Application of metal boride nano material in preparation of immunosuppressant

Abstract

The invention discloses application of a metal boride nano material in preparation of an immunosuppressant, and belongs to the technical field of biological medicine. Specifically, through a series of researches, it is found that the metal boride nano material catalyzes an organic substrate containing a-CH-OH group in cells, and meanwhile, NAD (P) < + > is converted to generate NAD (P) H, GSH rising is promoted, and cell reductive stress is initiated. The immune cells are further induced to differentiate to an immunosuppressive phenotype, secretion of immunosuppressive factors is promoted, secretion of immune activating factors is inhibited at the same time, and finally the immunosuppressive effect is achieved. The catalytic action of the substance can provide a lasting and stable immunosuppression effect, and the feasibility of the substance in initiation of reduction stress and immunosuppression is proved through in-vivo and in-vitro experiments. The invention provides a new immunosuppression strategy, which is expected to make up the defects of the traditional immunosuppressor, and provides a new choice for related treatment of clinical organ transplantation, autoimmune diseases, inflammatory diseases and the like.

Description

Technical Field

[0001] The invention relates to application of metal boride nanomaterials in preparing immunosuppressants, belonging to the technical field of biomedicine. Background Art

[0002] Immunosuppressants inhibit or regulate the activity of the immune system, thereby preventing abnormal immune responses from causing tissue damage or organ rejection. They are widely used in organ transplantation, autoimmune diseases, allergies, inflammatory diseases, etc. With the discovery of aminopurine drugs, the exploration of immunosuppressive therapy has entered a new stage. Subsequently, the discovery and introduction of cyclosporine was considered a milestone in the history of the development of immunosuppressants, which greatly improved the success rate of organ transplantation and made more complex transplant operations possible. In recent years, the development direction of immunosuppressants has gradually shifted from non-specific inhibitors to more precise targeted therapies. With our in-depth understanding of the molecular mechanisms of the immune system, a new generation of immunosuppressants (such as monoclonal antibodies, immune checkpoint inhibitors, mRNA, and drugs specifically targeting cytokines) have gradually been developed, which not only improves the effectiveness of treatment, but also reduces the side effects of traditional immunosuppressants. Therefore, the development of new immunosuppressants is of great significance in the field of clinical medicine.

[0003] Compared with traditional small molecule drug immunosuppressants, the development of nano-immunosuppressants has many advantages, especially in terms of drug delivery, efficacy and side effect control. At present, the development of nano-immunosuppressants mainly focuses on two aspects: ① Nanomaterials are used as carriers to deliver immunosuppressive drugs, such as cyclosporine A lipid nanoparticles, mRNA lipid nanoparticles, tacrolimus polymer nanoparticles, gold nanoparticles loaded with cyclosporine A, etc.; ② Nanoparticles themselves have immunosuppressive activity. For example, CeO2 nanomaterials are used to deliver immunosuppressive drugs through Ce 3+ / Ce 4+ The dynamic balance between them can play a continuous role in scavenging free radicals, thereby inhibiting inflammatory responses and reducing excessive immune activation [Biomaterials, 29 (18), 2705-2709; Nanoscale, 12 (3), 2243-2250]; MnO2, Pt, Pb and metal composite nanomaterials have superoxide dismutase (SOD) activity, which can catalyze superoxide anion free radicals (O2 -), produce H2O2 and O2, inhibit inflammation [Small, 13 (36), 1700611; Chemical Communications, 46 (16), 2736-2738; ACS Nano, 12 (4), 3567-3582]; in addition, nanomaterials with catalase activity such as Fe3O4, carbon nanotubes (CNTs) and graphene quantum dots (GQDs) can catalyze H2O2 to produce water and O2, exerting antioxidant activity [Nature Nanotechnology, 2 (9), 577-583; Chemical Reviews, 120 (6), 3223-3266].

[0004] However, existing nanomaterials with immunosuppressive activity are all dedicated to reducing the level of cellular reactive oxygen species (ROS), downregulating oxidative stress, exerting antioxidant activity, and then producing immunosuppressive effects. However, the organism is a redox-balanced system, in which oxidative stress has been widely studied, but its opposite, reductive stress, is still in the preliminary research stage. There have been no reports on inducing immunosuppressive effects by regulating reductive stress. Summary of the invention

[0005] To solve the above problems, the present invention provides a substance that can achieve the induction of immunosuppression effect from the aspect of reducing stress regulation - metal boride nanomaterials, which can enter cells to simulate natural dehydrogenases to accelerate the dehydrogenation reaction of biological systems, catalyze NAD(P) + The cumulative production of NAD(P)H leads to the formation of three redox pairs (NADPH / NADP + ,NADH / NAD + , GSH / GSSG) ratio increased significantly, inducing cell reductive stress and producing immunosuppressive effects.

[0006] The first object of the present invention is to provide an application of a metal boride nanomaterial in the preparation of an immunosuppressant. The metal boride nanomaterial exerts an immunosuppressive effect, including inducing intracellular reductive stress and / or causing high expression of NAD(P)H and GSH.

[0007] Furthermore, in the metal boride nanomaterial, the metal includes one or more of the alkaline metals of group IIA (corresponding nanomaterials such as MgB2, CaB2) and the transition metals of group IIB, group IVB, group VB, and group VIB (corresponding nanomaterials such as LaB6, CeB6, TiB2, ZrB2, HfB2, VB2, TaB2, NbB2, WB2, MoB2, CrB2).

[0008] Furthermore, the metal boride nanomaterial is preferably one or more of MgB2, CaB2, MoB2, LaB6, VB2, WB2, CeB6, TaB2, NbB2, and ZrB2.

[0009] Furthermore, the preparation method of the metal boride nanomaterial is: mixing a metal source and a boron source, and heat-treating the mixture to obtain the metal boride nanomaterial.

[0010] Further, the temperature of the heat treatment is 600-1000°C, for example, 610°C, 630°C, 650°C, 680°C, 700°C, 730°C, 750°C, 780°C, 800°C, 820°C, 850°C, 870°C, 900°C, 950°C, 970°C, 990°C, and most preferably 800-900°C.

[0011] Furthermore, the heat treatment time is 4-12 hours, such as 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 9.5 hours, 10.5 hours, 11 hours, 12 hours, and most preferably 8-10 hours.

[0012] The second object of the present invention is to provide a composition for immunosuppression, wherein the composition comprises metal boride nanomaterials.

[0013] Furthermore, the composition is a pharmaceutical composition.

[0014] Furthermore, the composition also contains substances that assist immunosuppression, such as immune adjuvants or any other substances that can exert immunosuppressive functions.

[0015] The third object of the present invention is to provide an application of a metal boride nanomaterial in the preparation of a reductive stress initiator.

[0016] Likewise, when acting as a reductive stress initiator:

[0017] Furthermore, in the metal boride nanomaterial, the metal includes one or more of the alkaline metals of group IIA (corresponding nanomaterials such as MgB2, CaB2) and the transition metals of group IIB, group IVB, group VB, and group VIB (corresponding nanomaterials such as LaB6, CeB6, TiB2, ZrB2, HfB2, VB2, TaB2, NbB2, WB2, MoB2, CrB2).

[0018] Furthermore, the metal boride nanomaterial is preferably one or more of MgB2, CaB2, MoB2, LaB6, VB2, WB2, CeB6, TaB2, NbB2, and ZrB2.

[0019] Furthermore, the preparation method of the metal boride nanomaterial is: mixing a metal source and a boron source, and heat-treating the mixture to obtain the metal boride nanomaterial.

[0020] Furthermore, the temperature of the heat treatment is 600-1000°C, most preferably 800-900°C.

[0021] Furthermore, the heat treatment time is 4-12 hours, most preferably 8-10 hours.

[0022] A fourth object of the present invention is to provide a composition for inducing reductive stress, wherein the composition comprises metal boride nanomaterials.

[0023] Furthermore, the composition is a pharmaceutical composition.

[0024] Furthermore, the composition also contains substances that inhibit oxidative stress, so as to better induce reductive stress or regulate the balance of redox. As immunosuppressants, nanomaterials with antioxidant activity have relatively weak immunosuppressive effects and can usually only alleviate mild inflammatory reactions or immune-related diseases. For severe autoimmune diseases or transplant rejection reactions, the antioxidant mechanism is often insufficient to produce sufficient immunosuppressive effects and needs to be combined with other more potent immunosuppressive therapies. Therefore, the present invention proposes a possibility that has potential in the treatment of related diseases.

[0025] The fifth object of the present invention is to provide the use of metal boride nanomaterials in the preparation of therapeutic drugs for organ transplantation, autoimmune diseases or inflammatory diseases.

[0026] Furthermore, the therapeutic drug also contains pharmaceutically acceptable excipients.

[0027] Furthermore, the auxiliary materials include one or more of fillers, excipients, stabilizers, diluents, binders, disintegrants, lubricants, glidants, wetting agents, effervescent agents, colorants, sweeteners, flavoring agents, preservatives, dispersants, film formers, plasticizers, pore formers, opacifiers, retardants, and solvents.

[0028] Furthermore, the therapeutic drug is composed of 0.1-100% of metal boride nanomaterials and 99.9-0% of auxiliary materials.

[0029] In the present invention, the above definitions are only examples and are actually common in applications, pharmaceutical compositions and pharmaceutical products.

[0030] Beneficial effects of the present invention:

[0031] The present invention proposes for the first time that metal boride nanomaterials can be used for immunosuppression. Specifically, the present invention finds that metal boride nanomaterials have certain dehydrogenase activity, and due to this property, they can induce reductive stress in vivo or in vitro, catalyze organic substrates containing -CH-OH groups in cells, and simultaneously convert NAD(P) + Generate NAD(P)H, promote the increase of GSH, and induce cellular reductive stress. The generation of reductive stress further induces immune cells to differentiate into immunosuppressive phenotypes and promotes the secretion of immunosuppressive factors, ultimately exerting an immunosuppressive effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 Schematic diagram of the process by which metal boride nanomaterials exert immunosuppressive activity.

[0033] Figure 2 Dehydrogenase-like activity and Michaelis-Menten equation for metal boride nanomaterials.

[0034] Figure 3 The reductive stress induced by metal boride nanomaterials in cells.

[0035] Figure 4 Relative enzyme activity and reductive stress level of MoB2 nanomaterials after H2O2 treatment.

[0036] Figure 5 The immunosuppressive effect of MoB2 nanomaterials in BMDM cells.

[0037] Figure 6 The reductive stress induced by MoB2 nanomaterials in the lungs of mice.

[0038] Figure 7 The immunosuppressive effect of MoB2 in the lungs of mice.

[0039] Figure 8 For the application of MoB2 in pneumonia in mice.

[0040] Fig. 9 For the application of MoB2 in organ transplantation. DETAILED DESCRIPTION

[0041] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0042] The scheme involved in the present invention is as follows:

[0043] Metal boride nanomaterials are a class of materials with unique physical and chemical properties. Due to the electron deficiency of boron, the short covalent radius, and the compatibility of sp2 hybrid orbitals with three-center bonds, these materials exhibit many special properties at the nanoscale, making them a hot topic of research. The metal to boron ratio of metal borides is usually from 3:1 (M3B) to 1:12 (MB 12 ). Boron-rich borides (such as MB4, MB6 and MB l2 ) in which the ratio of boron to metal atoms is 4:1 or higher.

[0044] The structures of metal borides are diverse. Boron atoms can show various structural types in the crystal lattice, such as single boron atoms, paired boron atoms, chains, double chains, boron molecular networks and boron atomic skeletons. The diversity of these structures leads to a wide variety of metal borides, with about 24 types, including M2B, MB, MB2, MB4, MB6 and MB 12 The types are more common.

[0045] The present invention found that metal boride nanomaterials have dehydrogenase activity. After research, it was found that this property is also the key performance for inducing cell reduction stress. At the same time, it was found that regardless of different metal boride nanomaterials or different cells, the effect of inducing reduction stress is universal: NADPH / NADP in cells + ,NADH / NAD + , GSH / GSSG three classic redox ratios, significantly increased compared to normal cells (i.e., blank control group). Furthermore, the nanomaterials of the present invention can promote BMDM cells to differentiate into M2 immunosuppressive phenotypes, inhibit M1 immune activation phenotypes, promote the expression of immunosuppressive factors, and induce significant immunosuppressive effects.

[0046] Of course, due to differences in the structure and composition of metal boride nanomaterials, their effects may vary, resulting in certain differences in their effects in inducing reductive stress and suppressing immunity.

[0047] In the process of exerting immunosuppressive effects, the metal boride nanomaterials of the present invention can induce immune cells to differentiate into immunosuppressive phenotypes, including macrophages, T cells, and B cells, etc. Moreover, the proportion of immunosuppressive cells such as B regulatory cells, T regulatory cells, and M2 macrophages increased significantly, and the proportion of cells related to immune activation, such as NK cells, γδT cells, and CD4 and CD8 positive T cells, decreased significantly.

[0048] The present invention also provides a composition. Preferably, the composition is a pharmaceutical composition, which contains the above-mentioned metal boride nanomaterial, and may also contain other effective ingredients, and a pharmaceutically acceptable carrier. Generally, these substances can be formulated in a non-toxic, inert and pharmaceutically acceptable aqueous carrier medium, wherein the pH is generally about 5-8, preferably about 6-8, and the pH value may vary with the properties of the formulated substance, and the technician can adjust it as needed. The formulated pharmaceutical composition can be administered by conventional routes, including (but not limited to): intraperitoneal, intravenous or local administration.

[0049] The composition of the present invention contains a safe and effective amount (such as 0.001-99wt%, preferably 0.01-90wt%, more preferably 0.1-80wt%) of the metal boride nanomaterial of the present invention and a pharmaceutically acceptable carrier. Such carriers include (but are not limited to): fillers, excipients, stabilizers, diluents, adhesives, lubricants, surfactants or combinations thereof. The pharmaceutical preparation should match the mode of administration. The pharmaceutical composition of the present invention can be prepared in the form of an injection, for example, by conventional methods using physiological saline or an aqueous solution containing glucose and other adjuvants. Pharmaceutical compositions such as injections and solutions are preferably manufactured under sterile conditions. The dosage of the active ingredient is a therapeutically effective amount. In addition, the metal boride nanomaterial of the present invention can also be used with other therapeutic agents.

[0050] When using a pharmaceutical composition, a safe and effective amount of the drug is administered to an individual. The specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skills of a skilled physician.

[0051] Example 1: Synthesis of Metal Boride Nanomaterials

[0052] A series of transition metal boride nanomaterials were synthesized by vacuum quasi-solid-state replacement reaction. Taking MoB2 as an example, anhydrous molybdenum pentachloride (1 mmol) and magnesium diboride (2.5 mmol) were used as metal source and boron source, respectively. The reagents were mixed under infrared light to prevent moisture, then transferred to a quartz tube and sealed under vacuum (about 0.9 Pa). Subsequently, the quartz tube was placed in a tube furnace, heated to 850°C at a heating rate of 2°C / min and kept at high temperature for 10 hours. After cooling, the product was ground into powder and dispersed in 0.5M H2SO4 solution to remove unreacted residues. Afterwards, the obtained sample was washed and dried in an oven at 80°C. The required reagents and key synthesis conditions for synthesis or weighing are listed in Table 1.

[0053] Table 1 Key conditions for the synthesis of transition metal borides

[0054]

[0055] Example 2: Characterization of the dehydrogenation catalytic activity of metal boride nanomaterials

[0056] In order to investigate the dehydrogenation activity of boride nanomaterials, lactic acid was used as the dehydrogenation substrate, 3-(4,5-dimethylthiazol-2-yl)-5-(triazol-2-yl)-2,5-diaminothiazole was used as the chromogenic substrate, and NAD + Different metal borides have different catalytic activities, among which MoB2 and MgB2 show strong dehydrogenase-like activity, while TiB2, CrB2, and HfB2 have weaker activities. The catalytic reaction kinetics of MoB2 and MgB2 nanomaterials conform to the Michaelis-Menten equation, and both show a stronger maximum reaction rate (V max ). It is demonstrated that various metal boride nanomaterials have dehydrogenase-like catalytic activity ( Figure 2 ).

[0057] Example 3: In vitro verification of metal boride nanomaterials inducing reductive stress

[0058] Taking MoB2, LaB6 and MgB2 as examples, reductive stress was induced in macrophage THP-1 cells. The results showed that compared with the control group, the NADPH / NADP + ,NADH / NAD + , the redox ratio of GSH / GSSG increased by 1.2-3.0 times ( Figure 3 AC). It was demonstrated that three metal boride nanomaterials can induce reductive stress in cells.

[0059] To further prove the universality of the material inducing reductive stress, MoB2 was used as an example to test the reductive stress of the other five cells, including fibroblasts NIH-3T3, Jurkat cells, epithelial cells BEAS-2B, renal cells Vero and liver cancer cells HepG2. The results showed that MoB2 could induce 1.6-3.2 times of NADH / NAD in the above five cells. + The proportion increased ( Figure 3 D) It is demonstrated that metal boride nanomaterials can induce reductive stress in cells and have universal applicability.

[0060] Example 4: Mechanism of metal boride nanomaterials inducing reductive stress

[0061] After treating MoB2 nanomaterials with 50, 100, 200 and 800 mM H2O2 for 48 hours, a series of MoB2 with different degrees of inactivation can be obtained, named m1-MoB2, m2-MoB2, m3-MoB2, and m4-MoB2. The dehydrogenase activity detection kit proved that the catalytic activity of MoB2 nanomaterials decreased significantly with the increase of H2O2 treatment concentration. At the same time, the reduction stress induced by m-MoB2 in cells was compared. Intracellular NADH and NAD were quantitatively detected by LC-MS / MS. + The results showed that with the increase of H2O2 treatment concentration, MoB2 nanomaterials triggered the expression of NADH / NAD + The level of reductive stress decreased significantly. This proves that the dehydrogenase activity of MoB2 nanomaterials is the key property that triggers cellular reductive stress ( Figure 4 ).

[0062] Example 5: In vitro verification of the immunosuppressive effect of metal boride nanomaterials

[0063] Taking MoB2 as an example, its immunosuppressive effect at the cellular level was investigated. First, according to the method of abcam official website, mouse bone marrow-derived macrophages (BMDM) were extracted and separated, and BMDM maturation was stimulated. 50μg / mL MoB2 or inactivated MoB2 nanomaterials (m4-MoB2) were added, and the supernatant was collected after 24 hours of treatment for ELISA kit to detect inflammatory factors; cells were collected, flow cytometry antibody staining (anti-F4 / 80, anti-CD80 and anti-CD206 antibodies) was performed to evaluate cell differentiation. The results showed that MoB2 nanomaterials can significantly increase the proportion of CD206-positive cells and reduce the CD80-positive cell population, indicating that BMDM cells are promoted to differentiate into the M2 immunosuppressive phenotype and inhibit the M1 immune activation phenotype; while the m4-MoB2 treatment group and the control group were basically the same, and did not affect the differentiation of macrophages. The results of ELISA kit detection of inflammatory factors showed that MoB2 nanomaterials promoted the high expression of immunosuppressive factors IL-10 and TGF-β; similarly, the inflammatory factors in the m4-MoB2 treatment group were basically the same as those in the control group. This proves that MoB2 induces a significant immunosuppressive effect at the cellular level ( Figure 5 ).

[0064] Example 6: In vivo verification of metal boride nanomaterials inducing reductive stress

[0065] Taking MoB2 as an example, the reductive stress induced at the animal level was investigated. 50 μL of MoB2 or m4-MoB2 nanomaterials were exposed to the lungs of BALB / c mice at a dose of 2.5 mg / Kg by oropharyngeal drip irrigation. The drug was administered once every five days. After three doses, the lung lavage fluid of the mice was extracted, and the macrophages in the lavage fluid were stained with GSHtracer dye and observed under a confocal fluorescence microscope. The results showed that after the drip irrigation of MoB2 nanomaterials, the GSH in the lung macrophages increased significantly; and after the exposure of m4-MoB2 nanomaterials, the GSH in the lung macrophages was not significantly different from that of the control group. At the same time, the lung tissue was homogenized to extract NAD(P)H and NAD(P) + LC-MS / MS quantification showed that MoB2 nanomaterials significantly increased NADPH / NADP in lung tissue after exposure + and NADH / NAD + The ratio of MoB2 exposure to mouse lungs can induce reductive stress ( Figure 6 ).

[0066] Example 7: In vivo verification of the immunosuppressive effect of metal boride nanomaterials

[0067] Taking MoB2 as an example, the immunosuppressive effect induced at the animal level was investigated. According to the animal administration method in Example 6, the lung tissue was collected and digested to extract single cells. The differentiation of immune cells and the expression of related immune factors in the lung tissue after treatment with MoB2 nanomaterials were detected using mass spectrometry flow cytometry. The results showed that seven types of immune cells changed significantly, including the proportion of three types of immunosuppressive cells, including B regulatory cells, T regulatory cells and M2 macrophages, which were significantly upregulated in the lungs after MoB2 administration; while four types of immune activation-related cell types, including NK cells, γδT cells and CD4 and CD8-positive T cells, were significantly downregulated in the lungs after MoB2 administration; in terms of immune factor expression, it was proved that four immunosuppressive factors, including IL-10, IL-4, TGF-β and IFN-γ, were significantly upregulated. The above examples show that MoB2 can induce obvious immunosuppressive effects at the animal level ( Figure 7 ).

[0068] Example 8: Application of metal boride nanomaterials in inflammatory diseases

[0069] Taking MoB2 as an example, an immunosuppressant for inflammatory diseases was developed. According to the animal administration method in Example 6, an LPS-induced acute pneumonia infection model was first constructed. Figure 8Animal experiment operation process: drip irrigation of MoB2 nanomaterials, and collection of mouse bronchoalveolar lavage fluid and neutrophils after 24 hours of treatment. The results showed that the release of TNF-α, IL-6, and IL-1β in the bronchoalveolar lavage fluid of mice in the LPS group were 523.95, 576.31, and 218.44 pg / mL, respectively, while the inflammatory factors were downregulated to 291.81, 428.21, and 127.23 pg / mL after MoB2 administration. At the same time, the neutrophils in the alveolar lavage fluid taken out were counted. The results showed that there was no significant difference in the number of neutrophils in the bronchoalveolar lavage fluid of mice administered with MoB2 compared with the PBS group; the number of neutrophils in the bronchoalveolar lavage fluid of the LPS group was 5.271×10 4 / mL, which was 10.22 times that of the PBS group. However, the number of neutrophils induced by LPS was significantly reduced to 1.931×10 4 / mL. The above examples show that MoB2 has an immunosuppressive effect on pneumonia in mice ( Figure 8 ).

[0070] Example 9: Application of Metal Boride Nanomaterials in Organ Transplantation

[0071] Using MoB2 as an example, we developed an immunosuppressant for organ transplantation. We used C57BL / 6 mice as donors and BALB / c mice as recipients for liver transplant rejection research. First, we removed the liver of the C57BL / 6 mouse by aseptic surgery, and performed a liver transplantation operation on the recipient BALB / c mouse within 2 hours. After surgery, we administered MoB2 intravenously once a week for 4 months, and observed the weight and survival rate of the mice ( Fig. 9 ). The results showed that there was no significant difference in the body weight of mice in the drug administration group compared with the control group, but the survival rate of mice was significantly improved. Flow cytometry was used to detect the activated T cell subsets in peripheral blood, and it was found that the proportion of CD4+ and CD8+ T cells in the drug administration group was significantly reduced. The above examples show that MoB2 can be used as an immunosuppressant to exert an immunosuppressive effect in organ transplantation.

[0072] Obviously, the above embodiments are only examples for clear explanation and are not intended to limit the implementation methods. For ordinary technicians in the relevant field, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from this are still within the protection scope of the invention.

Claims

1. Application of metal boride nanomaterials in the preparation of immunosuppressants.

2. The use according to claim 1, characterized in that: In the metal boride nanomaterial, the metal includes one or more of the alkali metals of group IIA and the transition metals of group IIB, group IVB, group VB and group VIB.

3. The use according to claim 1, characterized in that: The metal boride nanomaterial includes one or more of MgB2, CaB2, MoB2, LaB6, VB2, WB2, CeB6, TaB2, NbB2, and ZrB2.

4. The use according to claim 1, characterized in that: The preparation method of the metal boride nanomaterial comprises: mixing a metal source and a boron source, and heat-treating the mixture to obtain the metal boride nanomaterial; Preferably, the temperature of the heat treatment is 600-1000°C; Preferably, the heat treatment time is 4-12 hours.

5. A composition for immunosuppression, characterized in that: The composition comprises metal boride nanomaterials.

6. The composition according to claim 5, characterized in that Contains at least one of the following characteristics: (1) The composition is a pharmaceutical composition; (2) The composition further comprises a substance that inhibits oxidative stress.

7. Application of metal boride nanomaterials in the preparation of reductive stress initiators.

8. A composition for inducing reductive stress, characterized in that The composition comprises metal boride nanomaterials.

9. Application of metal boride nanomaterials in the preparation of therapeutic drugs for organ transplantation, autoimmune diseases or inflammatory diseases.

10. The use according to claim 9, characterized in that: Contains at least one of the following characteristics: (1) The therapeutic drug also contains pharmaceutically acceptable excipients; (2) The therapeutic drug is composed of 0.1-100% of metal boride nanomaterials and 99.9-0% of excipients; (3) The excipients include one or more of fillers, excipients, stabilizers, diluents, binders, disintegrants, lubricants, glidants, wetting agents, effervescent agents, colorants, sweeteners, flavoring agents, preservatives, dispersants, film formers, plasticizers, pore formers, opacifiers, retardants, and solvents.

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