Functionalized bionic nano-particles of targeted synovial macrophages and application of functionalized bionic nano-particles

Abstract

The invention provides a functional bionic nanoparticle of targeted synovial macrophages, which is prepared by the following steps: mixing a macrophage membrane and I-coated UN according to a weight ratio of (1.5-2.5): 1, and extruding the mixture through a polycarbonate filter membrane for 19-21 times; wherein the I (at) UN is obtained by adding azide modified IL-10 into NO-UIO-DBCO, stirring and centrifuging. An MI-coated UN nano treatment system is developed, after NO-prednisolone is encapsulated into UIO-66-NH2, the UIO-66-NH2 is modified by using IL-10 in a click chemistry manner, and finally, a macrophage membrane is covered, so that after macrophages are swallowed, IL-10 is burst and released and NO-prednisolone is continuously released, and the MI-coated UN nano treatment system has potential application in preparation of medicines for treating osteoarthritis.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to functionalized bionic nanoparticles targeting synovial macrophages and applications thereof. Background Art

[0002] Osteoarthritis is a common joint degenerative disease that usually causes pain and dysfunction. The occurrence of osteoarthritis affects all joint tissues, including cartilage erosion, subchondral sclerosis, synovitis, articular surface vascular invasion, subchondral bone remodeling, and osteophyte formation. In the early stages of osteoarthritis, synovial inflammation often precedes structural changes in bone and cartilage, and it is also associated with the progression of osteoarthritis. The normal synovium is formed by two different tissue layers, the lining of the inner membrane and the subsynovial lining. Macrophages accumulate in the lining layer, and the abundance of macrophages is the main feature of synovitis. Previous studies have inhibited osteoarthritis by reversing the polarization of synovial macrophages. The activation of macrophages determines the expression of inflammatory markers during synovial inflammation. However, the M1 macrophages that cause inflammation mainly rely on glycolysis to provide energy. Energy metabolism imbalance is one of the risk factors for the occurrence of osteoarthritis.

[0003] Ferroptosis is a lethal iron-dependent accumulation of lipid reactive oxygen species (ROS), and in most cases, ferroptosis is independent of known cell death pathways. In articular cartilage, chondrocytes are the only cell type that play an important role in maintaining the stability of cartilage. Ferroptosis of articular cartilage is closely related to OA. The death of chondrocytes usually leads to matrix degradation and imbalance of cartilage homeostasis. The occurrence of ferroptosis in osteoarthritis is usually accompanied by abnormal iron metabolism, lipid peroxidation, and inactivation of glutathione peroxidase (GPX4). Chondrocytes undergo ferroptosis under inflammatory conditions, and ferroptosis can promote the progression of osteoarthritis. Therefore, the survival of chondrocytes is essential for maintaining the integrity of cartilage.

[0004] Hypoxia-inducible factor-1A is the main regulator of cell adaptation to hypoxic stimulation. HIF-1A can induce glycolysis and plays a key role in the synthesis of proinflammatory factors. The synovium of osteoarthritis is usually in a partially hypoxic environment. Inflammatory response and limited joint movement can lead to insufficient blood supply to the synovial blood vessels, thus forming a hypoxic state. These studies have shown that synovial hypoxia may aggravate the development and symptoms of osteoarthritis. Therefore, improving the excessive glycolysis of the synovial hypoxia state may help alleviate the related symptoms of osteoarthritis.

[0005] IL-10 is an important cytokine that can inhibit inflammatory responses and regulate immune responses to promote tissue homeostasis. IL-10 can inhibit the production and function of key proinflammatory cytokines in OA. The IL-10 receptor is composed of the IL-10 receptor A subunit and the IL-10 receptor B. Studies have shown that the main function of IL-10A is to receive IL-10 and exert its effect. The receptor sequential assembly sequence is initiated by IL-10 binding to IL-10RA, followed by binding to IL-10B, allowing the assembly of the signaling complex. However, IL-10 has significant disadvantages as a stand-alone therapy, which is caused by its short half-life in vivo. Therefore, a long-acting, targeted drug delivery method is sought to produce a strong therapeutic effect in osteoarthritis.

[0006] Cell membrane-coated nanoparticles are made by coating nanoparticles with natural cell membranes, thereby inheriting the characteristics of parent cells, such as specific targeting, achieving efficient targeted delivery, and showing excellent effects. Based on this, the present invention provides a functionalized bionic nanoparticle targeting synovial macrophages and its application. Summary of the invention

[0007] The purpose of the present invention is to provide a functionalized bionic nanoparticle targeting synovial macrophages and application of the nanoparticle in preparing a drug for preventing and treating osteoarthritis.

[0008] On the one hand, the present invention provides a functionalized bionic nanoparticle targeting synovial macrophages, comprising the steps of: mixing macrophage membrane and I@UN in a weight ratio of (1.5-2.5):1, and extruding through a polycarbonate filter membrane 19-21 times; wherein I@UN is obtained by adding azide-modified IL-10 to NO-UIO-DBCO, stirring, and centrifuging.

[0009] Furthermore, the method for preparing the macrophage membrane includes: culturing RAW264.7 cells in a culture dish, collecting macrophages when the density reaches 80%, resuspending the macrophages in Tris magnesium salt buffer and then crushing them, mixing the crushed macrophages with sucrose and cell homogenate, centrifuging the obtained product, and purifying the cell membrane to obtain the macrophage membrane.

[0010] Further, the Tris magnesium salt buffer includes 1 mM MgCl 2 and 10 mM Tris, and the pH was adjusted to 7.4 using deionized water.

[0011] Furthermore, the preparation method of the azide-modified IL-10 comprises: adding 6 mL of NHS-N 3 Obtained by mixing with 5 mg IL-10.

[0012] Furthermore, the preparation method of NO-UIO-DBCO comprises: taking 1 mg / mL of UIO-66-NH 2 The mixture was reacted with 10 mmol / L diphenylcyclooctyne-tetraethylene glycol-active ester PBS solution at room temperature. After the reaction was completed, the mixture was centrifuged with an ultrafiltration tube and washed with PBS to obtain the obtained product.

[0013] Furthermore, the UIO-66-NH 2 The preparation method comprises: taking 1 mg / mL of UIO-66-NH 2 1.25 mg was dissolved in 50 μL of NO-prednisolone and magnetically stirred at room temperature for 24 hours, followed by centrifugation to obtain the precipitate.

[0014] Furthermore, the UIO-66-NH 2 The preparation method comprises: dissolving dimethylsiloxane-polyoxy-polypropylene ether in deionized water, adding acetic acid and NaClO 4 ·H 2 O, stir thoroughly to form a uniform solution, and ZrO(NO 3 ) 2 ·2H 2 O and BDC-NH 2 Add to the above mixture, stir and centrifuge to obtain precipitate, wash with deionized water and centrifuge again to obtain.

[0015] Furthermore, the dimethylsiloxane-polyoxy-polypropylene ether, deionized water, acetic acid, NaClO 4 ·H 2 O、ZrO(NO 3 ) 2 ·2H 2 O and BDC-NH 2 The dosage ratio is 50mg:3mL:0.4mL:150mg:115.6mg:50mg.

[0016] In a second aspect, the functionalized bionic nanoparticles targeted to synovial macrophages provided by the present invention are used in the preparation of drugs for treating osteoarthritis.

[0017] Furthermore, the medicine includes tablets, capsules, pills, granules, oral liquids, and solutions.

[0018] Beneficial effects:

[0019] The bionic nanoparticles coated with macrophage membrane (MM) in the present invention inhibit excessive glycolysis of macrophages by targeting synovial macrophages, alleviate ferroptosis of chondrocytes, and thus treat osteoarthritis. The MI@UN nano-therapeutic system developed in the present invention encapsulates NO-prednisolone into UIO-66-NH 2 Then, IL-10 was used to modify UIO-66-NH 2 , and finally covered with macrophage membrane, the purpose is to allow the macrophages to release IL-10 burst and NO-prednisolone continuously after engulfing.

[0020] The present invention analyzes the characteristics of nanoparticles, conducts biodistribution and pharmacodynamics experiments on mice, evaluates the inhibition of glycolysis and articular cartilage ferroptosis in mouse joints, and verifies the effect on osteoarthritis. The results show that MI@UN can block excessive glycolysis in the synovium and the subsequent inflammatory cascade, successfully alleviates chondrocyte damage, and has obvious anti-inflammatory and repair effects. The mechanism of action of IL-10RA was also revealed in the in vitro model, and the efficient delivery and therapeutic effects of MI@UN were used in the DMM model, demonstrating its potential as a drug for the preparation of osteoarthritis treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Develop the components of MI@UN and build a flow chart;

[0022] Figure 2 UIO-66-NH for TEM observation 2 The loose porous structure diagram;

[0023] Figure 3 TEM image of macrophage membrane (MM);

[0024] Figure 4 TEM image of MI@UN;

[0025] Figure 5 This is an image of macrophages engulfing MI@UN observed by confocal microscopy. The nucleus was stained with DAPI, the macrophage membrane was stained with DIO, IL-10 was stained with CY3, and NO-prednisolone was stained with CY5.5. Scale bar: 20 nM.

[0026] Figure 6 Cell viability of macrophages and chondrocytes after incubation with different doses of NO-prednisolone, MM, IL-10, UIO-66-NH2, and MI@UN.

[0027] Figure 7Particle size distribution diagram of UIO-66-NH2 (red) and MI@UN (blue);

[0028] Figure 8 (A) Flow chart of mouse modeling, action, sampling and subsequent experiments;

[0029] Fig. 9 and Fig.10 (B, C) HE staining of mouse synovial tissue and quantification of synovitis scores. Scale bar: 100 μm.

[0030] Fig.11 and Fig.12 (D, E) Safranin O staining of mouse knee joints and quantification of osteoarthritis scores. Scale bar: 100 μm.

[0031] Fig.13 and Fig.14 (F, G) Immunohistochemical staining of GLUT1 in mouse synovial tissue and quantification of positive areas. Scale bar: 100 μm.

[0032] Fig.15 and Fig.16 (H, I) Immunohistochemical staining of GPX4 in mouse cartilage tissue and quantification of positive areas. Scale bar: 100 μm.

[0033] Fig.17 and Fig.18 (J, K) Micro-CT top view of the knee joint of mice and quantitative analysis of BV. Scale bar: 1 mm.

[0034] Figure 9-Figure 18 In the figure, from left to right are Sham, DMM, MU, IN and MI@UN. DETAILED DESCRIPTION

[0035] The technical solution of the present invention is described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0036] It should be noted that, in the present invention, fetal bovine serum and DMEM medium were purchased from Corning, trypsin was purchased from Gibco, Ereastin-1 was purchased from MCE, all antibodies HIF-1α, IL-10RA, GLUT1, LDHA, HK1, GPX4, ACSL4, β-actin were purchased from Wuhan Mitaka; RIPA, BCA kit, DIO were purchased from Beyotime, Cell Counting Kit-8 was purchased from Yeasen; IL-10 cytokine, NO-prednisolone, CY5.5, CY3, DBCO-PEG4-NHS were purchased from MCE, acetic acid (AA), NaClO 4 ·H 2 O、ZrO(NO 3 ) 2 ·2H 2 O、BDC-NH 2 Purchased from Aladdin, dimethylsiloxane-polyoxy-polypropylene ether (F127), purchased from Sigma, NHS-N 3 Purchased from Meryer.

[0037] The embodiments of the present invention will be described in detail below in conjunction with examples. The following examples take the best examples as illustrations, but those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. The specific conditions not specified in the examples are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used without indicating the manufacturer are all conventional products that can be purchased commercially.

[0038] Example

[0039] UIO-66-NH 2 Preparation: Dissolve 50 mg of dimethylsiloxane-polyoxy-polypropylene ether (F127) in 3 mL of deionized water, add 0.4 mL of acetic acid and 150 mg of NaClO 4 ·H 2 O, stir thoroughly to form a uniform solution, and add 115.6 mg of ZrO(NO 3 ) 2 ·2H 2 O and 50 mg of BDC-NH 2 Add to the above mixture, stir magnetically at 40°C for 12 hours, centrifuge the solution at 10,000 rpm to obtain a precipitate, wash the precipitate once with deionized water and centrifuge again, and resuspend the product with anhydrous ethanol and store it.

[0040] UIO-66-NH of NO-prednisolone 2Preparation: Take 1 mg / mL UIO-66-NH 2 1.25 mg was dissolved in 50 μL of NO-prednisolone and magnetically stirred for 24 hours at room temperature (RT) and then centrifuged to obtain the precipitate.

[0041] Preparation of NO-UIO-DBCO: 1 mg / mL of UIO-66-NH loaded with NO-prednisolone 2 The product was reacted with 10 mmol / L diphenylcyclooctyne-tetraethylene glycol-active ester (DBCO-PEG4-NHS) in PBS at room temperature (RT). After 4 hours of reaction, the product was centrifuged at 12000 g for 10 minutes using an ultrafiltration tube, and washed 3 times with PBS to remove unreacted DBCO-PEG4-NHS.

[0042] Preparation of azide-modified IL-10: Next, 6 mL of 64 ng / mL NHS- 3 The mixture was mixed with 5 mg of IL-10 to obtain azide-modified IL-10.

[0043] Preparation of I@UN: Azide-modified IL-10 was then added to NO-UIO-DBCO in a weight ratio of 1:2, and magnetic stirring was performed at 4°C for 4 hours. The purified I@UN was obtained by centrifugation at 12,000 rpm using an ultrafiltration tube.

[0044] RAW264.7 and ATDC5 cells were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). The cells were cultured in DMEM supplemented with 10% fetal bovine serum in an incubator at 37°C with 5% CO 2 or 1% O 2 After reaching 80%-90%, RAW264.7 did not need to be trypsinized, and ADTC5 cells were trypsinized and passaged twice a week at a split ratio of 1:3. The cultured cells were used for subsequent experiments.

[0045] Preparation of macrophage membranes: RAW264.7 cells cultured in a culture dish were taken. When the density reached 80%, macrophages were collected and the macrophages were washed with Tris magnesium salt buffer (1 mM MgCl 2 and 10 mM Tris, deionized water to adjust pH to 7.4), resuspended, and then disrupted on ice with an ultrasonic disruptor. After disruption, 1 M sucrose was mixed with the cell homogenate to reach a final sucrose concentration of 0.25 M. The obtained product was gradient centrifuged to purify the cell membrane, and the extracted macrophage membrane was quantified by the BCA protein quantification method to ensure the protein concentration.

[0046] Preparation of MI@UN: The macrophage membrane obtained in the previous step was mixed with I@UN in a weight ratio of 2:1 (0.05 mg of macrophage membrane, 0.025 mg / mL of I@UN), and extruded through a polycarbonate filter membrane 20 times using a micro extruder (Aranti mini, Benro, Shanghai) to obtain MI@UN.

[0047] 1. Material Characterization

[0048] To evaluate the loading of NO-prednisolone and the successful conjugation of IL-10, N3-CY5.5-NHS was used to label IL-10, CY3 was used to label NO-prednisolone, the macrophage membrane was stained with DIO, and the nucleus of the macrophage was labeled with DAPI. The quadruple fluorescently labeled MI@UN was photographed by confocal microscopy (CLSM, Zeiss, Germany).

[0049] The prepared UIO-66-NH 2 , macrophage membrane and MI@UN, use a pipette to take 10ul of the suspension and drop it on the prepared Parafilm sealing film, and place the copper mesh with the front side facing down to allow it to naturally absorb the suspension drops for 10-15 minutes; then use a pipette to take 10ul of 2% phosphotungstic acid solution and drop it on the sealing film, and place the copper mesh with the adsorbed surface facing the staining solution, turn it upside down and let it stand for 3-5 minutes; use a filter paper strip to absorb excess droplets, dry it under an incandescent lamp, and observe and take pictures: observe and take pictures under a transmission electron microscope.

[0050] Encapsulation of NO-prednisolone into UIO-66-NH 2 In order to modify UIO-66-NH with IL-10 2 , proposed a click chemistry reaction to react DBCO-PEG4-NHS with UIO-66-NH 2 The amino groups of UIO-66-NH 2 DBCO groups were introduced into the surface of IL-10-N. 3 The final product is then encapsulated with the macrophage cell membrane to obtain a stable triazole bond ( Figure 1 ).

[0051] TEM observation of UIO-66-NH 2 , you can see UIO-66-NH 2 Loose porous structure ( Figure 2 TEM observation of cell membrane vesicles obtained by squeezing the cell membrane of macrophages ( Figure 3The modified MOFs and macrophage membranes were passed through a film extruder to obtain the final product, and the morphology was observed by TEM. Figure 4 shown.

[0052] To verify the loading of NO-prednisolone and the conjugation of IL-10, three different fluorescent dyes were used for labeling: CY3 for IL-10, CY5.5 for NO-prednisolone, and DIO-Green for macrophage membranes. The results are shown in Figure 5 It shows that the three dyes overlap almost completely. CY3-labeled IL-10 is wrapped inside the macrophage membrane and does not form clumps. There is more scattered fluorescence outside, while the aggregation of NO-prednisolone is more concentrated. It can be seen that the release of IL-10 is better than that of NO-prednisolone. Therefore, the short-term and large-scale release of IL-10 relieves the inflammatory environment, and NO-prednisolone can release it slowly for a long time and promote the production of IL-10. And the phagocytosis of MI@UN by macrophages is also excellent.

[0053] When observing the phagocytosis of MI@UN by chondrocytes, it was found that the number of vesicles inside chondrocytes was very small, and the number of MI@UN engulfed was far less than that of macrophages. Then, the cell viability of the components of MI@UN was tested in macrophages and chondrocytes. The results showed that the use of MM and IL-10 alone had little effect on macrophages and chondrocytes. When NO-prednisolone was greater than 10μM, the cell viability decreased significantly. When UIO-66-NH 2 When the concentration was greater than 80 μg / mL, the cell viability decreased significantly. 2 When the concentration of MI@UN reached 120 μg / mL, the cell viability was comparable to that of 80 μg / mL UIO-66-NH 2 similar( Figure 6 ). 2 The particle size of MI@UN was tested, among which UIO-66-NH 2 The diameter of MI@UN is concentrated at 100nm, while that of MI@UN is concentrated at 110nm ( Figure 7 ).

[0054] In summary, the modified UIO-66-NH 2 , targeted delivery of IL-10 and NO-prednisolone, and achieved sequential release.

[0055] 2. Animal experiments

[0056] Histologically, DMM was induced by meniscus injury in mice, and the mice were randomly divided into groups. Different modes of action were given to different groups 7 days after surgery, and the joints of the mice were removed after 90 days of action to further evaluate the effect of functionalized bionic nanoparticles targeting synovial macrophages on osteoarthritis ( Figure 8 ).

[0057] In order to verify the retention time of MI@UN in the mouse joint cavity, IL-10 and NO-prednisolone were labeled with CY5.5, and the retention time of the drug in the joint cavity after direct IN injection was observed by live imaging. Live imaging showed that in the absence of macrophage membranes and UIO-66-NH 2 With the help of , IN can only last for 2 days, while MI@UN can achieve a sustained release time of 14 days, which greatly maintains the drug concentration and increases the duration of drug action.

[0058] HE staining was performed on the joints of all the mice sacrificed to observe the proliferation of the synovium. The synovial tissue structure of the sham-operated group was clear. After modeling, the synovial tissue of the cell proliferation became dense and chaotic. The effect of MU was almost invisible, and the synovium was still in a state of proliferation. Although IN had a preliminary therapeutic effect, the density of the synovial tissue was reduced compared with that of the DMM group, but IL-10 and NO-prednisolone were not significantly inhibited in the absence of UIO-66-NH 2 The best effect was not achieved with the assistance of MM, although the synovium did improve to a certain extent.

[0059] Due to the UIO-66-NH 2 The best effect was achieved by the injection of MI@UN. The synovial structure was similar to that of the sham operation group. The cartilage had no depressions or cracks, the surface was relatively smooth, and the thickness of the cartilage was normal ( Figure 8 ). Fig. 9 and Fig.10 The results showed that the effect of MI@UN significantly reduced the Synovitis Score. Safranin O staining showed that the normal cartilage layer showed uniform staining, and each layer was clearly visible. The cartilage in the DMM group was severely worn, the degenerated cartilage surface was irregular, and the cartilage distribution was abnormal and unevenly colored. The effect of MU still showed severe cartilage wear and abnormal cartilage distribution. Although the effect of the IN group showed a certain repair effect on the cartilage, the effect of MI@UN was more significant. The addition of MI@UN significantly reduced the erosion of the cartilage, and the uneven cartilage surface and cartilage cracks were significantly reduced ( Fig.11Although IN reduced the score of osteoarthritis, due to the lack of targeting and sustained release functions, it was inferior to MI@UN in terms of space and time, and its efficacy was significantly lower than MI@UN ( Fig.12 ).

[0060] Similarly, the synovium was histochemically stained to detect the expression of GLUT1 in the synovium. It was found that the hyperplastic synovium in the DMM group and the MU group showed strong expression of GLUT1. Due to the short half-life of IN, it could not achieve the best effect, while the addition of MI@UN significantly inhibited the expression of GLUT1, and the effect was far better than the direct injection of IN. This is consistent with the predicted results. Due to the protection of the macrophage membrane and UIO-66-NH 2 The sustained release of MI@UN has a significant effect on the synovial membrane. Synovial macrophages engulf MI@UN and successfully inhibit excessive glycolysis in the synovial membrane. Fig.13 , 14). At the same time, histochemical staining was performed on the cartilage to detect cartilage iron death. It was found that the expression of GPX4 in the DMM and MU groups was very low, and almost not expressed in areas where the cartilage was severely worn. However, the expression level in the MI@UN group was almost the same as that in the sham operation group ( Fig.15 , 16). The subchondral bone of mice was also scanned. The subchondral bone structure of the sham group was loose and porous, while the cartilage of the DMM group was significantly hardened and the loose and porous structure disappeared. Quantitative calculations showed that the bone volume of the DMM group was significantly reduced. The effect of IN did provide a certain therapeutic effect, and the dense structure was improved to a certain extent. However, after the effect of MI@UN, the trabeculae were arranged in an orderly manner and the osteophytes were reduced, which was very similar to the sham group ( Fig.17 , 18).

[0061] MI@UN can restore normal joint parameters and have a certain effect on subchondral bone. Therefore, it can be used as an effective method for preparing drugs for the treatment of OA. It also shows that the clinical application of MI@UN in the treatment of OA has certain prospects.

[0062] In the present invention, the macrophage membrane encapsulates the modified UIO-66-NH 2 Due to the wrapping of macrophage membrane, MI@UN can be actively engulfed by macrophages, and IL-10 is effectively conjugated to the MOF material UIO-66-NH 2 The surface of UIO-66-NH is released in large quantities in a short period of time after injection. In order to enhance the efficacy of IL-10, the IL-10 agonist NO-prednisolone is loaded into UIO-66-NH 2 Due to the loose and porous natural structure of MOF materials, UIO-66-NH 2The NO-prednisolone inside can achieve long-term slow release, achieving the purpose of maintaining local drug concentration. Compared with the IN group, MI@UN has an action time of up to 14 days, and has good biocompatibility and no effect after degradation, which provides a good basis for the therapeutic effect of MI@UN.

[0063] Finally, it should be noted that the above embodiments are only used to illustrate the present invention and are not intended to limit the technical solutions described in the present invention. Those skilled in the art should understand that the present invention can still be modified or replaced by equivalents. All technical solutions and improvements that do not depart from the spirit and scope of the present invention should be included in the scope of the claims of the present invention.

Claims

1. A functionalized biomimetic nanoparticle targeting synovial macrophages, characterized in that: The preparation steps include: mixing macrophage membrane and I@UN in a weight ratio of (1.5-2.5):1, and squeezing through a polycarbonate filter membrane 19-21 times; wherein I@UN is obtained by adding azide-modified IL-10 to NO-UIO-DBCO, stirring, and centrifuging.

2. The functionalized biomimetic nanoparticles targeting synovial macrophages according to claim 1, characterized in that: The method for preparing the macrophage membrane comprises: culturing RAW264.7 cells in a culture dish, collecting macrophages when the density reaches 80%, resuspending the macrophages in Tris magnesium salt buffer and then breaking them, mixing sucrose with the cell homogenate after breaking, centrifuging the obtained product, and purifying the cell membrane to obtain the macrophage membrane.

3. The functionalized biomimetic nanoparticles targeting synovial macrophages according to claim 2, characterized in that: The Tris magnesium salt buffer comprises 1 mM MgCl2 and 10 mM Tris, and the pH is adjusted to 7.4 using deionized water.

4. The functionalized biomimetic nanoparticles targeting synovial macrophages according to claim 1, characterized in that: The preparation method of the azide-modified IL-10 comprises: mixing 6 mL of NHS-N3 with a concentration of 64 ng / mL with 5 mg of IL-10.

5. The functionalized biomimetic nanoparticles targeting synovial macrophages according to claim 1, characterized in that: The preparation method of NO-UIO-DBCO comprises: taking 1 mg / mL UIO-66-NH2 loaded with NO-prednisolone and reacting it with 10 mmol / L diphenylcyclooctyne-tetraethylene glycol-active ester PBS solution at room temperature, and after the reaction is completed, centrifuging with an ultrafiltration tube and washing with PBS to obtain the product.

6. The functionalized biomimetic nanoparticles targeting synovial macrophages according to claim 1, characterized in that: The preparation method of UIO-66-NH2 of NO-prednisolone comprises: taking 1.25 mg of 1 mg / mL UIO-66-NH2 and dissolving it in 50 μL of NO-prednisolone, stirring it magnetically at room temperature for 24 hours, and then centrifuging to obtain a precipitate.

7. The functionalized biomimetic nanoparticles targeting synovial macrophages according to claim 6, characterized in that: The preparation method of UIO-66-NH2 comprises: dissolving dimethylsiloxane-polyoxy-polypropylene ether in deionized water, adding acetic acid and NaClO4·H2O, stirring well to form a uniform solution, adding ZrO(NO3)2·2H2O and BDC-NH2 to the mixture, stirring and centrifuging to obtain a precipitate, washing with deionized water and centrifuging again to obtain the precipitate.

8. The functionalized biomimetic nanoparticles targeting synovial macrophages according to claim 7, characterized in that: The dosage ratio of the dimethylsiloxane-polyoxy-polypropylene ether, deionized water, acetic acid, NaClO4·H2O, ZrO(NO3)2·2H2O and BDC-NH2 is 50mg:3mL:0.4mL:150mg:115.6mg:50mg.

9. Use of the functionalized bionic nanoparticles targeting synovial macrophages according to any one of claims 1 to 8 in the preparation of a drug for treating osteoarthritis.

10. The use according to claim 9, characterized in that: The medicine includes tablets, capsules, pills, granules, oral liquids and solutions.

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