subject, comprising administering to the subject an engineered cell composition comprising neutrophils or macrophages and a polymer particle. In some embodiments of any of the above aspects, the polymer particle does not comprise a polarization inducer. In some embodiments of any of the above aspects, the polymer particle comprises an N1 / M1 polarization inducer.

[0132] In one aspect of any of the above embodiments, described herein is a method of providing or preparing N2 neutrophils and / or M2 macrophages, comprising contacting neutrophils and / or macrophages with polymer particles comprising an N2 / M2 polarization inducer. In some embodiments of any of the above aspects, described herein is a method of inducing an N2 / M2 immune response in a subject, comprising administering to the subject an engineered cell composition comprising neutrophils or macrophages and polymer particles comprising an N2 / M2 polarization inducer.

[0133] Embodiments of the particles described herein can be controllably degraded, for example, to control the delivery of a payload (e.g., temporally or spatially) or to regulate the effect of the particle on carrier cells (e.g., monocytes or macrophages). One approach to such controllably degrading is to utilize a particle in which a region comprises a degradable polymer or polymer linker. In some embodiments of any of the above aspects, the region that comprises a degradable polymer or polymer linker is the second region or the third region.

[0134] In some embodiments of any of the above aspects, the degradable polymer or polymer linker is present in a mixture with the structural polymer. In some embodiments of any of the above aspects, the degradable polymer or polymer linker is present in a second region of the polymer particle that is disposed between the first region and the third region, for example, as a layer between the first region and the third region, or in the interior space of the particle.

[0135] In some embodiments of any of the above aspects, the degradable polymer or polymer linker comprises or further comprises a near infrared degradable polymer or near infrared degradable polymer linker. Non-limiting examples of such near infrared degradable materials can include those that contain quinone-methide photolabile groups. These are described in more detail in Fomina et al. J. Am. Chem. Soc. 132:9540-9542, which is incorporated herein by reference in its entirety.

[0136] In some embodiments of any of the above aspects, the polymer particle further comprises one or more cell targeting ligands. The ligands may be located in a first region, a second region, a third region, or multiple regions. In some embodiments of any of the above aspects, the polymer particle further comprises one or more additional cell targeting ligands. In some embodiments of any of the above aspects, the polymer particle further comprises one or more cell targeting ligands in the first region. Such targeting ligands may also act as polarization inducers, or may not affect the phenotype of the cell, but only function to increase the binding affinity and / or specificity of the particle.

[0137] The particles described herein may include a payload reagent, e.g., a therapeutic molecule (e.g., a chemotherapeutic molecule or an anti-inflammatory molecule), an imaging molecule, etc. The payload reagent may act on monocytes or macrophages, or on a second cell / cell type. The payload reagent may be any type of drug. In some embodiments of any of the above aspects, the payload reagent is a small molecule or a polypeptide.

[0138] In some embodiments of any of the above aspects, the composition includes an additional active agent or component, e.g., a drug, e.g., a drug for a condition or disease. As used herein, an "active compound" or "active agent" is any agent that exerts an effect on a target cell or organism. The terms "compound" and "agent" refer to any entity that is not normally present or does not exist at the levels administered and / or provided to a cell, tissue, or subject. An agent can be selected from the group including: chemicals; organic or inorganic small molecules; signaling molecules; nucleic acid sequences; nucleic acid analogs; proteins; peptides; enzymes; aptamers; peptidomimetics, peptide derivatives, peptide analogs, antibodies; intracellular antibodies; biological macromolecules, extracts made from biological materials such as bacterial, plant, fungal, or animal cells or tissues; natural or synthetic compositions or functional fragments thereof. In some embodiments, the agent is any chemical, entity, or moiety, including but not limited to synthetic and natural non-proteinaceous entities. An agent may be known to have a desired activity and / or property, and may be selected from a library of diverse compounds.

[0139] In some embodiments of any of the preceding aspects, the first region comprises one or more payload agents. In some embodiments of any of the preceding aspects, the second region comprises one or more payload agents. In some embodiments of any of the preceding aspects, the third region comprises one or more payload agents. In some embodiments of any of the preceding aspects, the second region and / or the third region comprise one or more payload agents. In some embodiments of any of the preceding aspects, the second region and / or the third region each comprise one or more payload agents.

[0140] The term "small molecule" as used herein refers to a chemical agent that may include, but is not limited to, peptides, peptidomimetics, amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, aptamers, nucleotides, nucleotide analogs, organic or inorganic compounds having a molecular weight of less than about 10,000 grams / mole (i.e., including heteroorganic and organometallic compounds), organic or inorganic compounds having a molecular weight of less than about 5,000 grams / mole, organic or inorganic compounds having a molecular weight of less than about 1,000 grams / mole, organic or inorganic compounds having a molecular weight of less than about 500 grams / mole, as well as salts, esters, and other pharma- ceutically acceptable forms of such compounds.

[0141] In some embodiments of any of the above aspects, the payload reagent is a therapeutic compound or drug. In some embodiments of any of the above aspects, the active compound can be a therapeutic compound or drug, for example, a therapeutically effective drug or compound for treating at least one condition in a subject. Therapeutic compounds for various conditions are known in the art. For example, see the database available on the World Wide Web at drugs.com, or the catalog of FDA-approved compounds available on the World Wide Web at catalog.data.gov / dataset / drugsfda-database. Each of these is incorporated herein by reference in its entirety.

[0142] In some embodiments of any of the above aspects, the payload reagent is present in admixture with the structural polymer. In some embodiments of any of the above aspects, the payload reagent is present in a second region of the polymer particle that is disposed between the first region and the third region, e.g., as a layer between the first region and the third region, or in the interior space of the particle.

[0143] In some embodiments of any of the preceding aspects, the one or more payload agents are N2 / M2 polarization inducers. In some embodiments of any of the preceding aspects, the one or more payload agents are IL-4 and / or dexamethasone. In some embodiments of any of the preceding aspects, the one or more payload agents are N2 / M2 polarization inducers. In some embodiments of any of the preceding aspects, the second region comprises IL-4 and the third region comprises dexamethasone. In some embodiments of any of the preceding aspects, the second region comprises IL-4 and heparin and the third region comprises dexamethasone.

[0144] In some embodiments of any of the above aspects, the one or more payload agents are N1 / M1 polarization inducers.

[0145] As described herein, certain embodiments of the particles described herein can be destroyed or degraded in a controllable and / or inducible manner. The particles can also be localized. One way to provide such functionality is to incorporate liposomes or nanoparticles into the particles that can be destroyed or removed by controllable external stimuli. For example, echogenic liposomes are known in the art and can be destroyed by sound waves, e.g., ultrasound of a certain frequency. For further details, see, for example, Paul et al. 2014 Comput. Mech. 53(3) 413-435; Immordino et al. 2006 Int. J. Nanomedicine 1(3):294-315; Nahire et al. 2014 Mol. Pharmaceutics 11(11):4059-4068; U.S. Patent No. 6,261,537; and U.S. Patent Application Publication No. 2001 / 0051131. Each of these is incorporated herein by reference in its entirety.Magnetic nanoparticles and gold nanoparticles respond to magnetic and electromagnetic fields, respectively, and this functionality can be used to locate particles, locate cells to which the particles are attached, and / or destroy particles.Further details of such nanoparticles and their use in such methods can be found, for example, in Thanh "Magnetic Nanoparticles" 2012 CRC Press; Khan et al. 2015 Curr. Drug Metab. 16:685-704; Yeh et al. 2012 Nanoscale 6; Sengani et al. 2017 OpenNano 2:37-46; and Menon et al. 2017 Resource-Efficient Technologies 3:516-527.Each of these is incorporated herein by reference in its entirety.Further discussion of the aforementioned exemplary embodiments and other sustained release means is detailed in Mishra "Handbook of Encapsulation and Controlled Release" CRC Press (2015), which is incorporated herein by reference in its entirety. In some embodiments of any of the above aspects, the aforementioned liposomes and / or nanoparticles may be in a second region of the polymer particle.

[0146] In some embodiments of any of the above aspects, the release of one or more of the polarization inducers is triggered by contacting the particle with small molecule or nucleic acid.The illustrative non-limiting example of such method and reagent includes the particle that contains phenylboronic acid (PBA), which releases cargo in response to insulin.Further details of this approach are described in Shiino et al. Biomaterials 15:121-128 (1994), the entirety of which is incorporated herein by reference.

[0147] In one aspect of any of the above embodiments, the present invention describes an engineered cell composition comprising a cell; and a polymer particle as described herein, wherein the particle is disposed on the cell surface of the cell.In some embodiments of any of the above aspects, the cell may be a monocyte, a macrophage, a natural killer cell, a T cell, or a neutrophil.In some embodiments of any of the above aspects, the composition further comprises a medium or serum.

[0148] In some embodiments of any of the above aspects, the polymer particle comprises a binding reagent selected from Table 3 and the cell is a cell of the corresponding type shown in Table 3. In some embodiments of any of the above aspects, the polymer particle comprises a binding reagent selected from Table 4 and the cell is a cell of the corresponding type shown in Table 4. In some embodiments of any of the above aspects, the polymer particle comprises a binding reagent selected from Table 4 attached to a backpack by a linkage shown in Table 4 and the cell is a cell of the corresponding type shown in Table 4.

[0149] (Table 3) TIFF2024529341000006.tif142160

[0150] In some embodiments of any of the above aspects, the polymer particles described herein further comprise at least one priming agent. In some embodiments of any of the above aspects, the method described herein further comprises contacting the cells with at least one primary agent before, during, or after contacting the cells with the polymer particles described herein. As used herein, a "priming agent" refers to an agent that induces increased adhesion and / or viability, e.g., increased adhesion and / or viability of neutrophils. Such agents are known in the art, as evidenced, for example, by the references listed in Figure 38A, each of which is incorporated herein by reference in its entirety.

[0151] Non-limiting examples of priming agents may include caspase inhibitors; fMLF; C5A; LTB4; PAF; TNF-α; GCSF; GM-CSF; IFN-γ; IL-1β; IL8; IL-15; IL-18; IL-33; adiponectin; LPS; LAM; lipopeptide; flagellin; ATP; substance P; CL097; and CL075. Figure 48A shows such priming agents known in the art and their effects. In some embodiments of any of the above aspects, the at least one priming agent is selected from the group consisting of a caspase inhibitor; GCSF; and GM-CSF. In some embodiments of any of the above aspects, the caspase inhibitor is a pan-caspase inhibitor (e.g., iCASP, Z-VAD-FMK, Q-VD(OMe) -OPh, Z-VAD(OMe) -FMK, Boc-D-FMK, etc.). In some embodiments of any of the preceding aspects, the at least one priming agent is selected from the group consisting of a caspase inhibitor; GCSF; and GM-CSF. In some embodiments of any of the preceding aspects, the at least one priming agent is selected from the group consisting of IL-2 and IL-15.

[0152] The polymer particles described herein can be made by one or more of layer-by-layer techniques, stamping, soft lithography, spin-coating, and printing.Suitable production methods are illustrated in the examples herein and are detailed in International Patent Publications WO2019 / 139892 and WO2020 / 247576. These are incorporated herein by reference in their entirety.Layer-by-layer techniques are also detailed in US Patent Application Publication No. 2004 / 01152791; Park et al. Advanced Materials 2005 17:2575-2579; and Decher et al. "Multilayer Thin Films: Sequential Assembly of Nanocomposite Materials" 2012 John Wiley & Sons, together with the general procedures for suitable fabrication methods.Each of these is incorporated herein by reference in its entirety.

[0153] In some embodiments of any of the above aspects, the compositions described herein comprise two or more different polymer particles described herein, for example, two structurally different polymer particles.In some embodiments of any of the above aspects, the engineered cell compositions described herein comprise individual cells with two or more types of polymer particles described herein attached, for example, two structurally different polymer particles.In some embodiments of any of the above aspects, the engineered cell compositions described herein comprise two different cells that differ in terms of cell type or in terms of the structure of the polymer particles attached to each cell.

[0154] In one aspect of any of the above embodiments, described herein is a method of obtaining an image (e.g., an MRI image) of a subject in need of an image, comprising administering to a subject a polymer particle described herein, and then subjecting the subject to an imaging exposure or scan (e.g., an MRI scan), wherein the particle comprises an imaging agent (e.g., an MRI contrast agent) and / or an engineered cell composition comprising a polymer particle described herein, wherein the particle comprises an imaging agent (e.g., an MRI contrast agent). In some embodiments of any of the above aspects, the cell is a macrophage, monocyte, or T cell.

[0155] In one aspect of any of the above embodiments, described herein is a method of treating cancer and / or tumors in a subject in need of such treatment, comprising administering to the subject a polymer particle or engineered cell composition as described herein. In some embodiments of any of the above aspects, when the method relates to treating cancer and / or tumors, the polymer particle comprises a polarization inducer that is an M1 polarization inducer. In some embodiments of any of the above aspects, when the method relates to treating cancer and / or tumors, the polymer particle comprises one or more payload agents, including chemotherapeutic agents.

[0156] In one aspect of any of the above embodiments, described herein is a method of treating a fracture, wound, injury (e.g., TBI), or infection in a subject in need thereof, comprising administering to the subject a polymer particle or engineered cell composition described herein. In some embodiments of any of the above aspects, when the method relates to treating a fracture, wound, injury, or infection, the polymer particle comprises a polarization inducer that is an M2 polarization inducer. In some embodiments of any of the above aspects, when the method relates to treating a fracture, wound, injury, or infection, the polymer particle comprises one or more payload agents including an antibiotic, an antiviral agent, an antibacterial agent, a hemostatic agent, an analgesic agent, and / or an anti-inflammatory agent.

[0157] As used herein, "antiviral agent" refers to any chemical or biological agent that has therapeutic utility in inhibiting viral transmission, activity, or replication. Categories of antiviral agents may include, but are not limited to, entry inhibitors, uncoating inhibitors, viral synthesis inhibitors, assembly inhibitors, and release inhibitors. Exemplary non-limiting antiviral agents include enfuvirtide, amantadine, rimantadine, pleconaril, acyclovir, zidovudine, lamivudine, fomivirsen, rifampicin, zanamivir, oseltamivir, peramivir, abacavir, acyclovir, adefovir, amprenavir, baloxavir marboxil, boceprevir, cobicistat, combivir, daclatasvir, doravirine, etravirine, ganciclovir, ibalizumab, letermovir, rilpivirine, simeprevir, telbivudine, and valciclovir. Those skilled in the art can easily identify useful antiviral agents. See, e.g., Antiviral Drugs, Wieslaw M. Kazmierski (ed.) Wiley and Sons (2011); Antiviral Drugs, John S. Driscoll. Wiley and Sons (2005), each of which is incorporated by reference herein in its entirety.

[0158] As used herein, "antibiotics" refers to any chemical or biological agent that has therapeutic utility in inhibiting bacterial cell growth or killing bacteria, for example, chemical or biological agents that are bactericidal or bacteriostatic. Categories of antibiotics may include, but are not limited to, antibiotics that target bacterial cell walls (e.g., penicillins, cephalosporins), antibiotics that target bacterial cell membranes (e.g., polymyxins), antibiotics that target bacterial enzymes (e.g., rifamycins, lipiarmycins, quinolones, sulfonamides), protein synthesis inhibitors (e.g., macrolides, lincosamides, and tetracyclines), aminoglycosides, cyclic lipopeptides, glycyrrhizins, oxazolidinones, β-lactams, and lipiarmycins.Exemplary, non-limiting antibiotics include penicillin, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, ampicillin, amoxicillin, pivampicillin, hetacillin, bacampicillin, methampicillin, talamipicillin, epicillin, cavenicillin, ticaricillin, temocillin, mezlocillin, piperacillin, azlocillin, olocillin), clavulanic acid, sulbactam, tazobactam, cafadroxil, cephalexin, cefalotin, cephapirin, cefazolin, cephradine, cefaclor, cefonicid, cefprozil, cefuroxime, loracarbef, cefmetazole, cefotetan, cefoxitin, cefotiam, cefdinir, cefixime, cefotaxime, cefovecin, cefpodoxime, ceftibuten, ceftiofur, ceftizoxime, ceftriaxone , cefoperazone, ceftazimdime, latamoxef, cefepime, cefiderocol, cefpriome, rifampicin, rifabutin, rifapentine, rifamixin, fidaxomicin, ciproflaxicin, moxifloxacin, levofloxacin, sulfafurzole, azithromycin, clarithromycin, erythromycin, fidaxomicin, spiramycin Antibiotic agents that may be used include, for example, cyclosporine ...See, e.g., Antibiotics in Laboratory Medicine, Victor Lorian (ed.) Wolters Kluwer; and Antibotics Manual, David Schlossberg and Rafik Samuel, John Wiley and Sons (2017), each of which is incorporated herein by reference in its entirety.

[0159] Hemostatic agents are known in the art. As used herein, "hemostatic agent" refers to an agent that promotes clotting or clotting and / or stops bleeding. Exemplary hemostatic agents include microfibrillar collagen, gelatin, factor concentrators (e.g., QuikClot™ (Z-Medica LLC., Newington, CT, USA), QuikClot ACS™ (advanced clotting sponge) (Z-Medica LLC., Newington, CT, USA), TraumaDex™ (Medafor Inc, Minneapolis, MN, USA), and self-expanding hemostatic polymers (Payload Systems Inc., Cambridge, MA, USA)), muscoadhesive agents (e.g., HemCon™ (HemCon Medical Technologies Inc. Portland, OR, USA) and Celox™ (Medtrade Products Ltd. Crewe, UK)), procoagulant supplementors (e.g., dry fribrin sealant dressing, In some embodiments, the agents may include, but are not limited to, riboflavin, fibrin, thrombin, collagen, adrenaline, VBP, CBP, Factor VIII, Factor IX, as well as agents described in U.S. Patent Application Publication No. 2018 / 0311378, which is incorporated by reference in its entirety.

[0160] Anti-inflammatory agents are known in the art.Exemplary anti-inflammatory agents include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs--e.g., aspirin, ibuprofen, or naproxen); corticosteroids, including glucocorticoids (e.g., cortisol, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, and beclomethasone); methotrexate; sulfasalazine; leflunomide; anti-TNF drugs; cyclophosphamide; pro-resolving drugs; mycophenolic acid; opiates (e.g., endorphins, enkephalins, and dynorphins), steroids, analgesics, barbiturates, oxycodone, morphine, lidocaine, etc. In some embodiments, the anti-inflammatory agent is a steroid (e.g., a corticosteroid or a glucocorticoid); a calcineurin inhibitor (e.g., cyclosporine, tacrolimus, pimecrolimus, or FK506); an mTOR inhibitor (e.g., everolimus, temsirolimus, rapamycin, deforolimus, TOP216, OSI-027, TAFA93, nab-rapamycin, tacrolimus, biolimus, CI-779, ABT-578, AP-23675, BEZ-235, QLT-0447, ABI-009, BC-210, salirasib, AP-23841, AP-23573, KU- 0059475, 32-deoxorapamycin, 16-pent-2-nyloxy-32-deoxorapamycin, 16-pent-2-nyloxy-32(S or R)-dihydro-rapamycin, 16-pent-2-nyloxy-32(S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, 32-deoxorapamycin; 16-pentyl-2-nyloxy-32(S)-dihydrorapamycin; socalled rapalogs; AP23464; PI-103, PP242, PP30, Torin1; and derivatives or pharma- ceutically acceptable salts thereof, and, for example, U.S. Patent Application Publication Nos. 2011 / 0178070; 2011 / 0021515;2007 / 0112005; 2011 / 0054013; International Patent Publication Nos. WO98 / 02441; WO01 / 14387; WO99 / 15530; WO07 / 135411; WO03 / 64383; WO96 / 41807; WO95 / 16691; WO94 / 09010; European Patent No. EP1880723; and U.S. Patent Nos. 8,163,775; 6,329,386; 6,200,985; 6,117,863; 6,015,815; 6,015,809; 6,004,973; 5,985,890; 5,955,457; 5,922,730; 5,912,253; 5,780,462; 5,665,772; 5,637,590; 5,567,709; 5,563,145; 5,559,122; 5,559,120; 5,559,119; 5,559,112; 5,550,133; 5,541,192; 5,541,191; 5,532,355; 5,530,121; 5,530,007; 5,525,610; 5,521,194; 5,519,031; 5,516,780; 5,508,399; 5,508,290; 5,508,286; 5,508,285; 5,504,291; 5,504,204; 5,491,231; 5,489,680; 5,489,595; 5,488,054; 5,486,524; 5,486,523; 5,486,522; 5,484,791; 5,484,790; 5,480,989; 5,480,988; 5,463,048; 5,446,048; 5,434,260; 5,411,967; 5,391,730; 5,389,639; 5,385,910; 5,385,909; 5,385,908; 5,378,836; 5,378,696; 5,373,014; 5,362,718; 5,358,944; 5,346,893; 5,344,833; 5,302,584; 5,262,424; 5,262,423; 5,260,300; 5,260,299; 5,233,036; 5,221,740; 5,221,670; 5,202,332; 5,194,447; 5,177,203; 5,169,851; 5,164,399;5,162,333; 5,151,413; 5,138,051; 5,130,307; 5,120,842; 5,120,727; 5,120,726; 5,120,725; 5,118,678; 5,118,677; 5,100,883; 5,023,264; 5,023,263; and compounds described in 5,023,262; which are incorporated by reference herein in their entireties; rapamycin (sirolimus) or an analog thereof (e.g., everolimus, temsirolimus, ridaforolimus, deforolimus); or an antiproliferative agent (e.g., mycophenolate moeficidin, In some embodiments, the mTOR inhibitor may be rapamycin or an analog thereof, such as everolimus, temsirolimus, ridaforolimus, or deforolimus. Antiproliferative agents may include, by way of non-limiting example, alkylating agents (e.g., cyclophosphamide, platinum compounds, and nitrosoureas), antimetabolites (e.g., methotrexate, azathioprine, mercaptopurine, fluorouracil, and the like), and cytotoxic antibiotics (e.g., dactinomycin, anthracyclines, mitomycin C, bleomycin, and mithramycin);

[0161] Pain relievers or analgesics are known in the art and may include, by way of non-limiting example, acetaminophen, NSAIDs (e.g., aspirin, ibuprofen, naproxen), COX-2 inhibitors (e.g., rofecoxib, celecoxib, etoricoxib), opioids (e.g., codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, tramadol, venlafaxine, tapentadol, cannabanoids, opioid potentiators (e.g., hydroxyzine, promethazine, carisoprodol, or tripelennamine), analgesic adjuvants (e.g., orphenadrine, mexiletine, pregabalin, gabapentin, cyclobenzaprine, hyoscine (scopolamine)), carbamazepine, and gabapentinoids.

[0162] In one aspect of any of the above embodiments, described herein is a method of treating inflammation in a subject in need of such treatment, comprising administering to the subject a polymer particle or engineered cell composition as described herein. In some embodiments of any of the above aspects, when the method relates to treating inflammation, the polymer particle comprises a polarization inducer that is an M2 polarization inducer. In some embodiments of any of the above aspects of treating inflammation, the M2 polarization inducer is a cytokine, e.g., an IL-4 polypeptide. In some embodiments of any of the above aspects, when the method relates to treating inflammation, the polymer particle comprises one or more payload agents, including an anti-inflammatory agent.

[0163] In some embodiments of any of the above aspects, the inflammation is in the lungs and is caused by or results from an infection or injury. In some embodiments of any of the above aspects, the inflammation is in the joints and is caused by or results from arthritis. In some embodiments of any of the above aspects, the inflammation is in the skin and is caused by or results from an infection or autoimmune disorder. In some embodiments of any of the above aspects, the inflammation is caused by, results from, or is a symptom of acute respiratory distress (ARDS), arthritis, infection, or an autoimmune disorder.

[0164] In one aspect of any of the above embodiments, described herein is a method of treating an autoimmune condition in a subject in need thereof, comprising administering to the subject a polymer particle or engineered cell composition as described herein. In some embodiments of any of the above aspects, when the method relates to treating an autoimmune condition, the polymer particle comprises a polarization inducer that is an M2 polarization inducer. In some embodiments of any of the above aspects treating inflammation, the M2 polarization inducer is a cytokine, e.g., an IL-4 polypeptide. In some embodiments of any of the above aspects, when the method relates to treating an autoimmune condition, the polymer particle comprises one or more payload agents, including an immunosuppressant.

[0165] As used herein, the term "autoimmune disease" or "autoimmune disease or disorder" refers to a disease or disorder that originates from and is directed against an individual's own tissues or cells, or the manifestation or resulting condition that results from it. Autoimmune-related diseases and disorders result from the body's overactive and / or abnormal immune response to substances (self-antigens) and tissues that are normally present in the body, also known as autologous or self-substances. This dysregulated inflammatory response causes an excessive response by macrophages, granulocytes, and / or T-lymphocytes, leading to abnormal tissue damage and cell death. The subsequent loss of function is associated with inflammatory tissue damage.

[0166] In some embodiments of any of the above aspects, the autoimmune condition is rheumatoid arthritis, lupus, or celiac disease. In one embodiment of any of the described methods, the autoimmune disorder is thyroiditis, type 1 diabetes, Hashimoto's thyroiditis, Graves' disease, celiac disease, multiple sclerosis, Guillain-Barré syndrome, Addison's disease, and Raynaud's phenomenon, Goodpasture's disease, arthritis (rheumatoid arthritis, e.g., acute arthritis, chronic rheumatoid arthritis, gout or gouty arthritis, acute gouty arthritis, acute immunological arthritis, chronic inflammatory arthritis, degenerative arthritis, collagen II-induced arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, Still's disease, vertebral arthritis, and juvenile onset rheumatoid arthritis, arthritis chronica progrediente, osteoarthritis, chronic primary polyarthritis, polyarthritis chronica. primaria), reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis, e.g., plaque psoriasis, guttate psoriasis, pustular psoriasis, and ungual psoriasis, atopic diseases, e.g., atopy including hay fever and Job's syndrome, contact dermatitis, chronic contact dermatitis, exfoliative dermatitis, allergic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, nummular dermatitis, seborrheic dermatitis, nonspecific dermatitis, primary irritant contact dermatitis, and atopic dermatitis, X-linked hyper IgM syndrome, allergic eye internal inflammatory diseases, urticaria, e.g. chronic allergic urticaria including chronic autoimmune urticaria and chronic idiopathic urticaria, myositis, polymyositis / dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma (including systemic scleroderma), sclerosis, e.g. systemic sclerosis, multiple sclerosis (MS), e.g. spino-optical MS, primary progressive MS (PPMS), and relapsing remitting MS (RRMS), progressive systemic sclerosis, atherosclerosis, arteriosclerosis, sclerosis disseminata, ataxic sclerosissclerosis, neuromyelitis optica (NMO), inflammatory bowel disease (IBD) (e.g., Crohn's disease, autoimmune-mediated gastrointestinal diseases, colitis, e.g., ulcerative colitis, colitis ulcerosa, microscopic colitis, collagenous colitis, colitis polyposa, necrotizing enterocolitis, and transmural colitis, and autoimmune inflammatory bowel disease), intestinal inflammation, pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, respiratory distress syndromes, including adult respiratory distress syndrome or acute respiratory distress syndrome (ARDS), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, autoimmune blood disorders, rheumatoid spondylitis, rheumatic synovitis, hereditary angioedema, cranial nerve damage as in meningitis, herpes gestationis, pemphigoid of gestationis gestationis, pruritis scroti, autoimmune premature ovarian failure, sudden deafness due to autoimmune conditions, diseases mediated by IgE, such as anaphylaxis and allergic and atopic rhinitis, encephalitis, such as Rasmussen's encephalitis and limbic and / or brainstem encephalitis, uveitis, such as anterior uveitis, acute anterior uveitis, granulomatous uveitis, non-granulomatous uveitis, phacoantigenic uveitis, uveitis, posterior uveitis, or autoimmune uveitis, glomerulonephritis (GN) with and without nephrotic syndrome, e.g., chronic glomerulonephritis or acute glomerulonephritis, e.g., primary GN, immune-mediated GN, membranous GN (membranous nephropathy), idiopathic membranous GN or idiopathic membranous nephropathy, membranoproliferative GN or membranous proliferative GN (MPGN), including types I and II, and rapidly progressive GN, proliferative nephritis, autoimmune polyglandular endocrine failure, balanitis, including plasma cell-limited balanitis, balanoposthitis, erythema annulare centrifugally, erythema dyschromicus perstans, erythema multiforme ...multiform), granuloma annulare, lichen nitidus, lichen sclerosus atrophicus, localized neurodermatitis, lichen spinous, lichen planus, ichthyosis lamellar, epidermolytic hyperkeratosis, premalignant keratosis, pyoderma gangrenosum, allergic conditions and responses, allergic reactions, eczema including allergic or atopic eczema, asteatotic eczema, dyshidrotic eczema, and vesicular palmoplantar eczema, asthma, e.g. asthma bronchiale, bronchial asthma, and autoimmune asthma, conditions with infiltration of T cells and chronic inflammatory responses, immune responses to foreign antigens, e.g. fetal ABO blood groups during pregnancy, chronic pulmonary inflammatory diseases, autoimmune myocarditis, leukocyte adhesion deficiency, lupus nephritis, lupus encephalitis, childhood lupus, non-renal lupus lupus, extra-renal lupus, discoid lupus, and discoid lupus erythematosus, alopecia lupus, systemic lupus erythematosus (SLE), including cutaneous or subacute cutaneous SLE, neonatal lupus syndrome (NLE), and disseminated lupus erythematosus, juvenile-onset (Type I) diabetes including insulin-dependent diabetes mellitus (IDDM) of childhood, adult-onset diabetes mellitus (Type II diabetes), autoimmune diabetes, idiopathic diabetes insipidus, diabetic retinopathy, diabetic nephropathy, diabetic large-artery disease,immune responses related to acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, granulomatous diseases including sarcoidosis, lymphomatoid granulomatosis, and Wegener's granulomatosis, granulocytopenia, vasculitis, large vasculitis (including polymyalgia rheumatica and giant cell (Takayasu) arteritis), medium vasculitis (including Kawasaki disease and polyarteritis nodosa / periarteritis nodosa), microscopic polyarteritis, immunovasculitis, Vasculitis including CNS vasculitis, cutaneous vasculitis, hypersensitivity vasculitis, necrotizing vasculitis, e.g., systemic necrotizing vasculitis, and ANCA-associated vasculitis, e.g., Churg-Strauss vasculitis or syndrome (CSS), and ANCA-associated small vessel vasculitis, temporal arteritis, autoimmune aplastic anemia, Coombs positive anemia, Diamond-Blackfan anemia, hemolytic anemia or immune hemolytic anemia, including autoimmune hemolytic anemia (AIHA), pernicious anemia anemia (perniciosa), Addison's disease, pure red cell anemia or pure red cell aplasia (PRCA), factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases with leukocyte leakage, CNS inflammatory disorders, multiple organ injury syndromes e.g. sepsis, multiple organ injury syndromes secondary to trauma or hemorrhage, diseases mediated by antigen-antibody complexes, antiglomerular basement membrane disease, antiphospholipid syndrome, allergic neuritis, Behcet's disease / syndrome, Castleman syndrome, Goodpasture's syndrome, Raynaud's syndrome, Sjogren's syndrome, Stevens-Johnson syndrome, pemphigoid, e.g. pemphigoid bullous and cutaneous pemphigoid pemphigoid, pemphigus vulgaris, pemphigus foliaceus, pemphigus mucus-membranepemphigoid, and pemphigus erythematosus), autoimmune polyendocrinopathy, Reiter's disease or syndrome, immune complex disorders, e.g. immune complex nephritis, antibody mediated nephritis, polyneuropathy, chronic neuropathy, e.g. IgM polyneuropathy or IgM mediated neuropathy, and autoimmune or immune mediated thrombocytopenia, e.g. idiopathic thrombocytopenic purpura (ITP), including chronic or acute ITP, scleritis, e.g. idiopathic keratoscleritis, episcleritis, autoimmune diseases of the testes and ovaries, including autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, thyroiditis, e.g. autoimmune thyroiditis, Hashimoto's disease, chronic thyroiditis (Hashimoto's thyroiditis), or subacute thyroiditis, idiopathic hypothyroidism, Graves' disease, polyglandular syndrome, autoimmune endocrine disorders, including autoimmune polyglandular syndrome (or polyglandular endocrinopathy syndrome); neurologic paraneoplastic syndrome, including paraneoplastic syndromes, including Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, stiff-man or stiff-person syndrome; encephalomyelitis, including allergic encephalomyelitis or allergic encephalomyelitisallergica) and experimental allergic encephalomyelitis (EAE), myasthenia gravis, e.g., thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus-myoclonus syndrome (OMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan syndrome, autoimmune hepatitis, lupoid hepatitis, giant cell hepatitis, autoimmune chronic active hepatitis, lymphocytic interstitial pneumonia (LIP), bronchiolitis obliterans (non-transplant) vs. NSIP, Guillain-Barré syndrome, and pulmonary embolism. Barre syndrome, Berge's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, acute febrile neutrophilic dermatosis, subcorneal pustular purulence, transient acantholytic dermatosis, cirrhosis, e.g. primary biliary cirrhosis and pneumonocirrhosis, autoimmune enteropathy syndrome, celiac or celiac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia, amyotrophic lateral sclerosis autoimmune ear diseases, e.g. autoimmune inner ear disease (AIED), autoimmune hearing loss, polychondritis, e.g. refractory or relapsing or relapsing polychondritis, pulmonary alveolar proteinosis, Cogan's syndrome / nonsyphilitic interstitial keratitis, Bell's palsy, Sweet's disease / syndrome, autoimmune rosacea autoimmune, herpes zoster-associated pain, amyloidosis, non-cancerous lymphocytosis, primary lymphocytosis including monoclonal B-cell lymphocytosis (e.g., monoclonal gammopathy and monoclonal gammopathy of undetermined significance, MGUS), peripheral neuropathy, paraneoplastic syndromes, channelopathies including channelopathies of the CNS, autism, inflammatory myopathy, focal or segmental glomerulosclerosis or focal segmental glomerulosclerosis (FSGS), endocrine opthalmopathy, uveitis retinitis, chorioretinitis, autoimmune hepatological disorder, fibromyalgia, multiple endocrine deficienciesfailure), Schmidt's syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases such as autoimmune demyelinating diseases and chronic inflammatory demyelinating polyneuropathy, Dressler's syndrome, alopecia areata, alopecia totalis, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), autoimmune infertility in men and women due to antispeltozoan antibodies, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent abortions, farmer's lung, erythema multiforme, postcardiotomy syndrome, Cushing's syndrome, bird breeder's lung, allergic granulomatous vasculitis, benign lymphocytic angiitis, Alport's syndrome, alveolitis such as allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reactions, Sampter's syndrome syndrome, Kaplan's syndrome, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial pulmonary fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endophthalmitis, erythema elevatum et diutinum, erythroblastosis fetalis, eosinophilic faciitis, Charmant's syndrome, Felty's syndrome, cyclitis, e.g. chronic cyclitis, heterochronic cyclitis, iridocyclitis (acute or chronic), or Fuch's cyclitis, Henoch-Schönlein purpura, SCID, sepsis, endotoxemia, post-vaccination syndrome syndrome, Evans syndrome, autoimmune gonadal failure, Sydenham's chorea, poststreptococcal nephritis, thromboangitis ubiterans, thyrotoxicosis, spinal fistula, choroiditis, giant cell polymyalgia, chronic hypersensitivity pneumonitis, keratoconjunctivitis sicca, idiopathic nephritic syndrome, microlesion disease, benign familial Benign familial and ischemia-reperfusion injury, transplanted organ reperfusion, retinal autoimmunity, aphthous stomatitis, arteriosclerotic disorders, aspermiogenesis, autoimmune hemolysis, Beck's disease, enteritis allergica, erythema nodosum leprosum, idiopathic facial nerve palsy, chronic fatigue syndrome, rheumatic fever, Hamman-Rich disease, sensorineural hearing loss, ileitis regionalis, leukopenia, transverse myelitis, primary idiopathic myxedema, ophthalmia symphatica, polyradiculitis acuta, pyoderma gangrenosum, acquired splenic atrophy atrophy, vitiligo, toxic shock syndrome, conditions with T cell infiltration, leukocyte adhesion deficiency, immune responses related to acute and delayed hypersensitivity mediated by cytokines and T lymphocytes, diseases with leukocyte leakage, multiple organ injury syndrome, diseases mediated by antigen-antibody complexes, antiglomerular basement membrane disease, allergic neuritis, autoimmune polyendocrinopathy, oophoritis, primary myxedema, autoimmune atrophic gastritis, rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, polyendocrine insufficiency failure, autoimmune polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), myocarditis, nephrotic syndrome, primary sclerosing cholangitis, acute or chronic sinusitis, ethmoid, frontal, maxillary, or sphenoid sinusitis, eosinophil-related disorders such as eosinophilia, pulmonary infiltration eosinophilia, eosinophilic myalgia syndrome, Löffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, eosinophil-containing granulomas, seronegative spondyloarthritides, polyendocrine autoimmune diseasesdisease), sclerosing cholangitis, sclera, episclera, Bruton's syndrome, transient infantile hypogammaglobulinemia, Wiskott-Aldrich syndrome, ataxia telangiectasia syndrome, vascular ectasia, autoimmune disorders associated with collagen diseases, rheumatism, allergic hypersensitivity disorder, glomerulonephritides, reperfusion injury, ischemic reperfusion injury, lymphomatous tracheobronchitis, inflammatory dermatoses, skin diseases with an acute inflammatory component, and autoimmune uveoretinitis (AUR).

[0167] Treatments for autoimmune disorders are known in the art and include immunosuppressant drugs such as cyclosporine (Neoral, Sandimmune, Gengraf, and Restasis), tacrolimus (Prograf, Protopic, AstagrafXL, and EnvarsusXR), methotrexate (Trexall, Rasuvo, Rheumatrex, and Otrexup (PF)), sirolimus (Rapamune), mycophenolic acid (Myfortic and CellCept), rituximab (Rituxan), etanercept (Enbrel), pentostatin (Nipent), ruxolitinib (Jakafi); chemotherapeutic agents such as methotrexate (Trexall, Rasuvo, Rheumatrex, and Otrexup (PF)), antithymocyte globulin (Atgam, Thymoglobulin); Steroids such as prednisone (Deltasone, Rayos, and Prednisone Intensol), methylprednisolone (Medrol, Solu-Medrol, and Depo-Medrol), budesonide (Entocort EC, Uceris); antifungals such as posaconazole (Noxafil); antivirals such as acyclovir (Zovirax and Sitavig), valacyclovir (Valtrex); and antibiotics such as sulfamethoxazole / trimethoprim (Bactrim, Sulfatrim, and Bactrim DS); protease inhibitors such as alpha 1-proteinase inhibitors (Zemaira); extracorporeal photopheresis; These may include, but are not limited to, monoclonal antibodies (daclizumab (Zinbryta), basiliximab (Simulect)), brentuximab vedotin (Adcetris), alemtuzumab (Campath, Lemtrada), tocilizumab (Actemra); injection of mesenchymal stromal cells.

[0168] In one aspect of any of the above embodiments, methods of providing hemostatic therapy to a subject in need thereof are described herein, comprising administering to the subject a polymer particle or engineered cell composition as described herein. In some embodiments of any of the above aspects, when the method is associated with providing hemostatic therapy, the polymer particle comprises a polarization inducer that is an M2 polarization inducer. In some embodiments of any of the above aspects, when the method is associated with providing hemostatic therapy, the polymer particle comprises one or more payload agents that include a hemostatic agent.

[0169] A subject in need of hemostatic treatment may be a subject who is bleeding, has a wound, has trauma, has a bleeding disorder (e.g., hemophilia, von Willebrand disease, disseminated intravascular coagulation, thrombocytopenia, end-stage liver failure, congential afibrogenemia, Glanzmann thrombasthenia, or Bernard-Soulier syndrome), has an acute traumatic coagulopathy, or is a subject undergoing surgery.

[0170] In one aspect of any of the above embodiments, described herein is a method of treating a neurodegenerative disorder, a central nervous system disorder, or a peripheral nervous system disorder in a subject in need of such treatment, comprising administering to the subject a polymer particle or an engineered cell composition as described herein. In some embodiments of any of the above aspects, when the method relates to treating a neurodegenerative disorder, a central nervous system disorder, or a peripheral nervous system disorder, the polymer particle comprises one or more payload agents, including a therapeutic agent for the neurodegenerative disorder, a central nervous system disorder, or a peripheral nervous system disorder.

[0171] In one aspect of any of the above-mentioned embodiments, a method of providing a payload reagent to the central nervous system of a subject is described herein, comprising administering to the subject a polymer particle or engineered cell composition as described herein.In some embodiments of any of the above-mentioned aspects, when the method relates to the delivery of a payload to the central nervous system, the cell is a monocyte and / or the binding reagent is CD11b.In some embodiments of any of the above-mentioned aspects, the payload delivered to the central nervous system can be a therapeutic agent for a neurodegenerative disorder, a central nervous system disorder, or a peripheral nervous system disorder, or can be a therapeutic agent for a disease or disorder found in the CNS (e.g., a chemotherapy agent for glioblastoma).

[0172] Non-limiting examples of neurodegenerative disorders, central nervous system disorders, or peripheral nervous system disorders may include brain tumors; encephalitis; hydrocephalus; Parksinson's disease; neuropathic pain; conditions treated by administration of psychiatric drugs; neurodegenerative diseases; multiple sclerosis; Huntington's disease; Pick's disease; ALS; dementia; stroke; or Alzheimer's disease. In some embodiments of any of the above aspects, the method is a method of treating a subject. In some embodiments of any of the above aspects, the method is a method of treating brain cancer; brain tumors; encephalitis; hydrocephalus; Parksinson's disease; neuropathic pain; conditions treated by administration of psychiatric drugs; neurodegenerative diseases; multiple sclerosis; Huntington's disease; Pick's disease; ALS; dementia; stroke; and Alzheimer's disease in a subject.

[0173] Medication for treating neurodegenerative disorders, central nervous system disorders, or peripheral nervous system disorders is known in the art, and may include, by way of non-limiting example, antibiotics, antibodies, gabapentin, chemotherapeutic agents, anti-inflammatory agents, neurotransmitters, morphine, peptides, polypeptides, nucleic acids (e.g., RNAi-based therapies), psychiatric drugs, and / or therapeutic agents for treating brain cancer; encephalitis; hydrocephalus; Parkinson's disease; neuropathic pain; and conditions treated by administration of psychiatric drugs.The identity of such CNS therapeutic agents is known in the art, and is described, for example, in Ghose et al. J Comb Chem 1999 1:55-68 and Pardridge. NeuroRx 2005 2:3-14, each of which is incorporated herein by reference in its entirety.

[0174] In one aspect, described herein is a method of vaccinating a subject, immunizing a subject, or inducing an immune response in a subject in need thereof, comprising administering to a subject a polymer particle or engineered cell composition as described herein, wherein the polymer particle comprises a payload reagent that is an antigen. In some embodiments of any of the above aspects, the cell is a B cell.

[0175] The terms "immunize" and "vaccinate" tend to be used synonymously in the art. However, with respect to administration of the vaccine compositions described herein to provide protection against disease, e.g., infectious diseases caused by a pathogen, it should be understood that "vaccinate" refers to administration of the vaccine composition and the term "immunize" refers to the process of conferring, increasing, or inducing the passive protection conferred by the administered vaccine composition.

[0176] An "antigen" as described herein is a molecule that is specifically bound by a B cell receptor (BCR), a T cell receptor (TCR), and / or an antibody, thereby activating an immune response. An antigen may be derived from or arise from a pathogen. An antigen may be a polypeptide, a protein, a nucleic acid, or other molecule or a portion thereof. The term "antigenic determinant" refers to an epitope on an antigen that is recognized by an antigen-binding molecule, more particularly by an antigen-binding site of said molecule. In some embodiments of any of the above aspects, a vaccine or composition described herein comprises a nucleic acid encoding the antigen.

[0177] In some embodiments of any of the above aspects, the antigen may be a molecule or motif obtained or derived from a pathogen, such as coronavirus; SARS-CoV-2 virus; pneumococcus; influenza virus; hepatitis B virus (HBV); Bordetella pertussis; Corynebacterium diphtheria; Clostridium tetani; hepatitis A virus (HAV); and meningococcus. In some embodiments of any of the above aspects, the antigen may be a molecule found in coronavirus; SARS-CoV-2 virus; pneumococcus; influenza virus; hepatitis B virus (HBV); Bordetella pertussis; Corynebacterium diphtheria; Clostridium tetani; hepatitis A virus (HAV); and meningococcus. In some embodiments of any of the above aspects, the antigen may be a molecule (or an antigenic portion thereof) having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or more sequence identity (nucleotide or amino acid) to a molecule found in a pathogen, such as coronavirus; SARS-CoV-2 virus; Streptococcus pneumoniae; influenza virus; Hepatitis B virus (HBV); Bordetella pertussis; Corynebacterium diphtheriae; Clostridium tetani; Hepatitis A virus (HAV); and Neisseria meningitidis. In some embodiments of any of the above aspects, the antigen may be a nucleic acid encoding a protein (or an antigenic portion thereof) having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or more sequence identity to a protein found in a pathogen, such as coronavirus; SARS-CoV-2 virus; Streptococcus pneumoniae; influenza virus; Hepatitis B virus (HBV); Bordetella pertussis; Corynebacterium diphtheriae; Clostridium tetani; Hepatitis A virus (HAV); and Neisseria meningitidis.In some embodiments of any of the above aspects, a protein having a designated sequence identity to a protein found in a pathogen retains a wild-type activity of the reference protein found in the pathogen.

[0178] In some embodiments of any of the above aspects, the antigen can be a viral spike protein or antigenic portion thereof, e.g., a coronavirus or SARS-CoV-2 virus spike protein or antigenic portion thereof. In some embodiments of any of the above aspects, the antigen can be a protein having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or more sequence identity to a viral spike protein, e.g., a coronavirus or SARS-CoV-2 virus spike protein or antigenic portion thereof.

[0179] The scientific name for coronaviruses is Orthocoronavirinae or Coronavirinae. Coronaviruses belong to the family Coronaviridae, order Nidovirales, and realm Riboviria. Coronaviruses are divided into alphacoronaviruses and betacoronaviruses, which infect mammals, and gammacoronaviruses and deltacoronaviruses, which mainly infect birds. Non-limiting examples of alphacoronaviruses include human coronavirus 229E, human coronavirus NL63, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, porcine epidemic diarrhea virus, Rhinolophus bat coronavirus HKU2, Scotophilus bat coronavirus 512, and feline infectious peritonitis virus (FIPV, also known as feline infectious hepatitis virus). Non-limiting examples of betacoronaviruses include betacoronavirus 1 (e.g., bovine coronavirus, human coronavirus OC43), human coronavirus HKU1, mouse coronavirus (also known as mouse hepatitis virus (MHV)), Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, severe acute respiratory syndrome-associated coronavirus (e.g., SARS-CoV, SARS-CoV-2), Tylonycteris bat coronavirus HKU4, Middle East respiratory syndrome (MERS)-associated coronavirus, and hedgehog coronavirus 1 (EriCoV). Non-limiting examples of gammacoronaviruses include Beluga whale coronavirus SW1 and infectious bronchitis virus. Non-limiting examples of deltacoronaviruses include Bulbul coronavirus HKU11 and porcine coronavirus HKU15.

[0180] In some embodiments of any of the above aspects, the coronavirus is selected from the group consisting of severe acute respiratory syndrome-related coronavirus (SARS-CoV); severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2); Middle East respiratory syndrome-related coronavirus (MERS-CoV); HCoV-NL63; and HCoV-HKu1. In some embodiments of any of the above aspects, the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the cause of coronavirus disease 2019 (COVID19 or simply COVID). In some embodiments of any of the above aspects, the coronavirus is severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1), which is the cause of SARS. In some embodiments of any of the above aspects, the coronavirus is Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is the cause of MERS.

[0181] The nucleic acids and proteins of the aforementioned pathogens are known in the art; for example, the complete genome of SARS-CoV-2 Jan. 2020 / NC_045512.2 Assembly (wuhCor1) can be obtained on the World Wide Web.

[0182] In some embodiments of any of the above aspects, the vaccine may include one or more adjuvants. In some embodiments of any of the above aspects, the payload molecule may include one or more adjuvants.

[0183] In some embodiments of any of the above aspects, at least one antigen is included in the vaccine. In some embodiments of any of the above aspects, the vaccine is an attenuated vaccine. An attenuated vaccine includes a weakened or impaired version or variant of a disease-causing microorganism. An attenuated vaccine may include a mutated or engineered strain of a microorganism, and / or a strain that has been passaged in culture and thereby lost its pathogenicity.

[0184] In some embodiments of any of the above aspects, the vaccine may be a subunit vaccine, including recombinant subunit vaccines. Subunit vaccines do not contain the entire disease-causing microorganism, but only a subset of antigens obtained or derived from the disease-causing microorganism. Subunit vaccines may contain multiple different antigens. Subunit vaccines in which antigens are produced by recombinant technology are referred to as recombinant subunit vaccines.

[0185] In some embodiments of any of the above aspects, at least one antigen is included in a conjugate vaccine. In a conjugate vaccine, a polysaccharide derived from a disease-causing microorganism (e.g., a polysaccharide found on the surface of a microorganism) is administered in combination (e.g., conjugated) with an antigen that the patient's immune system already recognizes or that the patient's immune system readily responds to. This increases the patient's response to the polysaccharide, increasing protection against live versions of the disease-causing microorganism. In some embodiments of any of the above aspects, the antigen is a polysaccharide.

[0186] Exemplary, non-limiting vaccines suitable for use in the methods and compositions described herein may include a coronavirus vaccine; a SARS-CoV-2 vaccine; a pneumococcal vaccine; an influenza vaccine; a hepatitis B (HBV) vaccine; an acellular pertussis (aP) vaccine; a diphtheria-tetanus-acellular pertussis (DTaP) vaccine; a hepatitis A (HAV) vaccine; a meningococcal (MV) vaccine; and / or a pneumococcal conjugate vaccine (PCV) 13.

[0187] In some embodiments of any of the above aspects, multiple antigens are administered.In some embodiments of any of the above aspects, multiple vaccines are administered.

[0188] As used herein, "immune response" refers to a response by immune system cells, such as B cells, T cells (CD4 or CD8), regulatory T cells, antigen-presenting cells, dendritic cells, monocytes, macrophages, NKT cells, NK cells, basophils, eosinophils, or neutrophils, to a stimulus (e.g., a vaccine). In some embodiments of the aspects described herein, the response is specific to a particular antigen ("antigen-specific response") and refers to a response by CD4 T cells, CD8 T cells, or B cells via their antigen-specific receptors. In some embodiments of the aspects described herein, the immune response is a T cell response, such as a CD4+ response or a CD8+ response. Such responses by these cells may include, for example, cytotoxicity, proliferation, cytokine or chemokine production, trafficking, or phagocytosis, and may depend on the nature of the immune cells receiving the response. Stimulation of an immune response refers to induction or increase of an immune response.

[0189] CD4+ T cells may exhibit a Th1 or Th2 phenotype. Proinflammatory CD4+ T cells are responsible for the release of inflammatory Th1-type cytokines. Cytokines characterized as Th1-type include interleukin 2 (IL-2), gamma-interferon, TNFα, and IL-12. In some embodiments, cytokines characterized as Th1-type include interleukin 2 (IL-2), interferon gamma, and TNFα. Such proinflammatory cytokines act to stimulate immune responses, often destroying self-tissues. Cytokines associated with suppressing T cell responses are Th2-type and include IL-10, IL-4, and TGF-β. It has been found that Th1-type T cells and Th2-type T cells may use the same antigen receptor in response to immunogens. The former produces a stimulatory response, while the latter produces an inhibitory response.

[0190] In some embodiments of any of the above aspects, the immune response may be a Th1 or Th2 immune response, cytokine production / release, or an increase or induction in the levels of T cells exhibiting a Th1 or Th2 phenotype. In some embodiments of any of the above aspects, the increase is compared to levels or numbers in the absence of the vaccine.

[0191] In some embodiments of any of the preceding aspects, the immune response may be a Th1 response. In some embodiments of any of the preceding aspects, the immune response may be cytokine production by Th1 cells. In some embodiments of any of the preceding aspects, the immune response may be an increase in the level of Th1 antigen-specific CD4+ cells. In some embodiments of any of the preceding aspects, the immune response may be an increase in the level of Th1 CD4+ cells. In some embodiments of any of the preceding aspects, the immune response may be an increase in the level of Th1 cells. In some embodiments of any of the preceding aspects, the immune response may be an increase in the level of CD4+ cells. In some embodiments of any of the preceding aspects, the increase is compared to levels or numbers in the absence of the vaccine.

[0192] In some embodiments of any of the above aspects, the immune response is an increase in the IgG2a / c subclass.

[0193] In some embodiments of any of the preceding aspects, the immune response may be an increase in dendritic cell activation and / or infiltration. In some embodiments of any of the preceding aspects, the immune response may be an increase in the number and / or infiltration of CD4+ cells. In some embodiments of any of the preceding aspects, the immune response may be an increase in the number of CD4+ cells. In some embodiments of any of the preceding aspects, the immune response may be an increase in the infiltration of CD4+ cells. In some embodiments of any of the preceding aspects, the immune response may be an increase in the number and / or infiltration of Th1 CD4+ cells. In some embodiments of any of the preceding aspects, the immune response may be an increase in the number of NK cells and / or CD8+ cells. In some embodiments of any of the preceding aspects, the immune response may be an increase in the number of NK cells. In some embodiments of any of the preceding aspects, the immune response may be an increase in the number of CD8+ cells. In some embodiments of any of the preceding aspects, the increase is compared to levels or numbers in the absence of the vaccine.

[0194] An immune response to an antigen may be the development in a subject of a humoral and / or cellular immune response to the antigen of interest or to a molecule present in the vaccine composition. For the purposes of the present invention, a "humoral immune response" is an antibody-mediated immune response, involving the induction and development of antibodies that recognize and bind with some affinity to the antigen present in the immunogenic composition of the present invention, whereas a "cellular immune response" is an immune response mediated by T cells and / or other white blood cells. A "cellular immune response" is elicited by presenting an antigenic epitope in association with major histocompatibility complex (MHC) class I or class II molecules, CD1, or other non-classical MHC-like molecules. This activates antigen-specific CD4+ T helper cells or CD8+ cytotoxic lymphocyte cells ("CTLs"). CTLs have specificity for peptide antigens that are presented in association with proteins encoded by classical or non-classical MHC and expressed on the cell surface. CTLs are useful in inducing and promoting the intracellular destruction of intracellular microorganisms, or the lysis of cells infected with such microorganisms. Another aspect of cellular immunity involves antigen-specific responses by helper T cells. Helper T cells act in conjunction with classical or non-classical MHC molecules on their surface to help stimulate and focus the function of non-specific effector cells against cells that display peptides or other antigens. "Cellular immune response" also refers to the production of cytokines, chemokines, and other such molecules produced by activated T cells and / or other white blood cells, including white blood cells derived from CD4+ and CD8+ T cells. The ability of a particular antigen or composition to stimulate a cellular immunological response can be determined by a number of assays, for example, by lymphocyte proliferation (lymphocyte activation) assays, CTL cytotoxic cell assays, by assaying for the presence of antigen-specific T lymphocytes in sensitized subjects, or by measuring cytokine production by T cells in response to restimulation with antigen. Such assays are well known in the art.See, e.g., Erickson et al. (1993) J. Immunol. 151:4189-4199; and Doe et al. (1994) Eur. J. Immunol. 24:2369-2376.

[0195] In one aspect of any of the above embodiments, described herein is a method of providing a gene therapy vector to a subject in need thereof, comprising administering to the subject a polymeric particle or engineered cell composition as described herein, wherein the polymeric particle comprises a payload reagent that is a gene therapy vector. The gene therapy vector may comprise a plasmid, a CRISPR-Cas component or vector encoding same, a plasmid, an expression vector, a viral vector, or a viral particle.

[0196] In one aspect of any of the above embodiments, described herein is a method of providing a vector to a subject or cell comprising administering to a subject (or contacting a cell with a polymer particle or engineered cell composition described herein), wherein the polymer particle comprises a payload reagent that is a vector.

[0197] The term "vector" as used herein refers to a nucleic acid construct designed to be delivered to a host cell or to be transferred between different host cells. As used herein, a vector may be a viral vector or a non-viral vector. The term "vector" includes any genetic element that can replicate and transfer a genetic sequence to a cell when combined with appropriate control elements. Vectors can include, but are not limited to, cloning vectors, expression vectors, plasmids, phages, transposons, cosmids, artificial chromosomes, viruses, virions, and the like.

[0198] In some embodiments of any of the above aspects, the vector is recombinant, e.g., comprises sequences from at least two different sources. In some embodiments of any of the above aspects, the vector comprises sequences from at least two different species. In some embodiments of any of the above aspects, the vector comprises sequences from at least two different genes, e.g., comprises a nucleic acid encoding a fusion protein or expression product operably linked to at least one non-native (e.g., heterologous) genetic control element (e.g., promoter, suppressor, activator, enhancer, response element, etc.).

[0199] In some embodiments of any of the above aspects, the vectors or nucleic acids described herein are codon-optimized, e.g., the native or wild-type sequence of the nucleic acid sequence has been altered or engineered to include alternative codons, such that the altered or engineered nucleic acid encodes the same polypeptide expression product as the native / wild-type sequence, but is transcribed and / or translated with improved efficiency in a desired expression system. In some embodiments of any of the above aspects, the expression system is an organism other than the source of the native / wild-type sequence (or a cell obtained from such an organism). In some embodiments of any of the above aspects, the vectors or nucleic acid sequences described herein are codon-optimized for expression in a mammal or mammalian cell, e.g., a mouse, a mouse cell, or a human cell. In some embodiments of any of the above aspects, the vectors or nucleic acid sequences described herein are codon-optimized for expression in a human cell. In some embodiments of any of the above aspects, the vectors or nucleic acids described herein are codon-optimized for expression in a yeast or yeast cell. In some embodiments of any of the above aspects, the vectors or nucleic acid sequences described herein are codon-optimized for expression in a bacterial cell. In some embodiments of any of the above aspects, the vectors or nucleic acid sequences described herein are codon optimized for expression in E. coli cells.

[0200] The term "expression vector" as used herein refers to a vector that induces the expression of RNA or polypeptide from a sequence linked to a transcriptional regulatory sequence on the vector.The sequence that is expressed is often, but not necessarily, heterologous to the cell.Expression vectors may also contain additional elements, for example, expression vectors have two replication systems, thus allowing expression vectors to be maintained in two organisms, for example, in human cells for expression, and in prokaryotic hosts for cloning and amplification.

[0201] The term "viral vector" as used herein refers to a nucleic acid vector construct that contains at least one element derived from a virus and has the ability to be packaged into a viral vector particle. The viral vector can contain a nucleic acid encoding a polypeptide as described herein in place of non-essential viral genes. The vector and / or particle can be used to transfer any nucleic acid to cells in vitro or in vivo. Numerous forms of viral vectors are known in the art.

[0202] The viral vector system that can be utilized in the present invention includes, but is not limited to, (a) adenovirus vector; (b) retrovirus vector, such as lentivirus vector, mouse Moloney leukemia virus, etc.; (c) adeno-associated virus vector; (d) herpes simplex virus vector; (e) SV40 vector; (f) polyomavirus vector; (g) papillomavirus vector; (h) picornavirus vector; (i) poxvirus vector, such as orthopox, such as vaccinia virus vector or avipox, such as canarypox or fowlpox; and (j) helper-dependent or gutless adenovirus.Replication-defective viruses may also be advantageous.In some embodiments, the vector is an adeno-associated virus vector.

[0203] In some embodiments, viral vectors are used, such as adeno-associated viral (AAV) vectors.AAV usually infects mammals, including humans, but is non-pathogenic, and has been developed and used as gene therapy vectors in clinical trials in the United States and Europe (Daya and Berns, Clinical Microbiology Reviews 2008, 21, 583-593).AAV vectors can be prepared by any one of a number of methods available to those skilled in the art. Exemplary AAV vectors are disclosed in Walsh et al., Proc. Soc. Exp. Biol. Med. 204:289-300 (1993); U.S. Pat. No. 5,436,146, which is incorporated herein by reference; Gao et al., Gene Therapy 2005, 5, 285-297; Vandenberghe et al., Gene Therapy 2009, 16, 311-319; Gao et al., PNAS 2002, 99, 11854-11859; Gao et al., PNAS 2003, 100, 6081-6086; Gao et al., J. of Virology 2004, 78, 6381-6388.

[0204] In some embodiments, the vector is an adeno-associated virus (AAV) vector.In some embodiments, the AAV vector is AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV9.HR, AAVrh.10, AAVMYO or AAV2.5.In some embodiments, the AAV is AAV9.

[0205] In some embodiments, the vector is episomal. The use of a suitable episomal vector provides a means to maintain the nucleotide of interest in the subject in the form of high copy number extrachromosomal DNA, thereby eliminating the potential effects of chromosomal integration.

[0206] As a non-limiting example, in some embodiments, plasmid expression vectors can be used. Plasmid expression vectors include pcDNA3.1, pET vectors (Novagen®), pGEX vectors (GE Life Sciences), and pMAL vectors (New England labs. Inc.) for protein expression in E. coli host cells, such as BL21, BL21(DE3) and AD494(DE3)pLysS, Rosetta(DE3), and Origami(DE3) (Novagen®); the strong CMV promoter-based pcDNA3.1 (Invitrogen™ Inc.) and pCIneo vectors (Promega) for expression in mammalian cell lines, such as CHO, COS, HEK-293, Jurkat, and MCF-7; and the replication-deficient adenovirus vector pAdeno for adenovirus-mediated gene transfer and expression in mammalian cells. X, pAd5F35, pLP-Adeno-X-CMV (Clontech®), pAd / CMV / V5-DEST, pAd-DEST vectors (Invitrogen™ Inc.); pLNCX2, pLXSN, and pLAPSN retroviral vectors for use with Clontech's Retro-X™ system for retroviral-mediated gene transfer and expression in mammalian cells; pLenti4 / V5-DEST™, pLenti6 / V5-DEST™, and pLenti6.2 / V5-GW / lacZ (INVITROGEN™ Inc.) for lentiviral-mediated gene transfer and expression in mammalian cells; For adeno-associated virus-mediated gene transfer and expression in mammalian cells, examples include, but are not limited to, adenovirus-associated virus expression vectors, such as pAAV-MCS, pAAV-IRES-hrGFP, and pAAV-RC vectors (Stratagene®).

[0207] Retroviral vectors can also be used (see Miller et al., Meth. Enzymol. 217:581-599(1993)). These retroviral vectors contain the components necessary for correct packaging of the viral genome and integration into the host cell DNA. In another embodiment, the vector is a poxvirus, such as a vaccinia virus, such as an attenuated vaccinia, such as Modified Virus Ankara (MVA) or NYVAC, an avipox, such as fowlpox or canarypox. In another embodiment, a lentiviral vector is used, such as an HIV-based vector described in U.S. Pat. Nos. 6,143,520; 5,665,557; and 5,981,276, which are incorporated herein by reference. The vector may or may not integrate into the cell genome. The construct may include viral sequences for transfection if desired. Alternatively, the vectors, for example EPV and EBV vectors, are capable of episomal replication.

[0208] As used herein, a "viral particle" refers to a particle that contains at least one viral capsid polypeptide and a nucleic acid molecule, such as a viral genome and / or a viral vector. Viral vectors are discussed elsewhere herein.

[0209] The engineered cell composition may include cells that are autologous to the subject being treated, or may include cells that are xenogeneic to the subject being treated. In some embodiments of any of the above aspects, the treatment method may include a first step of obtaining cells from a donor and / or subject and contacting the cells with polymer particles ex vivo. Prior to performing the contacting / attaching step, the cells may be isolated, e.g., isolated from a blood sample obtained from the donor / subject, and the contacting / attaching may be performed in a sample containing multiple cell types, e.g., in a blood sample.

[0210] Alternatively, the method of treatment may involve administering polymer particles alone, which bind / contact / attach to the subject's own cells in vivo.

[0211] The methods described herein may further include localizing the engineered cell composition to a desired location or destroying / degrading / releasing the polymer particles at a desired time or location. Such controlled and / or inducible stimulus-responsive polymer particles are described herein above. In some embodiments of any of the above aspects, the second region of the polymer particle comprises poly(lactic acid-co-caprolactone) (PLCL), and the method further comprises increasing the temperature of at least one region of the subject to allow cells to phagocytose the polymer particles. In some embodiments of any of the above aspects, the second region of the polymer particle comprises a near-infrared degradable polymer or polymer linker, and the method further comprises subjecting at least one region of the subject to near-infrared light to allow cells to phagocytose the polymer particles. In some embodiments of any of the above aspects, the polymer particle comprises an echogenic liposome, and the method further comprises subjecting at least one region of the subject to ultrasound to allow cells to phagocytose the polymer particles or to release a payload reagent. In some embodiments of any of the above aspects, the polymer particles comprise magnetic nanoparticles and the method further comprises subjecting at least one region of the subject to a magnetic field to allow cells to phagocytose the polymer particles or to release a payload reagent. In some embodiments of any of the above aspects, the polymer particles comprise gold nanoparticles and the method further comprises subjecting at least one region of the subject to electromagnetic waves to allow cells to phagocytose the polymer particles or to release a payload reagent.

[0212] The term "cancer" as used herein generally relates to a type of disease or condition in which abnormal cells divide uncontrollably and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymphatic system. There are several major types of cancer. Carcinoma is cancer that begins in the skin or tissues that line or cover the internal organs. Sarcoma is cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supporting tissues. Leukemia is cancer that begins in blood-forming tissues, such as bone marrow, and causes the production and entry of large numbers of abnormal blood cells into the blood. Lymphoma and multiple myeloma are cancers that begin in immune system cells. Central nervous system cancer is cancer that begins in tissues of the brain and spinal cord.

[0213] In some embodiments of any of the above aspects, the cancer is a primary cancer. In some embodiments of any of the above aspects, the cancer is a malignant cancer. As used herein, the term "malignant" refers to a cancer in which a group of tumor cells exhibit one or more of the following: uncontrolled proliferation (i.e., dividing beyond normal limits), invasion (i.e., invading and destroying adjacent tissues), and metastasis (i.e., spreading to other parts of the body via lymph or blood). As used herein, the term "metastasizing" refers to the spread of cancer from one part of the body to another. A tumor formed by the spreading cells is called a "metastatic tumor" or "metastasis." A metastatic tumor contains cells that resemble cells in the original (primary) tumor. As used herein, the term "benign" or "non-malignant" refers to a tumor that may grow larger but does not spread to other parts of the body. Benign tumors are self-limited and typically do not invade or metastasize.

[0214] "Cancer cell" or "tumor cell" refers to an individual cell of a cancerous growth or tissue. A tumor generally refers to a swelling or lesion formed by abnormal proliferation of cells, which may be benign, pre-malignant, or malignant. Most cancer cells form tumors, but some, e.g., leukemia, do not always form tumors. For tumor-forming cancer cells, the terms cancer (cell) and tumor (cell) are used interchangeably.

[0215] As used herein, the term "neoplasm" refers to any new and abnormal growth of tissue, e.g., an abnormal tissue mass, growth that exceeds and is uncoordinated with the growth of normal tissue. Thus, a neoplasm may be a benign neoplasm, a premalignant neoplasm, or a malignant neoplasm.

[0216] A subject with cancer or tumor is a subject with objectively measurable cancer cells present in the subject's body.This definition includes malignant, actively growing cancers as well as tumors or micrometastases that may be dormant.Cancer that migrates from its original location and disseminates to other vital organs may ultimately lead to the death of the subject due to the functional deterioration of the affected organ.

[0217] Examples of cancer include: carcinoma, lymphoma, blastoma, sarcoma, leukemia, basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and CNS cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectal cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer (including gastrointestinal cancer); glioblastoma (GBM); liver cancer; hepatoma; intraepithelial neoplasia; kidney or renal cancer; laryngeal cancer; leukemia; liver cancer; lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung); lymphomas, including Hodgkin's lymphoma and non-Hodgkin's lymphoma; melanoma; myeloma; neuroblastoma; Oral cavity cancer (e.g., lips, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; respiratory system cancer; salivary gland cancer; sarcoma; skin cancer; squamous cell carcinoma; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; urinary system cancer; vulvar cancer; other carcinomas and sarcomas; and B-cell lymphomas (low-grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-cleaved cell NHL; bulky mass disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disease (PTLD), as well as abnormal vascular proliferation associated with phacomatosis, edema (e.g., edema associated with brain tumors), and Meigs' syndrome.

[0218] A "cancer cell" is a cancer cell, precancerous cell, or transformed cell in vivo, ex vivo, or in tissue culture that has a spontaneous or induced phenotypic change that does not necessarily involve the incorporation of new genetic material. Transformation can occur from infection with a transforming virus and the incorporation of new genomic nucleic acid, or from the incorporation of exogenous nucleic acid, but can also occur naturally or following exposure to a carcinogen and the resulting mutation of an endogenous gene. Transformation / cancer is associated with, for example, morphological changes, cellular immortalization, aberrant growth control, foci formation, anchorage independence, malignant potential, loss of contact inhibition and density restriction of growth, growth factor or serum independence, tumor-specific markers, invasiveness or metastasis, and tumor growth in a suitable animal host, such as nude mice.

[0219] As used herein, "inflammation" refers to a complex biological response to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and initiate healing processes to tissues. Thus, the term "inflammation" includes any cellular process resulting from the production of proinflammatory cytokines, inflammatory mediators, and / or the action of the cytokines so produced, leading to associated downstream cellular events, such as fever, fluid accumulation, swelling, abscess formation, and cell death. Inflammation can include both acute responses (i.e., responses characterized by vigorous inflammatory processes) and chronic responses (i.e., responses characterized by slow progression and the formation of new connective tissue). Acute and chronic inflammation may be differentiated by the cell types involved. Acute inflammation often involves polymorphonuclear neutrophils. In contrast, chronic inflammation is usually characterized by lymphohistiocytic and / or granulomatous responses.

[0220] Inflammatory condition is any disease state characterized by inflamed tissue (e.g., infiltrates of leukocytes such as lymphocytes, neutrophils, macrophages, eosinophils, mast cells, basophils, and dendritic cells), or inflammatory process that induces or contributes to the abnormal clinical and histological characteristics of this disease state. Inflammatory condition includes, but is not limited to, inflammatory condition of skin, inflammatory condition of lung, inflammatory condition of joint, inflammatory condition of gastrointestinal tract, inflammatory condition of eye, inflammatory condition of endocrine system, inflammatory condition of cardiovascular system, inflammatory condition of kidney, inflammatory condition of liver, inflammatory condition of central nervous system, or sepsis-related condition. In some embodiments, inflammatory condition is related to wound healing. In some embodiments, inflammation treated according to the methods described herein may be inflammation of skin; inflammation caused by substance abuse or drug addiction; inflammation related to infection; inflammation of cornea; inflammation of retina; inflammation of spinal cord; inflammation related to organ regeneration; and inflammation of lung.

[0221] In some embodiments, the inflammatory condition may be an autoimmune disease.Non-limiting examples of autoimmune disease may include type 1 diabetes; systemic lupus erythematosus; rheumatoid arthritis; psoriasis; inflammatory bowel disease; Crohn's disease; and autoimmune thyroiditis.

[0222] In some embodiments, the subject who needs to treat inflammation may have temporomandibular joint disorder; COPD; smoke-induced lung injury; kidney dialysis-related disorder; spinal cord injury; graft-versus-host disease; bone marrow transplantation or its complications; infection; trauma; pain; incision; surgical incision; chronic pain disorder; chronic bone disorder; mastitis; and joint disease, and may be diagnosed with temporomandibular joint disorder; COPD; smoke-induced lung injury; kidney dialysis-related disorder; spinal cord injury; graft-versus-host disease; bone marrow transplantation or its complications; infection; trauma; pain; incision; surgical incision; chronic pain disorder; chronic bone disorder; mastitis; and joint disease.In some embodiments, trauma may include combat-related injury or tissue injury during surgery.Smoke-induced lung injury may be caused by exposure to tobacco smoke, environmental pollutants (e.g., smog or forest fire), or industrial exposure. As non-limiting examples, inflammatory conditions include inflammatory conditions of the skin, such as Sweet's syndrome, pyoderma gangrenosum, subcorneal pustulosis, erythema elevatum, Behcet's disease or acute generalized exanthematous pustulosis, bullous disorders, psoriasis, conditions resulting in pustular lesions, acne, acne vulgaris, dermatitis (e.g., contact dermatitis, atopic dermatitis, seborrheic dermatitis, eczematous dermatitis, fissure eczema, photoallergic dermatitis, phototoxic dermatitis, phytophotodermatitis, radiation dermatitis, stasis dermatitis, or allergic contact dermatitis), eczema, ulcers, and erosions resulting from trauma to the skin or mucous membranes, burns, ischemia, some types of ichthyosis, epidermolysis bullosa, hypertrophic scars, keloids, natural aging, photoaging skin changes, frictional blistering caused by mechanical shearing of the skin (frictional blistering caused by mechanical shearing of the skin). Symptoms may include blistering, skin atrophy due to topical use of corticosteroids, and inflammation of mucous membranes (e.g., cheilitis, chapped lips, nasal irritation, mucositis, and vulvovaginitis).

[0223] As non-limiting examples, the inflammatory condition may be a pulmonary inflammatory condition, such as asthma, bronchitis, chronic bronchitis, bronchiolitis, pneumonia, sinusitis, emphysema, adult respiratory distress syndrome, pulmonary inflammation, pulmonary fibrosis, and cystic fibrosis (which may additionally or alternatively involve the gastrointestinal tract or other tissues). As non-limiting examples, the inflammatory condition may be a joint inflammatory condition, such as rheumatoid arthritis, rheumatoid spondylitis, juvenile rheumatoid arthritis, osteoarthritis, gouty arthritis, infectious arthritis, psoriatic arthritis, and other arthritic conditions. As non-limiting examples, the inflammatory condition may be a gastrointestinal or intestinal inflammatory condition, such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, and distal proctitis. As a non-limiting example, the inflammatory condition may be an inflammatory condition of the eye, such as dry eye syndrome, uveitis (including iritis), conjunctivitis, scleritis, and keratoconjunctivitis sicca. As a non-limiting example, the inflammatory condition may be an inflammatory condition of the endocrine system, such as autoimmune thyroiditis (Hashimoto's disease), Graves' disease, type I diabetes, and acute and chronic inflammation of the adrenal cortex. As a non-limiting example, the inflammatory condition may be an inflammatory condition of the cardiovascular system, such as coronary infarction injury, peripheral vascular disease, myocarditis, vasculitis, revascularization of stenosis, atherosclerosis, and vascular disease associated with type II diabetes. As a non-limiting example, the inflammatory condition may be an inflammatory condition of the kidney, such as glomerulonephritis, interstitial nephritis, lupus nephritis, and nephritis secondary to Wegener's disease, acute renal failure secondary to acute nephritis, post-obstruction syndrome, and tubular ischemia. As a non-limiting example, the inflammatory condition may be an inflammatory condition of the liver, such as hepatitis (which may result from viral infection, autoimmune response, drug treatment, toxins, environmental agents, or secondary to primary injury), biliary atresia, primary biliary cirrhosis, and primary sclerosing cholangitis.As a non-limiting example, the inflammatory condition may be an inflammatory condition of the central nervous system, such as multiple sclerosis and neurodegenerative diseases, such as Alzheimer's disease or dementia associated with HIV infection.As non-limiting examples, the inflammatory condition may be an inflammatory condition of the central nervous system, such as MS; all types of encephalitis and meningitis; acute disseminated encephalomyelitis; acute transverse myelitis; neuromyelitis optica; focal demyelinating syndromes (e.g., Barrow's concentric sclerosis and the Marburg variant of MS); progressive multifocal leukoencephalopathy; subacute sclerosing panencephalitis; acute hemorrhagic leukoencephalitis (Hurst's disease); human T-lymphotropic virus type 1 associated myelopathy / tropical spastic paraparesis; Devic's disease; human immunodeficiency virus encephalopathy; human immunodeficiency virus vacuolar myelopathy; peripheral neuropathies; Guillain-Barré syndrome and other immune-mediated neuropathies; and myasthenia gravis. As a non-limiting example, the inflammatory condition can be a sepsis-associated condition, such as systemic inflammatory response syndrome (SIRS), septic shock, or multiple organ dysfunction syndrome (MODS).Further non-limiting examples of inflammatory conditions include endotoxic shock, periodontal disease, polychondritis; periarticular disorders; pancreatitis; systemic lupus erythematosus; Sjogren's syndrome; vasculitis sarcoidosis amyloidosis; allergies; anaphylaxis; systemic mastocytosis; pelvic inflammatory disease; multiple sclerosis; multiple sclerosis (MS); Celiac disease, Guillain-Barré syndrome, sclerosing cholangitis, autoimmune hepatitis, Raynaud's phenomenon, Goodpasture's syndrome, Wegener's granulomatosis, polymyalgia rheumatica, temporal arteritis / giant cell arteritis, chronic fatigue syndrome (CFS), autoimmune Addison's disease, ankylosing spondylitis, acute disseminated encephalomyelitis, antiphospholipid syndrome, aplastic anemia, idiopathic thrombocytopenic purpura, myasthenia gravis, opsoclonus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, pemphigus, pernicious anemia, polyarthritis in dogs, Reiter's syndrome, Takayasu's arteritis, warm autoimmune hemolytic anemia, fibromyalgia (FM), autoinflammatory PAPA syndrome, familial Mediterranean fever, polymyalgia rheumatica, polyarteritis nodosa, Churg-Strauss syndrome; Fibrinous alveolitis, hypersensitivity pneumonitis, allergic aspergillosis, cryptogenic pulmonary eosinophilia, bronchiolitis obliterans organising pneumonia; urticaria; lupoid hepatitis; familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal-onset multisystem inflammatory disease, transplant rejection (including allograft rejection and graft-versus-host disease), otitis, chronic obstructive pulmonary disease, sinusitis, chronic prostatitis, reperfusion injury, silicosis, inflammatory myopathy, hypersensitivity and migraine. In some embodiments, the inflammatory condition is associated with an infection, e.g., a viral infection, a bacterial infection, a fungal infection, a parasitic infection, or a prion infection. In some embodiments, the inflammatory condition is associated with an allergic response. In some embodiments, the inflammatory condition is associated with a pollutant (e.g., asbestosis, silicosis, or beryllium disease).

[0224] In some embodiments, the inflammatory condition may be a localized condition, such as a rash or an allergic reaction, hi some embodiments, the inflammation is associated with a wound.

[0225] In some embodiments, the technology described herein relates to a method for promoting wound healing. As used herein, "wound" broadly refers to damage to an organ or tissue of an organism, typically involving tissue disruption or membrane (e.g., skin) destruction resulting from external violence, mechanical action, or infection. A wound may be epithelial, endothelial, connective tissue, ocular, or any other type of wound in which the strength and / or integrity of the tissue is reduced, e.g., trauma has caused damage to the tissue. The term "wound" encompasses injuries including, but not limited to, lacerations, abrasions, avulsions, cuts, burns, velocity wounds (e.g., gunshot wounds), penetrating wounds, puncture wounds, contusions, diabetic wounds, hematomas, lacerated wounds, and / or crushing injuries. In one aspect, the term "wound" refers to damage to the skin and subcutaneous tissue that starts in any one of a variety of ways (e.g., pressure sores from prolonged bed rest, wounds caused by trauma, cuts, ulcers, burns, etc.) and has a variety of characteristics. The term "wound healing" as used herein refers to the process by which an injured organism's body initiates tissue repair at the wound site (e.g., skin). The wound healing process requires, in part, angiogenesis and revascularization of the injured tissue. Wound healing can be measured by assessing such parameters as contraction, wound area, closure percentage, closure rate percentage, and / or vascular infiltration, as known to those skilled in the art. In some embodiments, the particles and compositions described herein can be applied topically to promote wound healing.

[0226] The compositions and methods described herein can be administered to a subject having one of the conditions described herein or diagnosed as having one of the conditions described herein. In some embodiments, the methods described herein include administering to a subject an effective amount of a composition described herein, e.g., a polymer particle and / or engineered cell composition, to alleviate the symptoms of a condition described herein. In some embodiments of any of the above aspects, a therapeutically effective dose of the composition is administered. As used herein, "alleviating symptoms" refers to reversing any condition or symptom associated with a disease. Compared to an equivalent untreated control, such reduction is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, 99% or more reduction as measured by any standard technique. Various means for administering the compositions described herein to a subject are known to those skilled in the art. Such methods may include, but are not limited to, parenteral, intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, dermal, injection, or intratumoral administration. Administration can be local or systemic.

[0227] The term "effective amount" as used herein refers to the amount of a composition necessary to alleviate at least one or more symptoms of a disease or disorder, and relates to the amount of a pharmacological composition sufficient to produce a desired effect. Thus, the term "therapeutically effective amount" refers to an amount of a composition sufficient to produce a particular therapeutic effect when administered to a typical subject. Effective amount as used herein in various contexts will also include an amount sufficient to delay the onset of a disease symptom, alter the course of a disease symptom (e.g., but not limited to, slowing down the progression of a disease symptom), or reverse a disease symptom. Thus, it is generally not feasible to specify an exact "effective amount". However, for any given case, one of ordinary skill in the art can determine an appropriate "effective amount" using only routine experimentation.

[0228] Effective doses, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by standard pharmaceutical procedures for determining LD50 (the dose lethal to 50% of the population) and ED50 (the dose therapeutically effective in 50% of the population). Dosages may vary depending on the dosage form used and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Compositions and methods that exhibit high therapeutic indices are preferred. Therapeutically effective doses can be estimated initially from cell culture assays. A dose can also be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of active ingredient that achieves half-maximal inhibition of symptoms) as determined in cell culture or suitable animal models. Plasma levels can be measured, for example, by high performance liquid chromatography. The effect of any particular dosage can be monitored by suitable bioassays, in particular for tumor size and / or inflammation markers. Dosage can be determined by a physician and can be adjusted as necessary to meet the observed effects of the treatment.

[0229] In some embodiments of any of the above aspects, the composition described herein may be a pharmaceutical composition. In some embodiments, the technology described herein relates to a pharmaceutical composition comprising the polymer particles and / or engineered cell compositions described herein and, optionally, a pharmaceutically acceptable carrier. In some embodiments, the active ingredient of the pharmaceutical composition comprises the polymer particles and / or engineered cell compositions described herein. In some embodiments, the active ingredient of the pharmaceutical composition consists essentially of the polymer particles and / or engineered cell compositions described herein. In some embodiments, the active ingredient of the pharmaceutical composition consists of the polymer particles and / or engineered cell compositions described herein. Pharmaceutically acceptable carriers and diluents include saline, aqueous buffer solutions, solvents, and / or dispersion media. The use of such carriers and diluents is well known in the art.Some non-limiting examples of materials that can serve as pharma- ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, microcrystalline cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol (PEG); (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids; (23) serum components, such as serum albumin, HDL, and LDL; (22) C2-C. 12 Alcohol, e.g., ethanol; and (23) other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, coloring agents, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants may also be present in the formulation. Terms such as "excipient", "carrier", and "pharmaceutical acceptable carrier" are used interchangeably herein. In some embodiments, the carrier inhibits the degradation of the active agent as described herein.

[0230] In some embodiments, pharmaceutical compositions comprising the polymer particles and / or engineered cell compositions described herein may be in parenteral dosage forms. Because administration of parenteral dosage forms typically bypasses the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or can be sterilized before administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry or lyophilized products ready for dissolution or suspension in a pharma- ceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. In addition, sustained release parenteral dosage forms can be prepared for administration to a patient, including, but not limited to, DUROS®-type dosage forms and dose-dumping.

[0231] Suitable vehicles that can be used to provide parenteral dosage forms of the disclosed engineered cell compositions are well known to those skilled in the art. Examples include, but are not limited to, sterile water; water for injection USP; physiological saline; glucose solution; aqueous vehicles, such as but not limited to sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles, such as but not limited to ethyl alcohol, polyethylene glycol, and propylene glycol; and non-aqueous vehicles, such as but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0232] In some embodiments of any of the above aspects, the polymer particles and / or engineered cell compositions described herein are administered as a monotherapy, e.g., the subject is not receiving another treatment for the condition.

[0233] In some embodiments of any of the above aspects, the methods described herein may further comprise administering to the subject a second agent and / or treatment, e.g., as part of a combination therapy. Non-limiting examples of second agents and / or treatments include radiation therapy, surgery, gemcitabine, cisplatin, paclitaxel, carboplatin, bortezomib, AMG479, FK506, vorinostat, acriflavine, rituximab, temozolomide, rapamycin, ABT-737, PI-103; alkylating agents, e.g., thiotepa and CYTOXAN® cyclosphosphamide; alkylsulfonates, e.g., busulfan, improsulfan, and piposulfan; aziridines, e.g., benzodopa, carboquone, meturedopa, and uredopa; Ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamime; acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin, and biceresin synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including the synthetic analogs KW-2189 and CB1-TM1); erytherobin; pancratistatin; sarcodictyin; spongistatin;nitrogen mustards, such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics, such as the calicheamicins, especially calicheamicin gamma 1 and calicheamicin omega 1 (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994)); dynemicins, including dynemicin A; Bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, authramicin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® doxorubicin (morpholino-doxorubicin , cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins, such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU);Folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; Edatraxate; Defofamine; Demecolcine; Diaziquone; Elformithine; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Ronidynin; Maytansinoids, such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraerine; Pentostatin; Fenamet; Pirarubicin; Losoxantrone; Podophyllinic acid; 2-Ethylhydrazide; Procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); Razoxane; Rhizoxin; Sizofuran; Spirogermanium; Tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids such as TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® Cremophor free, an albumin engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE®; Vinorelbine; Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Xeloda; Ibandronate; Irinotecan (Camptosar, CPT-11) (including irinotecan with 5-FU and leucovorin treatment regimens); Topoisomerase inhibitors RFS2000; Difluoromethylornithine (DMFO); Retinoids, e.g., retinoic acid; Capecitabine; Combretastatins; Leucovorin (LV); Oxaliplatin, including oxaliplatin treatment regimens (FOLFOX); Lapatinib (Tykerb®); These may include inhibitors of PKC-α, Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva®)) and inhibitors of VEGF-A, which reduce cell proliferation, as well as pharma- ceutically acceptable salts, acids, or derivatives of any of the foregoing;

[0234] Additionally, the treatment methods may further include the use of radiation or radiotherapy. Additionally, the treatment methods may further include the use of surgical treatment.

[0235] As a non-limiting example, if a subject is to be treated for inflammation according to the methods described herein, the subject may also be administered / received a second agent and / or treatment known to be beneficial to subjects suffering from pain or inflammation. Examples of such agents and / or treatments include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs - e.g., aspirin, ibuprofen, or naproxen); corticosteroids including glucocorticoids (e.g., cortisol, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, and beclomethasone); methotrexate; sulfasalazine; leflunomide; anti-TNF drugs; cyclophosphamide; pro-resolving drugs; mycophenolate; or opiates (e.g., endorphins, enkephalins, and dynorphins), steroids, analgesics, barbiturates, oxycodone, morphine, lidocaine, and the like.

[0236] In certain embodiments, an effective dose of the composition comprising the polymer particles and / or engineered cell compositions described herein may be administered to the patient at one time. In certain embodiments, an effective dose of the composition may be administered to the patient repeatedly. In some embodiments, after an initial treatment regimen, treatment may be administered less frequently. For example, after biweekly treatment for three months, treatment may be repeated monthly for six months or a year or longer. Treatment according to the methods described herein may reduce marker levels or symptoms of a condition, for example, by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, or more.

[0237] The dosage of the compositions described herein is determined by a physician and can be adjusted, if necessary, to suit the observed effects of the treatment. With regard to duration and frequency of treatment, a skilled clinician will often monitor the subject to ascertain when the treatment is providing therapeutic benefit and to determine whether to increase or decrease the dosage, increase or decrease the frequency of administration, discontinue treatment, resume treatment, or make other changes to the treatment regimen. The dosing schedule can vary from once a week to daily, depending on a number of clinical factors, such as the subject's sensitivity to the composition. The desired dose or amount of activation may be administered once or divided into subdoses, e.g., 2-4 subdoses, and administered over a period of time, e.g., throughout the day, at appropriate intervals, or other suitable schedules. In some embodiments, administration may be chronic, e.g., one or more doses and / or treatments per day for a period of weeks or months. Exemplary dosing and / or treatment regimens are daily, twice daily, three times daily, or four times daily, or more, administration for a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, or more. Compositions comprising the polymer particles and / or engineered cell compositions described herein may be administered over a period of time, for example, over a period of 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 25 minutes.

[0238] The dosage range for administering the compositions described herein according to the methods described herein depends, for example, on the efficacy of the particles or cells and the degree to which symptoms, markers, or indicators of the conditions described herein are desired to be reduced, for example, the desired percent reduction in tumor growth, or, for example, the degree to which wound healing is desired to be induced. The dosage should not be so large as to cause adverse side effects, such as excessive inflammation or immunosuppression. In general, the dosage will vary according to the age, condition, and sex of the patient, and can be determined by those skilled in the art. The dosage can also be adjusted by the individual physician in the event of any complications.

[0239] For example, the efficacy of the polymer particles and / or engineered cell compositions in treating a condition described herein or inducing a response as described herein can be ascertained by one of skill in the art. However, as the term "effective treatment" is used herein, a treatment is deemed "effective treatment" if, following treatment according to the methods described herein, one or more of the signs or symptoms of a condition described herein are altered in a beneficial manner, other clinically recognized symptoms are improved or ameliorated, or a desirable response is induced, e.g., by at least 10%. Efficacy can be assessed, for example, by assessing markers, indicators, symptoms, and / or incidence, or any other suitable measurable parameter, of a condition treated according to the methods described herein. Efficacy can also be measured by the failure of an individual to deteriorate (i.e., the progression of symptoms ceases) as assessed by hospitalization or the need for medical intervention. Methods for measuring these indicators are known to those of skill in the art and / or described herein. Treatment includes any treatment of disease in an individual or animal (some non-limiting examples include humans or animals), including (1) inhibiting the disease, e.g., preventing the worsening of symptoms (e.g., pain or inflammation); or (2) alleviating the severity of the disease, e.g., causing regression of symptoms. An effective amount for treating a disease means an amount that, when administered to a subject in need of treatment, is sufficient to provide effective treatment for the disease, as this term is defined herein. The efficacy of an agent can be determined by assessing physical indicators of the condition or desired response. It is well within the capabilities of a person skilled in the art to monitor the efficacy of administration and / or treatment by measuring any one such parameter, or any combination of parameters. Efficacy can be evaluated in animal models of the treatment of conditions described herein, e.g., cancer. When using experimental animal models, efficacy of treatment is demonstrated when a statistically significant change in markers, e.g., tumor growth, tumor size, inflammation, wound size, etc., is observed.

[0240] For convenience, the meanings of some terms and phrases used in the specification, examples, and the appended claims are provided below. Unless otherwise specified or implied from the context, the following terms and phrases include the meanings provided below. The definitions are provided to help explain certain embodiments and are not intended to limit the claimed invention, since the scope of the invention is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention belongs. If there is an apparent discrepancy between the usage of a term in the art and the definition of a term provided herein, the definition provided herein shall prevail.

[0241] For convenience, certain terms employed in the specification, examples, and appended claims herein are collected here.

[0242] The terms "reduce", "reduced", "reduction", or "inhibit" are all used herein to mean a statistically significant reduction. In some embodiments, "reduce", "reduction", or "reduce" or "inhibit" typically means a reduction of at least 10% compared to a reference level (e.g., the absence of a given treatment or agent), and may include, for example, a reduction of at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more. As used herein, "reduce" or "inhibit" does not encompass complete inhibition or reduction compared to a reference level. "Complete inhibition" is 100% inhibition compared to a reference level. The reduction may preferably be to a level accepted as being within the normal range for individuals without a given disorder.

[0243] The terms "increased", "increase", "enhance", or "activate" are all used herein to mean an increase by a statistically significant amount. In some embodiments, the terms "increased", "increase", "enhance", or "activate" can mean an increase of at least 10% compared to a reference level, e.g., an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% compared to a reference level, or an increase of 100% or less, or any increase of 10-100%, or an increase of at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold, or any increase of 2-fold to 10-fold or more compared to a reference level. An "increase" in the context of a marker or symptom is a statistically significant increase in such level.

[0244] The term "antibody reagent" as used herein refers to a polypeptide that contains at least one immunoglobulin variable domain or immunoglobulin variable domain sequence and specifically binds to a particular antigen. An antibody reagent may include an antibody or a polypeptide that includes an antigen-binding domain of an antibody. In some embodiments of any of the above aspects, an antibody reagent may include a monoclonal antibody or a polypeptide that includes a monoclonal antigen-binding domain. For example, an antibody may include a heavy (H) chain variable region (abbreviated herein as VH) and a light (L) chain variable region (abbreviated herein as VL). In another example, an antibody includes two heavy (H) chain variable regions and two light (L) chain variable regions. The term "antibody reagent" encompasses antigen-binding fragments of antibodies (e.g., single chain antibodies, Fab and sFab fragments, F(ab')2, Fd fragments, Fv fragments, scFv, and domain antibody (dAb) fragments, as well as complete antibodies.

[0245] The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that immunospecifically binds to an antigen. The term also refers to antibodies composed of two immunoglobulin heavy chains and two immunoglobulin light chains, as well as various forms including full-length antibodies and antigen-binding portions thereof, including, for example, immunoglobulin molecules, monoclonal antibodies, chimeric antibodies, CDR-grafted antibodies, humanized antibodies, Fab, Fab', F(ab')2, Fv, disulfide-linked Fv, scFv, single domain antibodies (dAbs), diabodies, multispecific antibodies, dual specific antibodies, anti-idiotypic antibodies, bispecific antibodies, functionally active epitope-binding portions thereof, and / or bifunctional hybrid antibodies. Each heavy chain is composed of a variable region of the heavy chain (abbreviated herein as HCVR or VH) and a constant region of the heavy chain. The heavy chain constant region is composed of three domains, CH1, CH2, and CH3. Each light chain is composed of a variable region of said light chain (abbreviated herein as LCVR or VL) and a constant region of said light chain. The light chain constant region is composed of a CL domain. The VH and VL regions are further divided into hypervariable regions called complementarity determining regions (CDRs) and may be interspersed with conserved regions called framework regions (FRs). Thus, each VH and VL region is composed of three CDRs and four FRs, arranged from the N-terminus to the C-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. This structure is well known to those skilled in the art.

[0246] Antibodies and / or antibody reagents may include immunoglobulin molecules, monoclonal antibodies, chimeric antibodies, CDR-grafted antibodies, humanized antibodies, fully human antibodies, Fab, Fab', F(ab')2, Fv, disulfide-linked Fv, scFv, single domain antibodies, diabodies, multispecific antibodies, bispecific antibodies, anti-idiotypic antibodies, bispecific antibodies, and functionally active epitope-binding portions thereof.

[0247] The term "nanobody" or single domain antibody (sdAb) as used herein refers to antibodies containing a small single variable domain (VHH) of antibodies derived from camelids and dromedaries. Antibody proteins derived from members of the camel and dromedary (Camelus baclrianus and Calelus dromaderius) family, including New World members such as the Llama species (Lama paccos, Lama glama, and Lama vicugna), have been characterized with respect to size, structural complexity, and antigenicity to human subjects. Certain IgG antibodies from this family of mammals as found in nature lack light chains and are therefore structurally distinct from the typical four-chain quaternary structure with two heavy and two light chains of antibodies derived from other animals. See PCT / EP93 / 02214 (WO94 / 04678 published March 3, 1994), which is incorporated herein by reference in its entirety.

[0248] A region of a camelid antibody, a small single variable domain specified as VHH, can be engineered to give rise to small proteins with high affinity for targets, resulting in low molecular weight antibody-derived proteins known as "camelid nanobodies", see U.S. Patent No. 5,759,808, issued June 2, 1998. See also Stijlemans, B. et al., 2004 J Biol Chem 279: 1256-1261; Dumoulin, M. et al., 2003 Nature 424: 783-788; Pleschberger, M. et al. 2003 Bioconjugate Chem 14: 440-448; Cortez-Retamozo, V. et al. 2002 Int J Cancer 89: 456-62; and Lauwereys, M. et al. 1998 EMBO J. 17: 3512-3520, each of which is incorporated herein by reference in its entirety. Engineered libraries of camelid antibodies and antibody fragments are commercially available, for example, from Ablynx, Ghent, Belgium. As with other antibodies of non-human origin, the amino acid sequences of camelid antibodies can be recombinantly altered to obtain sequences that more closely resemble human sequences, i.e., the nanobodies can be "humanized", thus further reducing the naturally low antigenicity of camelid antibodies to humans.

[0249] The molecular weight of camelid nanobodies is approximately one-tenth that of human IgG molecules, and the physical diameter of the protein is only a few nanometers. One consequence of the small size is that camelid nanobodies can bind to antigenic sites that are functionally invisible to much larger antibody proteins. That is, camelid nanobodies are useful as reagents for detecting antigens that are obscure using classical immunological techniques, and as potential therapeutic agents. Thus, yet another consequence of the small size is that camelid nanobodies can bind to and inhibit specific sites in grooves or narrow clefts of target proteins, and thus serve in a capacity that more closely resembles the function of classical low molecular weight drugs than that of classical antibodies. Further consequences of the low molecular weight and compact size are that camelid nanobodies are extremely heat resistant, stable to extreme pH and proteolytic digestion, and have low antigenicity. See U.S. Patent Application No. 20040161738, published August 19, 2004, which is incorporated herein by reference in its entirety. These features, combined with low antigenicity to humans, indicate great therapeutic potential.

[0250] The term "specific binding" as used herein refers to a chemical interaction between two molecules, compounds, cells, and / or particles, where a first entity binds to a second target entity with greater specificity and affinity than it binds to a third, non-target entity. In some embodiments, specific binding may refer to an affinity of a first entity for a second target entity that is at least 10 times, at least 50 times, at least 100 times, at least 500 times, at least 1000 times, or more than its affinity for a third, non-target entity. A reagent specific for a particular target is one that exhibits specific binding to that target under the conditions of the assay being utilized.

[0251] The term "polymer" as used herein refers to oligomers, cooligomers, polymers, and copolymers, such as random block, multiblock, star, grafted, gradient copolymers, and combinations thereof. The average molecular weight of the polymer may be from 500 to about 500,000, such as from 20,000 to about 500,000, as determined by gel permeation chromatography. Without limitation, any polymeric material known in the art may be used in the present invention. Thus, in some embodiments, the polymer is a polysaccharide, a polypeptide, a polynucleotide, a fumaric / sebacic acid copolymer, a poloxamer, polylactic acid, polyglycolide, polycaprolactone, a copolymer of polylactic acid and polyglycolic acid, a polyanhydride, polyepsiloncaprolactone, a polyamide, a polyurethane, a polyesteramide, a polyorthoester, a polydioxanone, a polyacetal, a polyketal, a polycarbonate, a polyorthocarbonate, a polydihydropyran, a polyphosphazene, a polyhydroxybutyrate, a polyhydroxyvalerate, a polyalkylene oxalate, a polyalkylene succinate, a poly(malic acid), a poly(amino acid), a polyvinylpyrrolidone, a polyethylene glycol, a polyhydroxycellulose, a polymethylmethacrylate, a chitin, a chitosan, a polylactic acid and a polyglycolate, a polyanhydride, a polyepsiloncaprolactone, a polyamide, a polyurethane, a polyesteramide, a polyorthoester, a polydioxanone, a polyacetal, a polyketal, a polycarbonate, a polyorthocarbonate, a polydihydropyran, a polyphosphazene, a polyhydroxybutyrate, a polyhydroxyvalerate, a polyalkylene oxalate, a polyalkylene succinate, a poly(malic acid), a poly(amino acid), a polyvinylpyrrolidone, a polyethylene glycol, a polyhydroxycellulose, a polymethylmethacrylate, a chitin, a chitosan, a polylactic acid and a polyglycolate, ... The polymer is selected from the group consisting of copolymers of glycolic acid, poly(glycerol sebacate) (PGS), gelatin, collagen, silk, alginate, cellulose, polynucleic acid, cellulose acetate (including cellulose diacetate), polyethylene, polypropylene, polybutylene, polyethylene terephthalate (PET), polyvinyl chloride, polystyrene, polyamide, nylon, polycarbonate, polysulfide, polysulfone, hydrogels (e.g., acrylics), polyacrylonitrile, polyvinyl acetate, cellulose acetate butyrate, nitrocellulose, urethane / carbonate copolymers, styrene / maleic acid copolymers, poly(ethyleneimine), hyaluron, heparin, agarose, pullulan, and copolymers, terpolymers, and any combination thereof.

[0252] In some embodiments, the polymer is a biocompatible polymer. As used herein, the term "biocompatible" means that it is essentially non-cytotoxic and non-immunogenic when in contact with bodily fluids or tissues. The term "biocompatible polymer" refers to a polymer that is non-toxic, chemically inert, and substantially non-immunogenic when used internally in a subject, and is substantially insoluble in blood. Biocompatible polymers may be non-biodegradable, or preferably biodegradable. Preferably, biocompatible polymers are also non-inflammatory when used in situ.

[0253] Biodegradable polymers are disclosed in the art. Examples of suitable biodegradable polymers include, but are not limited to, linear polymers such as polypeptides, polynucleotides, polysaccharides, polylactic acid, polyglycolide, polycaprolactone, copolymers of polylactic acid and polyglycolic acid, polyanhydrides, polyepsiloncaprolactone, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polydihydropyrans, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycols, polyhydroxycelluloses, polymethyl methacrylates, chitin, chitosan, copolymers of polylactic acid and polyglycolic acid, poly(glycerol sebacate) (PGS), fumaric acid, sebacic acid, and copolymers and terpolymers comprising one or more of the foregoing. Other biodegradable polymers include, for example, gelatin, collagen, silk, chitosan, alginate, cellulose, polynucleic acid, and the like.

[0254] Suitable non-biodegradable biocompatible polymers include, by way of example, cellulose acetate (including cellulose diacetate), polyethylene, polypropylene, polybutylene, polyethylene terephthalate (PET), polyvinyl chloride, polystyrene, polyamide, nylon, polycarbonate, polysulfide, polysulfone, hydrogels (e.g., acrylics), polyacrylonitrile, polyvinyl acetate, cellulose acetate butyrate, nitrocellulose, urethane / carbonate copolymers, styrene / maleic acid copolymers, poly(ethyleneimine), poloxamers (e.g., Pluronics, e.g., poloxamer 407 and 188), hyaluronic acid, heparin, agarose, pullulan, and copolymers comprising one or more of the foregoing, e.g., ethylene / vinyl alcohol copolymer (EVOH).

[0255] In some embodiments, the biocompatible polymer is a copolymer of polylactic acid and polyglycolic acid, poly(glycerol sebacate) (PGS), poly(ethyleneimine), Pluronic (poloxamer 407, 188), hyaluronic acid, heparin, agarose, or Pullulan.

[0256] In some embodiments, the polymer is a homopolymer, copolymer, or block polymer.

[0257] In some embodiments, the polymer comprises side chains selected from the group consisting of amide or ester groups, hi some embodiments, the polymer is biodegradable, biocompatible, and non-toxic.

[0258] The polymer can be derivatized with a second polymer, where the first polymer and the second polymer can be the same or different, for example, the polymer can be derivatized with polyethylene glycol (PEG).

[0259] In some embodiments, polymer or part of polymer can be connected by linker.In some embodiments, the components of polymer particle, such as payload reagent or monocyte targeting ligand and / or macrophage targeting ligand, can be connected by linker.As used herein, the term "linker" refers to the moiety that connects two parts of a compound.The linker is typically a direct bond or an atom, such as oxygen or sulfur, a unit, such as NR, C(O), C(O)O, C(O)NR, SO, SO, SONH, or a chain of atoms, such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl alkyl, aryl alkenyl, aryl alkynyl, heteroaryl alkyl, heteroaryl alkenyl, heteroaryl alkynyl, heterocyclyl alkyl, heterocyclyl alkenyl, heterocyclyl alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylaryl alkyl, alkylaryl alkenyl, alkylaryl alkynyl, alkenylaryl alkyl, alkenylaryl alkenyl, alkenylaryl alkynyl, alkynylaryl alkyl, alkynylaryl alkenyl, alkynylaryl alkynyl, alkylheteroaryl alkyl, alkylheteroaryl alkenyl, alkylheteroaryl alkynyl, alkenylheteroaryl a alkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylheterocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, a and alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylhereroaryl, where one or more methylenes may be interrupted or terminated with O, S, S(O), SO, N(R), C(O), a cleavable linking group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic, and R is hydrogen, acyl, aliphatic, or substituted aliphatic.

[0260] The linker may be a branched linker. The branching site of the branched linker may be at least divalent, but may also be a trivalent, tetravalent, pentavalent, or hexavalent atom or group exhibiting such multiple valencies. In certain embodiments, the branching site may be -N, -N(Q)-C, -OC, -SC, -SS-C, -C(O)N(Q)-C, -OC(O)N(Q)-C, -N(Q)C(O)-C, or -N(Q)C(O)OC, where Q is independently, in each instance, H or an alkyl that may be substituted. In some embodiments, the branching site may be an acrylic acid ester (acrylate), a cyanoacrylic acid ester (cyanoacrylate), or a methylacrylic acid ester (methylacrylate).

[0261] In various embodiments, the linker is a cleavable linker. A cleavable linker means that the linker can be cleaved to release the two sites that the linker is anchoring. The cleavable linker can be sensitive to a cleavage agent, including but not limited to enzymes, pH, redox potential, or the presence of degradable molecules. Examples of such agents include: redox agents that are selected for a specific substrate or have no substrate specificity, including, for example, oxidases or reductases, or reducing agents that exist in cells and can degrade redox-cleavable linking groups by reduction, such as mercaptans; esterases; amidases; agents that can create endosomes or acidic environments, such as agents that make pH 5 or lower; enzymes that can act as general acids to hydrolyze or degrade acid-cleavable linking groups, peptidases (may be substrate-specific) and proteases, and phosphatases.

[0262] In some embodiments, the linker is polyethylene glycol. In some embodiments, the linker is a peptide comprising the sequence DEVD (SEQ ID NO:1). In further embodiments, the linker is a peptide comprising the sequence KDEVDAP (SEQ ID NO:2). In yet further embodiments, the linker is a peptide comprising the sequence GKDEVDAP (SEQ ID NO:3). In some embodiments, the cleavable linker can be cleaved by an enzyme.

[0263] In some embodiments, the cleavable linker is selected from the group consisting of a small molecule, hi some preferred embodiments, the cleavable linker is selected from the group consisting of a peptide or a polypeptide.

[0264] As used herein, "subject" refers to a human or animal. Typically, an animal is a vertebrate, such as a primate, rodent, livestock, or game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, such as rhesus monkeys. Rodents include mice, rats, woodchucks, ferrets, rabbits, and hamsters. Livestock and game animals include cattle, horses, pigs, deer, bison, buffalo, feline species, such as domestic cats, canine species, such as dogs, foxes, wolves, avian species, such as chickens, emus, ostriches, and fish, such as trout, catfish, and salmon. In some embodiments, the subject is a mammal, such as a primate, such as a human. The terms "individual," "patient," and "subject" are used interchangeably herein.

[0265] Preferably, the subject is a mammal. The mammal may be, but is not limited to, a human, a non-human primate, a mouse, a rat, a dog, a cat, a horse, or a cow. A non-human mammal can be conveniently used as a subject that represents an animal model of a disease. The subject may be male or female.

[0266] The subject may be a subject who has previously been diagnosed or identified as suffering from a condition that requires treatment or one or more complications associated with such a condition, and optionally has already undergone treatment for such a condition or one or more complications associated with such a condition. Alternatively, the subject may also be a subject who has not previously been diagnosed with such a condition or one or more complications associated with such a condition. For example, the subject may be a subject who shows one or more risk factors for such a condition or one or more complications associated with such a condition, or a subject who does not show risk factors.

[0267] A subject "in need of" treatment for a particular condition may be a subject who has the condition, who has been diagnosed with the condition, or who is at risk of developing the condition.

[0268] The terms "compound" and "drug" refer to any entity that is not normally present or does not exist at the levels administered and / or provided to a cell, tissue, or subject. A drug can be selected from the group including: chemicals; organic or inorganic small molecules; signaling molecules; nucleic acid sequences; nucleic acid analogs; proteins; peptides; enzymes; aptamers; peptidomimetics, peptide derivatives, peptide analogs, antibodies; intracellular antibodies; biological macromolecules, extracts made from biological materials such as bacterial, plant, fungal, or animal cells or tissues; natural or synthetic compositions or functional fragments thereof. In some embodiments, a drug is any chemical, entity, or moiety, including but not limited to synthetic and natural non-proteinaceous entities. In certain embodiments, a drug is a small molecule having a chemical moiety. For example, the chemical moiety includes unsubstituted or substituted alkyl, aromatic, or heterocyclyl moieties, including macrolides, leptomycin, and related natural products or analogs thereof. A drug may be known to have a desired activity and / or properties and may be selected from a library of diverse compounds.

[0269] The term "small molecule" as used herein refers to a chemical agent that may include, but is not limited to, peptides, peptidomimetics, amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, aptamers, nucleotides, nucleotide analogs, organic or inorganic compounds having a molecular weight of less than about 10,000 grams / mole (i.e., including heteroorganic and organometallic compounds), organic or inorganic compounds having a molecular weight of less than about 5,000 grams / mole, organic or inorganic compounds having a molecular weight of less than about 1,000 grams / mole, organic or inorganic compounds having a molecular weight of less than about 500 grams / mole, as well as salts, esters, and other pharma- ceutically acceptable forms of such compounds.

[0270] As used herein, the terms "protein" and "polypeptide" are used interchangeably herein to designate a series of amino acid residues connected together by peptide bonds between the α-amino and carboxyl groups of adjacent residues. The terms "protein" and "polypeptide" refer to a polymer of amino acids, including modified amino acids (e.g., phosphorylated amino acids, glycated amino acids, glycosylated amino acids, etc.) and amino acid analogs, regardless of their size or function. "Protein" and "polypeptide" are often used in reference to relatively large polypeptides, whereas the term "peptide" is often used in reference to small polypeptides. However, the usage of these terms in the art overlaps. The terms "protein" and "polypeptide" are used interchangeably herein when referring to gene products and fragments thereof. Thus, exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants, fragments, and analogs of the foregoing.

[0271] Furthermore, the various embodiments described herein are intended to encompass variants (natural or otherwise), alleles, homologs, conservatively modified variants, and / or conservatively substituted variants of any particular polypeptide described. For amino acid sequences, those skilled in the art will recognize that individual substitutions, deletions, or additions to a nucleic acid, peptide, polypeptide, or protein sequence that change a single amino acid or a small percentage of amino acids in the encoded sequence are "conservatively modified variants" in which the change replaces an amino acid with a chemically similar amino acid and retains the desired activity of the polypeptide. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles consistent with the present disclosure.

[0272] Certain amino acids can be replaced with residues having similar physicochemical characteristics, for example, an aliphatic residue can be replaced with another (e.g., Ile, Val, Leu, or Ala with another), or a polar residue can be replaced with another (e.g., between Lys and Arg; between Glu and Asp; or between Gln and Asn). Other such conservative substitutions, such as the substitution of entire regions with similar hydrophobic characteristics, are well known. Polypeptides containing conservative amino acid substitutions can be tested in any one of the assays described herein to confirm that the desired activity of the native or reference polypeptide, such as M1 polarizing activity and specificity, is retained.

[0273] Amino acids can be classified according to similarities in the properties of the amino acid side chains (A.L. Lehninger, in Biochemistry, 2nd ed., pp. 73-75, Worth Publishers, New York (1975)): (1) nonpolar: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M); (2) uncharged polar: Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q); (3) acidic: Asp (D), Glu (E); (4) basic: Lys (K), Arg (R), His (H). Alternatively, natural residues can be classified into groups based on shared side chain properties: (1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that affect chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe. Non-conservative substitutions involve exchanging a member of one of these classes for another. Particular conservative substitutions include, for example, Ala to Gly or Ser; Arg to Lys; Asn to Gln or His; Asp to Glu; Cys to Ser; Gln to Asn; Glu to Asp; Gly to Ala or Pro; His to Asn or Gln; Ile to Leu or Val; Leu to Ile or Val; Lys to Arg, Gln or Glu; Met to Leu, Tyr or Ile; Phe to Met, Leu or Tyr; Ser to Thr; Thr to Ser; Trp to Tyr; Tyr to Trp; and / or Phe to Val, Ile, or Leu.

[0274] In some embodiments, the polypeptides described herein (or nucleic acids encoding such polypeptides) may be functional fragments of one of the amino acid sequences described herein. As used herein, a "functional fragment" is a peptide fragment or segment that retains at least 50% of the wild-type reference polypeptide activity according to the assay described below. A functional fragment may include conservative substitutions of the sequences disclosed herein.

[0275] In some embodiments, the polypeptides described herein may be variants of the sequences described herein. In some embodiments, the variants are conservatively modified variants. Conservative substitution variants may be obtained, for example, by mutation of natural nucleotide sequences. A "variant" as referred to herein is a polypeptide that is substantially homologous to a natural or reference polypeptide, but has an amino acid sequence that differs from the amino acid sequence of the natural or reference polypeptide due to one or more deletions, insertions, or substitutions. The DNA sequence encoding the variant polypeptide includes sequences that encode variant proteins or fragments thereof that contain one or more additions, deletions, or substitutions of nucleotides when compared to the natural or reference DNA sequence, but retain activity. A wide variety of PCR-based site-directed mutagenesis approaches are known in the art and can be applied by those skilled in the art.

[0276] A variant amino acid sequence or DNA sequence may be at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more identical to a native or reference sequence. The degree of homology (percent identity) between a native and a variant sequence can be determined, for example, by comparing the two sequences using freely available computer programs commonly used for this purpose on the World Wide Web (e.g., BLASTp or BLASTn with default settings).

[0277] Alterations in the native amino acid sequence can be accomplished by any of a number of techniques known to those skilled in the art. Mutations can be introduced at specific loci, for example, by synthesizing oligonucleotides containing the mutated sequence, flanked by restriction sites that allow ligation with fragments of the native sequence. After ligation, the resulting reconstructed sequence encodes an analog with the desired amino acid insertion, substitution, or deletion. Alternatively, site-specific oligonucleotide-directed mutagenesis procedures can be used to provide altered nucleotide sequences with specific codons altered according to the required substitution, deletion, or insertion. Techniques for making such changes are well established and include, for example, those disclosed by Walder et al. (Gene 42:133, 1986); Bauer et al. (Gene 37:73, 1985); Craik (BioTechniques, January 1985, 12-19); Smith et al. (Genetic Engineering: Principles and Methods, Plenum Press, 1981); and U.S. Patent Nos. 4,518,584 and 4,737,462, which are incorporated herein by reference in their entirety. Any cysteine ​​residue that is not involved in maintaining the correct conformation of the molecule can also be generally replaced with serine to improve the oxidative stability of the polypeptide and prevent aberrant cross-linking. Conversely, cysteine ​​bonds can be added to the polypeptide to improve its stability or facilitate oligomerization.

[0278] In some embodiments of any of the above aspects, the polypeptide, nucleic acid, or cell described herein can be engineered.As used herein, "engineered" refers to an aspect that has been manipulated by the hand of man.For example, a polypeptide is considered to be "engineered" to be different from the aspect that exists in nature when at least one aspect of the polypeptide, such as its sequence, has been manipulated by the hand of man.As is a common practice and will be understood by those skilled in the art, even if actual manipulation has been performed on the previous entity, the descendants of the engineered cell are still typically referred to as "engineered".

[0279] The terms "treat", "treatment", "treating" or "amelioration" as used herein refer to therapeutic treatments that aim to reverse, alleviate, ameliorate, inhibit, slow or stop the progression or severity of a condition associated with a disease or disorder, e.g., cancer. The term "treat" includes reducing or alleviating at least one side effect or symptom of a condition, disease or disorder associated with a condition. A treatment is generally "effective" if one or more symptoms or clinical markers are reduced. Alternatively, a treatment is "effective" if the progression of a disease is slowed or stopped. That is, "treatment" includes not only improvement of a symptom or marker, but also a cessation or at least slowing of the progression or worsening of a symptom compared to that expected in the absence of treatment. Beneficial or desirable clinical results include, but are not limited to, alleviation of one or more symptoms, reduction in the extent of a disease, stabilization of a disease state (i.e., no worsening), delay or slowing of disease progression, amelioration or palliation of a disease state, remission (whether partial or complete), and / or reduction in mortality, whether detectable or undetectable. The term "treatment" of a disease also includes removing the symptoms or side effects of the disease (including symptomatic treatment).

[0280] The term "pharmaceutical composition" as used herein refers to an active agent in combination with a pharma- ceutically acceptable carrier, e.g., a carrier commonly used in the pharmaceutical industry. The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without causing undue toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. In some embodiments of any of the above aspects, the pharma- ceutically acceptable carrier may be a carrier other than water. In some embodiments of any of the above aspects, the pharma- ceutically acceptable carrier may be a cream, emulsion, gel, liposome, nanoparticle, and / or ointment. In some embodiments of any of the above aspects, the pharma- ceutically acceptable carrier may be an artificial or engineered carrier, e.g., a carrier in which the active ingredient is not found to occur in nature.

[0281] The term "administering" as used herein refers to placing a compound disclosed herein in a subject by a method or route that results in at least partial delivery of the agent at a desired site. Pharmaceutical compositions containing the compounds disclosed herein can be administered by any suitable route that results in effective treatment in the subject.

[0282] The terms "statistically significant" or "significantly" refer to statistical significance, generally meaning a difference of 2 standard deviations (2 SD) or greater.

[0283] Except as in the operating examples or unless otherwise specified, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about." The term "about" when used in connection with percentages can mean ±1%.

[0284] As used herein, the term "comprising" means that other elements may be present in addition to the elements shown and defined. The use of "comprising" indicates inclusion rather than limitation.

[0285] The term "consisting of" refers to the compositions, methods, and each component thereof described herein, excluding any element not recited in the description of the embodiment.

[0286] As used herein, the term "consisting essentially of" refers to elements required for a particular embodiment. The presence of the term allows for the presence of additional elements that do not materially affect the basic and novel or functional characteristics of the embodiment of the invention.

[0287] The term "specific binding" as used herein refers to the chemical interaction between two molecules, compounds, cells, and / or particles, where a first entity binds to a second target entity with greater specificity and affinity than it binds to a third entity that is a non-target.In some embodiments, specific binding can refer to the affinity of a first entity to a second target entity that is at least 10 times, at least 50 times, at least 100 times, at least 500 times, at least 1000 times, or more than its affinity to a third non-target entity.A reagent that is specific for a particular target is a reagent that exhibits specific binding to that target under the conditions of the assay being used.

[0288] In some cases, such as hyaluronic acid with adehyde modifications, specific binding can be achieved by covalent bonds to enhance cell / particle interactions.

[0289] The singular terms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The abbreviation "eg" is derived from the Latin exempli gratia and is used herein to denote a non-limiting example. Thus, the abbreviation "eg" is synonymous with the term "for example."

[0290] Grouping of different elements or aspects of the invention disclosed herein should not be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When any such inclusion or deletion is made, the specification is deemed to include the group as amended herein, and thus fulfills the written description of all Markush groups used in the appended claims.

[0291] Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meaning commonly understood by those skilled in the art to which this disclosure belongs.It should be understood that the present invention is not limited to the specific methods, protocols, and reagents described herein, and therefore may vary.The terminology used herein is intended only to describe specific embodiments, and is not intended to limit the scope of the present disclosure, which is defined only by the claims. Definitions of common terms in immunology and molecular biology can be found in The Merck Manual of Diagnosis and Therapy, 19th Edition, published by Merck Sharp & Dohme Corp., 2011 (ISBN 978-0-911910-19-3); Robert S. Porter et al. (eds.), The Encyclopedia of Molecular Cell Biology and Molecular Medicine, published by Blackwell Science Ltd., 1999-2012 (ISBN 9783527600908); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8); Immunology by Werner Luttmann, published by Elsevier, 2006; Janeway's Immunobiology, Kenneth Murphy, Allan Mowat, Casey Weaver (eds.), Taylor & Francis Limited, 2014 (ISBN 0815345305, 9780815345305); Lewin's Genes XI , Jones & Bartlett Publishers, 2014 (ISBN-1449659055); Michael Richard Green and Joseph Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, USA (2012)(ISBN 1936113414); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (2012)(ISBN 044460149X); Laboratory Methods in Enzymology: DNA, Jon Lorsch (ed.) Elsevier, 2013 (ISBN 0124199542); Current Protocols in Molecular Biology (CPMB), Frederick M. Ausubel (ed.), John Wiley and Sons, Inc., 2014 (ISBN 047150338X, 9780471503385); およびCurrent Protocols in Immunology (CPI)(John E. Coligan, ADA M Kruisbeek, David H Margulies, Ethan M Shevach, Warren Strobe, (eds.) John Wiley and Sons, Inc., 2003 (ISBN 0471142735, 9780471142737), the contents of all of which are incorporated herein by reference in their entireties.

[0292] Those of skill in the art can readily identify useful chemotherapeutic agents (see, e.g., Physicians' Cancer Chemotherapy Drug Manual 2014, Edward Chu, Vincent T. DeVita Jr., Jones & Bartlett Learning; Principles of Cancer Therapy, Chapter 85 in Harrison's Principles of Internal Medicine, 18th edition; Therapeutic Targeting of Cancer Cells: Era of Molecularly Targeted Agents and Cancer Pharmacology, Chs. 28-29 in Abeloff's Clinical Oncology, 2013 Elsevier; and Fischer DS (ed): The Cancer Chemotherapy Handbook, 4th ed. St. Louis, Mosby-Year Book, 2003).

[0293] In some embodiments of any of the above aspects, the disclosure described herein does not relate to processes for cloning humans, processes for altering the genetic identity of a human germ line, use of human embryos for industrial or commercial purposes, processes for altering the genetic identity of animals that are likely to cause suffering to humans or animals without substantial medical benefit, nor to animals resulting from such processes.

[0294] Other terms are defined herein within the description of various aspects of the invention.

[0295] All patents and other publications, including references, issued patents, published patent applications, and co-pending patent applications cited throughout this application, are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, methods described in such publications that may be used in conjunction with the technology described herein. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the content of these documents are based on the information available to the applicant and do not constitute an admission as to the accuracy of the dates or contents of these documents.

[0296] The description of the aspects of the present disclosure is not intended to be exhaustive or to limit the present disclosure to the precise form disclosed. Although certain aspects and examples of the present disclosure have been described herein for illustrative purposes, various equivalent modifications are possible within the scope of the present disclosure, as will be understood by those skilled in the relevant art. For example, although steps or functions of a method are shown in a certain order, alternative embodiments may perform the functions in a different order, or may accomplish the functions substantially simultaneously. The disclosure of the present disclosure provided herein can be applied to other procedures or methods as appropriate. Various embodiments described herein can be combined to provide further aspects. Aspects of the present disclosure can be modified, as necessary, to employ the compositions, functions, and concepts of the above references and applications to provide still further aspects of the present disclosure. Furthermore, the idea of ​​biological functional equivalence allows some changes to be made to protein structures without affecting biological or chemical actions in terms of type or amount. These and other changes can be made to the present disclosure in light of the detailed description. All such modifications are intended to be within the scope of the appended claims.

[0297] Particular elements of any of the above embodiments may be combined with elements of other embodiments or substituted for elements of other embodiments. Additionally, although advantages have been described in the context of these embodiments that are associated with certain embodiments of the present disclosure, other embodiments may also exhibit such advantages, and not all embodiments necessarily need to exhibit such advantages to be within the scope of the present disclosure.

[0298] In some aspects, the technology may be defined in any of the following numbered paragraphs: 1. A polymer particle comprising at least one imaging agent. 2. The polymer particle described in paragraph 1, wherein the at least one imaging agent is at least one MRI contrast agent. 3. The polymer particle of paragraph 1 or paragraph 2, further comprising at least one binding reagent selected from the group consisting of: a CD11b binding reagent; a CD3 binding reagent; a CD19 binding reagent; a CD49b binding reagent; and a CD56 binding reagent. 4. A polymeric particle comprising at least one binding reagent selected from the group consisting of: a CD11b binding reagent; a CD3 binding reagent; a CD19 binding reagent; a CD49b binding reagent; and a CD56 binding reagent. 5. The polymer particle of any of the preceding clauses, wherein the binding reagent is a CD11b-binding reagent; a CD3-binding reagent; or a CD19-binding reagent. 6. A polymer particle according to any preceding claim, wherein the binding reagent is an antibody or an antibody reagent. 7. A polymer particle according to any preceding paragraph, wherein the antibody or antibody reagent is an anti-CD11b antibody or an anti-CD11b antibody reagent. 8. The polymer particle of any of items 6 to 7, wherein the antibody or antibody reagent comprises one or more CDRs of an antibody or antibody reagent selected from Table 2. 9. The polymer particle according to any one of items 6 to 8, wherein the antibody or antibody reagent comprises six CDRs of an antibody or antibody reagent selected from Table 2. 10. The polymer particle of any preceding claim, wherein the binding reagent further comprises a streptavidin or biotin molecule. 11. The polymer particle of any of the preceding paragraphs, further comprising one or more cell adhesion molecules (e.g., polyelectrolytes). 12. A polymer particle according to any of the preceding paragraphs, comprising a single region comprising a hydrogel of one or more cell adhesion molecules (e.g., polyelectrolytes). 13. The polymer particle according to any one of items 1 to 10, further comprising one or more structural polymers. 14. A polymer particle as described in paragraph 13, comprising a single domain comprising a hydrogel of one or more structural polymers. 15. a) a first region comprising a first selected cell adhesion molecule or molecules (e.g., polyelectrolytes) and, optionally, one or more binding reagents; b) a second region comprising a second selected type or types of cell adhesion molecules (e.g., polyelectrolytes); and c) a third region comprising one or more structural polymers and, optionally, one or more binding reagents; 11. The polymer particles according to any one of items 1 to 10, comprising: 16. The polymer particle of paragraph 15, wherein the first selected cell adhesion molecule or molecules comprise one or more of hyaluronic acid (HA) and bovine serum albumin (BSA), the second selected cell adhesion molecule or molecules are poly(allylamine) hydrochloride (PAH), and the one or more structural polymers are one or more of poly(lactic-co-glycolic acid) (PLGA), PLGA-PEG, PLGA-PEG-maleimide, and PLGA-PEG-biotin. 17. a) a first region comprising a first selected structural polymer or polymers and, optionally, one or more binding reagents; and b) a second region comprising a second selected structural polymer or polymers; 11. The polymer particles according to any one of items 1 to 10, comprising: 18. a) a first region comprising a first selected structural polymer or polymers and, optionally, one or more binding reagents; b) a second region comprising a second selected structural polymer or polymers; and c) a third region comprising a third selected structural polymer or polymers and, optionally, one or more binding reagents. 11. The polymer particles according to any one of items 1 to 10, comprising: 19. A polymer particle described in any one of items 15 to 18, wherein the second region is disposed between the first region and the third region and / or the second region separates the first region and the third region from each other. 20. A polymer particle described in any one of paragraphs 10 to 19, wherein the cell adhesion molecule comprises one or more of a cell adhesion polyelectrolyte, an immunoglobulin, or a ligand for a receptor on the cell surface. 21. The polymer particle of paragraph 20, wherein the cell-adherent polyelectrolyte comprises one or more of hyaluronic acid (HA), methylacrylated HA, hyaluronic acid-aldehyde, bovine serum albumin (BSA), PEG, dimethylacrylate PEG, and / or poly(allylamine) hydrochloride (PAH). 22. The polymer particle described in paragraph 21, wherein the cell-adherent polyelectrolyte comprises one or more of hyaluronic acid (HA), methylacrylated HA, and hyaluronic acid-aldehyde; and one or more of PEG and PEG dimethylacrylate. 23. The polymer particle of any of paragraphs 10 to 22, wherein the structural polymer comprises one or more of poly(lactic-co-glycolic acid) (PLGA); a combination of PLGA and poly(D,L-lactide-co-glycolide); a combination of PLGA and acid-terminated poly(D,L-lactide-co-glycolide); a 50:50 molar ratio combination of PLGA and poly(D,L-lactide-co-glycolide); -polyvinyl alcohol (PVA); hyaluronic acid (HA); gelatin; collagen; PLGA-PEG; or poly(glycerol sebacate) (PGS). 24. The polymer particle of any one of items 15 to 23, wherein the second region further comprises poly(lactic acid-co-caprolactone) (PLCL). 25. A polymer particle according to any one of items 15 to 24, wherein the second region comprises or further comprises a near-infrared decomposable polymer or polymer linker. 26. A polymer particle according to any one of paragraphs 1 to 25, comprising a binding reagent comprising a streptavidin molecule conjugated to a structural polymer further comprising biotin. 27. The polymer particle according to claim 26, comprising a binding reagent comprising a streptavidin molecule bound to the PLGA-PEG-biotin. 28. A polymer particle according to any one of paragraphs 1 to 26, comprising a coupling reagent coupled to PLGA-PEG-maleimide via a DTT-catalyzed reaction. 29. A polymer particle according to any one of paragraphs 1 to 25, comprising a binding reagent comprising a biotin molecule bound to a structural polymer further comprising streptavidin. 30. The polymer particles of any of the preceding claims, further comprising one or more imaging agents. 31. The polymer particle described in item 30, wherein the one or more imaging agents are selected from the group consisting of one or more contrast agents, one or more MRI contrast agents, one or more microbubbles, one or more metal ions, one or more radioisotopes, one or more optical imaging agents, one or more SPECT imaging agents, and one or more PET imaging agents. 32. The polymer particle of paragraph 31, wherein the one or more MRI contrast agents comprise one or more of a gadolinium-based contrast agent, superparamagnetic iron oxide, ultrasmall superparamagnetic iron oxide, superparamagnetic iron-platinum, manganese chelate, iron salt, and perflubron. 33. The polymer particle of paragraph 32, wherein the gadolinium-based contrast agent comprises one or more of gadolinium, gadoxetate, gadobutrol, gadoterate, gadoteridol, gadopentetate, gadobenate, gadopentetate dimeglumine, gadoxetate, gadoversetamide, gadodiamide, gadofosveset, gadocholetic acid, gadomeritol, gadomer 17, and gadoxetic acid. 34. The polymer particle of any one of paragraphs 30 to 33, wherein the one or more imaging agents further comprise a methyl acrylate ester. 35. The polymer particle of any one of paragraphs 30 to 34, wherein the one or more imaging agents are methylacrylate esters crosslinked with one or more of methylacrylated HA and dimethylacrylate PEG. 36. Polymer particles according to any of the preceding paragraphs, which are substantially discoid in shape. 37. The polymer particles of paragraph 36, which are disk-shaped. 38. The polymer particles according to any of the preceding paragraphs, wherein the diameter of the polymer particles is from about 100 nm to about 10 μm. 39. The polymer particles according to any of the preceding paragraphs, wherein the diameter of the polymer particles is from about 100 nm to about 1 μm. 40. A polymer particle according to any of the preceding claims, having a size of about 6 μm×500 nm. 41. A polymer particle according to any of the preceding claims, having a size of about 6 μm×250 nm. 42. Polymer particles according to any of the preceding paragraphs, having a size of 1-2 μm×7-9 μm. 43. 0.5×10 -11 cm 3 ~10×10 -11 cm 3 4. The polymer particle according to any of the preceding claims, having a volume of 44. 1.25×10 -11 cm 3 ~5×10 -11 cm 3 4. The polymer particle according to any of the preceding claims, having a volume of 45. Polymer particles according to any of the preceding paragraphs, having the shape of a rod, cylinder, cube, rectangular prism, hexahedron, or pyramid. 46. ​​The polymer particle of any preceding paragraph, further comprising one or more cell targeting ligands. 47. The polymer particle described in paragraph 46, wherein the cell targeting ligand is disposed in a region that includes a cell adhesion molecule (eg, a polyelectrolyte). 48. The polymer particle according to any one of items 46 to 47, wherein the cell targeting ligand is an IgG, an antibody, a polypeptide, or an aptamer. 49. The polymer particle of any preceding paragraph, further comprising one or more payload agents. 50. The polymer particle according to paragraph 49, wherein the payload reagent is a therapeutic molecule. 51. The polymer particle according to paragraph 49, wherein the payload reagent is a small molecule or a polypeptide. 52. A polymer particle according to any one of items 50 to 51, wherein the payload reagent is present in a mixed state with the structural polymer. 53. The polymer particle according to any one of items 50 to 52, wherein a payload reagent is present in the second region. 54. The polymer particle of any preceding paragraph, further comprising echogenic liposomes. 55. A polymer particle according to any preceding paragraph, further comprising magnetic nanoparticles. 56. The polymer particles of any preceding paragraph, further comprising gold nanoparticles. 57. A polymer particle according to any preceding paragraph, wherein the region is a layer. 58. The polymer particles of any of the preceding claims, further comprising at least one polarization inducer. 59. The polymer particle according to paragraph 58, wherein the polarization inducer is an M1 polarization inducer. 60. The polymer particle according to paragraph 58, wherein the polarization inducer is an M2 polarization inducer. 61. The polymer particle according to paragraph 59, wherein the M1 polarization inducer is selected from the group consisting of IFN-γ; TNF; TNF-α; a Toll-like receptor agonist (e.g., LPS, muramyl dipeptide, or lipoteichoic acid); GM-CSF; IL-1β; IL-6; IL-12; IL-23, and CD11b. 62. The polymer particle according to paragraph 60, wherein the M2 polarization inducer is selected from the group consisting of IL-4; IL-10; glucocorticoids (e.g., cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, and deoxycorticosterone acetate); M-CSF, TGF-β, IL-6; and IL-13. 63. A polymer particle described in any of paragraphs 58 to 62, wherein release of one or more of the polarization-inducing agents is triggered by contacting the particle with a small molecule or a nucleic acid. 64. A polymer particle described in any one of paragraphs 58 to 63, wherein the phenotype of macrophages is regulated by the release of one or more polarization-inducing agents. 65. a) cells; and b) The polymer particles according to any of the preceding paragraphs, which are disposed on the cell surface of a cell. 2. An engineered cell composition comprising: 66. The composition described in paragraph 65, wherein the cell is a monocyte, macrophage, natural killer cell, or neutrophil. 67. The composition according to paragraph 66, wherein the macrophage is an M0 macrophage. 68. The composition described in paragraph 66, wherein the macrophages are M1 polarized macrophages. 69. The composition described in paragraph 66, wherein the macrophages are M2 polarized macrophages. 70. The composition described in paragraph 66, wherein the macrophages are substantially induced to an M1 or M2 phenotype. 71. A method for obtaining an image of a subject, comprising the steps of administering to a subject a polymer particle described in any one of paragraphs 1 to 64 or an engineered cell composition described in any one of paragraphs 65 to 70, wherein the polymer particle comprises an imaging reagent, and then subjecting the subject to an imaging scan capable of detecting the imaging reagent. 72. The method of paragraph 71, wherein the cell is a macrophage, monocyte, or T cell. 73. A method for treating cancer and / or tumors in a subject in need thereof, comprising administering to the subject a polymer particle described in any of paragraphs 1 to 64 or an engineered cell composition described in any of paragraphs 65 to 70. 74. The method of claim 73, wherein the polymer particle comprises a payload reagent that is a chemotherapeutic agent. 75. The method of paragraph 73 or paragraph 74, further comprising the step of administering radiation or at least one chemotherapy to the subject. 76. The method of any one of paragraphs 73 to 75, wherein the cell is a macrophage, a NK cell, or a T cell. 77. A method for treating a fracture, wound, injury, or infection in a subject in need thereof, comprising administering to the subject a polymer particle described in any of paragraphs 1 to 64 or an engineered cell composition described in any of paragraphs 65 to 70. 78. The method of claim 77, wherein the polymer particle comprises a payload agent that is an antibiotic, antiviral, antibacterial, hemostatic, anti-inflammatory, or analgesic. 79. A method for treating inflammation in a subject in need thereof, comprising administering to the subject a polymer particle described in any of paragraphs 1 to 64 or an engineered cell composition described in any of paragraphs 65 to 70. 80. The method of claim 79, wherein the polymer particles comprise a payload agent that is an anti-inflammatory agent. 81. The method of paragraph 79 or 80, wherein the inflammation is in the lungs, joints, or skin. 82. The method of any one of paragraphs 77 to 80, wherein the polymer particles comprise IL-4. 83. The method of any one of paragraphs 77 to 82, wherein the cell is a neutrophil. 84. A method for treating an autoimmune condition in a subject in need thereof, comprising administering to the subject a polymer particle described in any of paragraphs 1 to 64 or an engineered cell composition described in any of paragraphs 65 to 70. 85. The method of claim 84, wherein the polymer particle comprises a payload reagent that is an immunosuppressant. 86. The method of paragraph 84 or 85, wherein the autoimmune condition is multiple sclerosis, diabetes, or arthritis. 87. The method of any one of paragraphs 84 to 86, wherein the cell is a macrophage or a T cell. 88. A method for providing hemostatic therapy to a subject in need thereof, comprising the step of administering to the subject a polymer particle described in any of paragraphs 1 to 64 or an engineered cell composition described in any of paragraphs 65 to 70. 89. The method of claim 88, wherein the polymer particle comprises a payload agent that is a hemostatic agent. 90. A method for treating a neurodegenerative disorder, a central nervous system disorder, or a peripheral nervous system disorder in a subject in need thereof, comprising administering to the subject a polymer particle described in any of paragraphs 1 to 64 or an engineered cell composition described in any of paragraphs 65 to 70. 91. The method of claim 90, wherein the polymer particle comprises a payload agent that is a therapeutic agent for treating a neurodegenerative disorder, a central nervous system disorder, or a peripheral nervous system disorder. 92. A method for delivering a payload reagent to the central nervous system of a subject in need thereof, comprising administering to the subject a polymer particle described in any of paragraphs 1-64 or an engineered cell composition described in any of paragraphs 65-70, wherein the cells are monocytes and / or the binding reagent is an anti-CD11b binding reagent. 93. A method for providing a gene therapy vector to a subject in need thereof, comprising the step of administering to the subject a polymer particle described in any of paragraphs 1-64 or an engineered cell composition described in any of paragraphs 65-70, wherein the polymer particle comprises a payload reagent that is a gene therapy vector. 94. The method according to paragraph 93, wherein the gene therapy vector is AAV. 95. A method for vaccinating a subject or inducing an immune response in a subject in need thereof, comprising the step of administering to a subject a polymer particle described in any of paragraphs 1 to 64 or an engineered cell composition described in any of paragraphs 65 to 70, wherein the polymer particle comprises a payload reagent that is an antigen. 96. The method of paragraph 95, wherein the cell is a B cell. 97. The method of any of paragraphs 71 to 96, wherein the cells are autologous to the subject. 98. The method of any of paragraphs 71 to 96, wherein the cells are xenogeneic to the subject. 99. The method of any of paragraphs 71 to 98, further comprising a first step of obtaining cells from a donor and / or subject and contacting the cells with polymer particles ex vivo. 100. The method of any of paragraphs 71 to 99, wherein a therapeutically effective dose of the polymer particle or engineered cell composition is administered.

[0299] In some aspects, the technology may be defined in any of the following numbered paragraphs: 1. A polymer particle comprising at least one imaging agent. 2. The polymer particle described in paragraph 1, wherein the at least one imaging agent is at least one MRI contrast agent. 3. The polymer particle of paragraph 1 or 2, further comprising at least one binding reagent selected from the group consisting of a CD11b-binding reagent; a CD3-binding reagent; a CD19-binding reagent; a CD49b-binding reagent; a CD56-binding reagent; a CD11a-binding reagent; a CD27-binding reagent; a CD44-binding reagent; a CD45-binding reagent; an NKG2D-binding reagent; an NKp30-binding reagent; an NKp46-binding reagent; and an ICAM1-binding reagent. 4. A polymer particle comprising at least one binding reagent selected from the group consisting of a CD11b-binding reagent; a CD3-binding reagent; a CD19-binding reagent; a CD49b-binding reagent; a CD56-binding reagent; a CD11a-binding reagent; a CD27-binding reagent; a CD44-binding reagent; a CD45-binding reagent; an NKG2D-binding reagent; an NKp30-binding reagent; an NKp46-binding reagent; and an ICAM1-binding reagent. 5. The polymer particle of any preceding claim, wherein the binding reagent is a CD11b-binding reagent; a CD3-binding reagent; or a CD19-binding reagent. 6. The polymer particle of any preceding claim, wherein the binding reagent is a CD11b binding reagent. 7. The polymer particle according to any of the preceding paragraphs, wherein the binding reagent is a CD45 binding reagent. 8. A polymer particle according to any preceding claim, wherein the binding reagent is an antibody or an antibody reagent. 9. The polymer particle according to any of the preceding paragraphs, wherein the antibody or antibody reagent is an anti-CD11b antibody or an anti-CD11b antibody reagent. 10. The polymer particle according to any of items 8 to 9, wherein the antibody or antibody reagent comprises one or more CDRs of an antibody or antibody reagent selected from Table 2. 11. The polymer particle according to any one of items 8 to 10, wherein the antibody or antibody reagent comprises six CDRs of an antibody or antibody reagent selected from Table 2. 12. The polymer particle of any preceding claim, wherein the binding reagent further comprises a streptavidin or biotin molecule. 13. The polymer particle of any preceding claim, further comprising ICAM1, NKp30, and / or NKp46. 14. A polymer particle comprising ICAM1, NKp30, and / or NKp46. 15. A polymer particle according to any preceding paragraph, comprising ICAM1 and NKp30. 16. The polymer particle of any preceding paragraph, further comprising one or more cell adhesion molecules (e.g., polyelectrolytes). 17. A polymer particle according to any of the preceding paragraphs, comprising a single region comprising a hydrogel of one or more cell adhesion molecules (e.g., polyelectrolytes). 18. The polymer particle according to any one of items 1 to 17, further comprising one or more structural polymers. 19. A polymer particle as described in paragraph 18, comprising a single domain comprising a hydrogel of one or more structural polymers. 20. a) a first region comprising a hydrogel of one or more structural polymers; and b) a second region comprising one or more cell adhesion molecules (e.g., polyelectrolytes) and one or more binding reagents; 19. The polymer particle according to any one of items 1 to 18, comprising: 21. a) a first region comprising a first selected cell adhesion molecule or molecules (e.g., polyelectrolytes) and, optionally, one or more binding reagents; b) a second region comprising a second selected type or types of cell adhesion molecules (e.g., polyelectrolytes); and c) a third region comprising one or more structural polymers and, optionally, one or more binding reagents; 19. The polymer particle according to any one of items 1 to 18, comprising: 22. The polymer particle described in paragraph 21, wherein the first selected one or more cell adhesion molecules comprise one or more of hyaluronic acid (HA) and bovine serum albumin (BSA), the second selected one or more cell adhesion molecules are poly(allylamine) hydrochloride (PAH), and the one or more structural polymers are one or more of poly(lactic-co-glycolic acid) (PLGA), PLGA-PEG, PLGA-PEG-maleimide, and PLGA-PEG-biotin. 23. a) a first region comprising a first selected structural polymer or polymers and, optionally, one or more binding reagents; and b) a second region comprising a second selected structural polymer or polymers; 19. The polymer particle according to any one of items 1 to 18, comprising: 24. a) a first region comprising a first selected structural polymer or polymers and, optionally, one or more binding reagents; b) a second region comprising a second selected structural polymer or polymers; and c) a third region comprising a third selected structural polymer or polymers and, optionally, one or more binding reagents. 19. The polymer particle according to any one of items 1 to 18, comprising: 25. A polymer particle according to any one of items 21, 22, and 24, wherein the second region is disposed between the first region and the third region and / or the second region separates the first region and the third region from each other. 26. A polymer particle described in any one of items 21, 22, 24, and 25, wherein the third region comprises one or more binding reagents and the first region does not comprise one or more binding reagents. 27. A polymer particle described in any one of items 21, 22, and 24 to 26, wherein the first selected structural polymer or polymers comprise or consist of PLGA, the second selected structural polymer or polymers comprise or consist of PVA, and the third selected structural polymer or polymers comprise or consist of PLGA. 28. A polymer particle described in any one of items 21, 22, and 24 to 27, wherein the second region and / or the third region contain one or more active agents. 29. The polymer particle of any one of items 21, 22, and 24 to 28, wherein the second region and the third region each contain one or more payload agents. 30. A polymer particle described in any of paragraphs 28 and 29, wherein one or more payload agents are N2 / M2 polarization inducers. 31. The polymer particle according to any one of items 28 to 30, wherein the second region contains IL-4 and the third region contains dexamethasone. 32. The polymer particle according to any one of items 28 to 31, wherein the second region contains IL-4 and heparin, and the third region contains dexamethasone. 33. A polymer particle described in any one of items 16 to 32, wherein the cell adhesion molecule comprises one or more of a cell adhesion polyelectrolyte, an immunoglobulin, or a ligand for a receptor on the cell surface. 34. The polymer particle described in paragraph 33, wherein the cell-adherent polyelectrolyte comprises one or more of hyaluronic acid (HA), methylacrylated HA, hyaluronic acid-aldehyde, bovine serum albumin (BSA), PEG, dimethylacrylate PEG, and / or poly(allylamine) hydrochloride (PAH). 35. The cell-adherent polyelectrolyte, a) one or more of hyaluronic acid (HA), methylacrylated HA, and hyaluronic acid-aldehyde; and one or more of PEG and PEG dimethylacrylate; b) poly(allylamine) hydrochloride (PAH) and one or more of hyaluronic acid (HA), methylacrylated HA, and hyaluronic acid-aldehyde; c) poly(allylamine) hydrochloride (PAH) and hyaluronic acid-aldehyde; d) poly(allylamine) hydrochloride (PAH) and hyaluronic acid (HA); or e) Poly(allylamine) hydrochloride (PAH) and bovine serum albumin (BSA) 34. The polymer particle according to claim 33, comprising: 36. The polymer particle of any of paragraphs 18 to 35, wherein the structural polymer comprises one or more of poly(lactic-co-glycolic acid) (PLGA); a combination of PLGA and poly(D,L-lactide-co-glycolide); a combination of PLGA and acid-terminated poly(D,L-lactide-co-glycolide); a 50:50 molar ratio combination of PLGA and poly(D,L-lactide-co-glycolide); -polyvinyl alcohol (PVA); hyaluronic acid (HA); gelatin; collagen; PLGA-PEG; or poly(glycerol sebacate) (PGS). 37. The polymer particle of any one of items 18 to 36, wherein the structural polymer comprises or consists of poly(lactic-co-glycolic acid) (PLGA)-PEG. 38. The polymer particle according to any one of items 20 to 37, wherein the second region further contains poly(lactic acid-co-caprolactone) (PLCL). 39. A polymer particle according to any one of items 20 to 38, wherein the second region comprises or further comprises a near-infrared decomposable polymer or polymer linker. 40. A polymer particle according to any one of paragraphs 1 to 39, comprising a binding reagent comprising a streptavidin molecule conjugated to a structural polymer further comprising biotin. 41. A polymer particle according to any one of paragraphs 1 to 40, comprising a binding reagent comprising a streptavidin molecule bound to PLGA-PEG-biotin. 42. A polymer particle according to any one of paragraphs 1 to 41, comprising a coupling reagent coupled to PLGA-PEG-maleimide via a DTT-catalyzed reaction. 43. A polymer particle according to any one of paragraphs 1 to 42, comprising a binding reagent comprising a biotin molecule conjugated to a structural polymer further comprising streptavidin. 44. The polymer particles of any of the preceding claims, further comprising one or more imaging agents. 45. The polymer particle described in item 44, wherein the one or more imaging agents are selected from the group consisting of one or more contrast agents, one or more MRI contrast agents, one or more microbubbles, one or more metal ions, one or more radioisotopes, one or more optical imaging agents, one or more SPECT imaging agents, and one or more PET imaging agents. 46. ​​The polymer particle of paragraph 45, wherein the one or more MRI contrast agents comprise one or more of a gadolinium-based contrast agent, superparamagnetic iron oxide, ultrasmall superparamagnetic iron oxide, superparamagnetic iron-platinum, manganese chelate, iron salt, and perflubron. 47. The polymer particle of paragraph 46, wherein the gadolinium-based contrast agent comprises one or more of gadolinium, gadoxetate, gadobutrol, gadoterate, gadoteridol, gadopentetate, gadobenate, gadopentetate dimeglumine, gadoxetate, gadoversetamide, gadodiamide, gadofosveset, gadocholetic acid, gadomeritol, gadomer 17, and gadoxetic acid. 48. The polymer particle described in any one of items 44 to 47, wherein the one or more imaging agents further comprise a methyl acrylate ester. 49. A polymer particle described in any one of items 44 to 48, wherein the one or more imaging agents are methyl acrylate esters crosslinked with one or more of methyl acrylated HA and dimethyl PEG acrylate. 50. A polymer particle according to any preceding paragraph, which is substantially discoid in shape. 51. The polymer particles of paragraph 50, which are disk-shaped. 52. The polymer particles according to any of the preceding paragraphs, wherein the diameter of the polymer particles is from about 100 nm to about 10 μm. 53. The polymer particles according to any of the preceding paragraphs, wherein the diameter of the polymer particles is from about 100 nm to about 1 μm. 54. A polymer particle according to any of the preceding claims, having a size of about 6 μm x 500 nm. 55. A polymer particle according to any of the preceding claims, having a size of about 6 μm x 250 nm. 56. Polymer particles according to any of the preceding paragraphs, having a size of 1-2 μm×7-9 μm. 57. 0.5×10 -11 cm 3 ~10×10 -11 cm 3 4. The polymer particle according to any of the preceding claims, having a volume of 58. 1.25×10 -11 cm 3 ~5×10 -11 cm 3 4. The polymer particle according to any of the preceding claims, having a volume of 59. Polymer particles according to any of the preceding paragraphs, having the shape of a rod, cylinder, cube, rectangular prism, hexahedron, or pyramid. 60. The polymer particle of any preceding claim, further comprising one or more cell targeting ligands. 61. The polymer particle described in paragraph 60, wherein the cell targeting ligand is located in a region that includes a cell adhesion molecule (e.g., a polyelectrolyte). 62. The polymer particle described in any one of items 60 to 61, wherein the cell targeting ligand is an IgG, an antibody, a polypeptide, or an aptamer. 63. The polymer particle of any preceding paragraph, further comprising one or more payload agents. 64. The polymer particle described in paragraph 63, wherein the payload reagent is a therapeutic molecule. 65. The polymer particle according to paragraph 63, wherein the payload reagent is a small molecule or a polypeptide. 66. A polymer particle according to any one of items 63 to 65, wherein the payl...

Claims

1. A polymeric particle comprising at least one binding reagent selected from the group consisting of a CD11b binding reagent; a CD3 binding reagent; a CD19 binding reagent; a CD49b binding reagent; a CD56 binding reagent; a CD11a binding reagent; a CD27 binding reagent; a CD44 binding reagent; a CD45 binding reagent; an NKG2D binding reagent; an NKp30 binding reagent; an NKp46 binding reagent; and an ICAM1 binding reagent, wherein the polymeric particle is disc-shaped and has a diameter of 50 nm to 20 μm, and the binding reagent is an antibody or an antibody reagent.

2. The polymeric particle according to claim 1, wherein the binding reagent is a CD11b binding reagent; a CD3 binding reagent; a CD19 binding reagent, or a CD45 binding reagent.

3. The polymeric particle according to claim 2, wherein the binding reagent further comprises a streptavidin molecule or a biotin molecule.

4. The polymeric particle according to claim 3, further comprising ICAM1, NKp30, and / or NKp46.

5. (i) one or more cell adhesion molecules (e.g., polyelectrolytes); or (ii) a hydrogel of one or more cell adhesion molecules (e.g., polyelectrolytes); or (iii) one or more structural polymers; or (iv) a single region containing a hydrogel of one or more structural polymers; or (v) a) a first region containing a hydrogel of one or more structural polymers; and b) a second region containing one or more cell adhesion molecules (e.g., polyelectrolytes) and one or more binding reagents; or (vi) a) a first region containing a first selected one or more cell adhesion molecules (e.g., polyelectrolytes) and optionally one or more binding reagents; b) a second region containing a second selected one or more cell adhesion molecules (e.g., polyelectrolytes); and c) a third region containing one or more structural polymers and optionally one or more binding reagents (Here, optionally, the first selected one or more cell adhesion molecules include one or more of hyaluronic acid (HA) and bovine serum albumin (BSA), the second selected one or more cell adhesion molecules is poly(allylamine) hydrochloride (PAH), and the one or more structural polymers are one or more of poly(lactic-co-glycolic acid) (PLGA), PLGA-PEG, PLGA-PEG-maleimide, and PLGA-PEG-biotin) The polymeric particles according to claim 1, further comprising

6. a) a first region comprising a first selected one or more structural polymers and optionally one or more binding reagents; and b) a second region comprising a second selected one or more structural polymers comprising or a) a first region comprising a first selected one or more structural polymers and optionally one or more binding reagents; b) a second region comprising a second selected one or more structural polymers; and c) a third region comprising a third selected one or more structural polymers and optionally one or more binding reagents comprising The polymeric particles according to claim 5.

7. a) a first region comprising a first selected one or more structural polymers and optionally one or more binding reagents; b) a second region comprising a second selected one or more structural polymers; and c) a third region comprising a third selected one or more structural polymers and optionally one or more binding reagents comprising and the second region is disposed between the first region and the third region, and / or the second region separates the first region and the third region from each other The polymeric particles according to claim 6, optionally, the third region comprises one or more binding reagents and the first region does not comprise one or more binding reagents.

8. The one or more selected structural polymers of the first include or consist of PLGA, the one or more selected structural polymers of the second include or consist of PVA, and the one or more selected structural polymers of the third include or consist of PLGA, the polymeric particles according to claim 7.

9. The second region and / or the third region contain one or more active agents; and / or The second region and the third region each contain one or more payload agents, and optionally, one or more payload agents are N2 / M2 polarization inducers, The polymeric particles according to claim 8.

10. The second region contains IL-4 and the third region contains dexamethasone, or The second region contains IL-4 and heparin, and the third region contains dexamethasone, The polymeric particles according to claim 9.

11. (i) one or more cell adhesion molecules (e.g., polyelectrolytes); or (ii) a hydrogel of one or more cell adhesion molecules (e.g., polyelectrolytes); or (v) a) a first region containing a hydrogel of one or more structural polymers; and b) a second region containing one or more cell adhesion molecules (e.g., polyelectrolytes) and one or more binding reagents; or (vi) a) a first region containing a first selected one or more cell adhesion molecules (e.g., polyelectrolytes) and optionally one or more binding reagents; b) a second region containing a second selected one or more cell adhesion molecules (e.g., polyelectrolytes); and c) a third region containing one or more structural polymers and optionally one or more binding reagents; (wherein optionally, the one or more structural polymers are one or more of poly(lactic-co-glycolic acid) (PLGA), PLGA-PEG, PLGA-PEG-maleimide, and PLGA-PEG-biotin) further comprises, and the cell adhesion molecule is (i) comprising one or more of a cell - adhesive polyelectrolyte, an immunoglobulin, or a ligand for a receptor on the cell surface, and optionally, the cell - adhesive polyelectrolyte comprises one or more of hyaluronic acid (HA), methylacrylated HA, hyaluronic acid - aldehyde, bovine serum albumin (BSA), PEG, dimethylacrylated PEG, and / or poly(allylamine) hydrochloride (PAH), or (ii) a) one or more of hyaluronic acid (HA), methylacrylated HA, and hyaluronic acid - aldehyde; and one or more of PEG and dimethylacrylated PEG; b) poly(allylamine) hydrochloride (PAH), and one or more of hyaluronic acid (HA), methylacrylated HA, and hyaluronic acid - aldehyde; c) poly(allylamine) hydrochloride (PAH) and hyaluronic acid - aldehyde; d) poly(allylamine) hydrochloride (PAH) and hyaluronic acid (HA); or e) poly(allylamine) hydrochloride (PAH) and bovine serum albumin (BSA) comprising, the polymer particles according to claim 1.

12. (iii) one or more structural polymers; or (iv) a single region containing a hydrogel of one or more structural polymers; or (v) a) a first region containing a hydrogel of one or more structural polymers; and b) a second region containing one or more cell - adhesion molecules (e.g., polyelectrolytes) and one or more binding reagents; or (vi) a) a first region containing a first selected one or more cell - adhesion molecules (e.g., polyelectrolytes) and optionally one or more binding reagents; b) a second region containing a second selected one or more cell - adhesion molecules (e.g., polyelectrolytes); and c) a third region containing one or more structural polymers and optionally one or more binding reagents; (wherein optionally, the first selected one or more cell - adhesion molecules comprise one or more of hyaluronic acid (HA) and bovine serum albumin (BSA), and the second selected one or more cell - adhesion molecules is poly(allylamine) hydrochloride (PAH)) further comprising, The polymeric particles according to claim 1, wherein the structural polymer comprises one or more of poly(lactic-co-glycolic acid) (PLGA); a combination of PLGA and poly(D,L-lactide-co-glycolide); a combination of PLGA and poly(D,L-lactide-co-glycolide) having acid termini; a combination of PLGA and poly(D,L-lactide-co-glycolide) in a 50:50 molar ratio; - polyvinyl alcohol (PVA); hyaluronic acid (HA); gelatin; collagen; PLGA-PEG; or poly(glycerol sebacate) (PGS).

13. further comprising one or more imaging agents, optionally, the one or more imaging agents are selected from the group consisting of one or more contrast agents, one or more MRI contrast agents, one or more microbubbles, one or more metal ions, one or more radioisotopes, one or more optical imaging agents, one or more SPECT imaging agents, and one or more PET imaging agents, optionally, the one or more MRI contrast agents comprise one or more of a gadolinium-based contrast agent, superparamagnetic iron oxide, ultrasmall superparamagnetic iron oxide, superparamagnetic iron-platinum, manganese chelate, iron salts, and perfluorobutane, optionally, the gadolinium-based contrast agent comprises one or more of gadolinium, gadoxetate, gadobutrol, gadoterate, gadoteridol, gadopentetate, gadobenate, dimethylglucamine gadopentetate, gadoxetate, gadobesetamide, gadodiamide, gadofosveset, gadocolic acid, gadomeglumine, gadomer 17, and gadoxetic acid, the polymeric particles according to claim 11.

14. further comprising one or more imaging agents, optionally, the one or more imaging agents are selected from the group consisting of one or more contrast agents, one or more MRI contrast agents, one or more microbubbles, one or more metal ions, one or more radioisotopes, one or more optical imaging agents, one or more SPECT imaging agents, and one or more PET imaging agents, Optionally, the one or more MRI contrast agents include one or more of a gadolinium-based contrast agent, superparamagnetic iron oxide, ultrasmall superparamagnetic iron oxide, superparamagnetic iron-platinum, manganese chelate, iron salt, and perflubron, Optionally, the gadolinium-based contrast agent includes one or more of gadolinium, gadoxetate, gadobutrol, gadoterate, gadoteridol, gadopentetate, gadobenate, dimeglumine gadopentetate, gadoxetate, gadobutrol, gadobenate, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiamide, gadofosveset, gadocolic acid, gadopentetate dimeglumine, gadodiam ​ ​ ​ ​ ​ 0.5×10 -11 cm 3 ~10×10 -11 cm 3 、 or 1.25×10 -11 cm 3 ~5×10 -11 cm 3 having a volume of ​ ​ ​ ​ ​ 0.5×10 -11 cm 3 ~10×10 -11 cm 3 、 or 1.25×10 -11 cm 3 ~5×10 -11 cm 3 having a volume of ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ (iii) The cell is a monocyte, and the polymer particle comprises: a) a first region containing one or more selected structural polymers of a first selection; b) a second region containing one or more selected structural polymers of a second selection; and c) a third region containing a CD11b binding reagent and one or more selected structural polymers of a third selection. The composition according to claim 18.

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