Mitochondrial dysfunction bionic nano-drug as well as preparation and application thereof

Abstract

The invention discloses a bionic nano-drug for mitochondrial dysfunction as well as preparation and application of the bionic nano-drug. The bionic nano-drug comprises RGD engineered exosome serving as a carrier, dequalinium chloride modified on the surface of the carrier, and oxaliplatin encapsulated in the carrier. The bionic nano-drug (OXA at Exo-RD) can protect goods with mitochondrial disorder in the blood circulation process, mitochondrial accumulation of the goods is increased through sequential targeting, goods 1 (DQA) induces oxidative stress, and mitochondrial mediated apoptosis and mitochondrial dysfunction are triggered; cargo 2 (OXA) destroys mitochondrial DNA and prevents DNA repair starting, so that chemotherapy drug resistance is overcome. The two cargos cooperate to overcome CRC drug resistance and inhibit transfer.

Description

Technical Field

[0001] The invention relates to a bionic nano drug for mitochondrial dysfunction and the preparation and application thereof, belonging to the field of bionic nano drugs. Background Art

[0002] Colorectal cancer (CRC) is one of the most common malignant tumors, and its morbidity and mortality are both on the rise, seriously threatening human health and survival. Oxaliplatin (OXA) is a first-line chemotherapy drug for patients with advanced CRC. It targets and binds to DNA, preventing the unwinding of the DNA double helix, thereby inhibiting DNA replication and exerting an anti-tumor effect. Although OXA has good application prospects, its drug resistance and adverse reactions caused by nonspecific distribution seriously limit the therapeutic effect. More importantly, tumor metastasis is another obstacle to the effective treatment of CRC, which can lead to treatment failure.

[0003] DNA damage repair mechanisms reduce the effectiveness of chemotherapy by repairing intrachain crosslinks between platinum and DNA, which is one of the main causes of chemotherapy resistance. Due to the overexpression of DNA damage repair-related genes in resistant tumor cells, effective strategies are urgently needed to prevent the initiation of DNA repair and restore the sensitivity of resistant tumor cells to platinum drugs. Currently, there are a variety of inhibitors related to DNA repair, such as DNA-pk inhibitors, PARP inhibitors, MGMT inhibitors, etc., which are used in combination with platinum drugs to improve the anti-tumor efficacy. In addition, studies have shown that mitochondria do not have DNA damage repair functions.

[0004] Therefore, how to deliver platinum to mitochondria rather than the nucleus to circumvent chemotherapy resistance and / or inhibit tumor metastasis has become a technical problem that needs to be urgently solved in this field. Summary of the invention

[0005] To improve the above problems, the present invention provides a bionic nanomedicine, wherein the bionic nanomedicine comprises RGD engineered exosomes (Exo-R) as a carrier, dequalinium chloride (DQA) modified on the surface of the carrier, and oxaliplatin (OXA) encapsulated inside the carrier.

[0006] According to an embodiment of the present invention, the RGD engineered exosomes (Exo-R) refer to exosomes combined with RGD peptide.

[0007] According to an embodiment of the present invention, the RGD peptide is selected from peptides containing arginine-glycine-aspartic acid (Arg-Gly-Asp, RGD), such as cRGD (valine-arginine-glycine-aspartic acid-glutamic acid cyclic peptide).

[0008] According to an embodiment of the present invention, the exosome is also called exosome, which is a small membrane vesicle secreted by cells. The diameter of the exosome can be about 20nm to about 200nm, such as about 30nm to about 200nm.

[0009] According to an embodiment of the present invention, the surface of the carrier is modified with dequalinium chloride (DQA), preferably, the dequalinium chloride (DQA) is inserted into the surface of the carrier.

[0010] According to an embodiment of the present invention, the content of dequalinium chloride (DQA) on the surface of the carrier is 5-10wt%, preferably 6-9wt%, such as 6wt%, 7wt%, 8wt%, 9wt%, and an example is 7.3wt%.

[0011] According to an embodiment of the present invention, the content of oxaliplatin (OXA) in the carrier is 5-10wt%, preferably 5-8wt%, such as 5wt%, 6wt%, 7wt%, 8wt%, and an example is 5.8wt%.

[0012] The present invention also provides a method for preparing the above-mentioned bionic nanomedicine, which comprises the following steps:

[0013] (1) preparing dequalinium-modified RGD engineered exosomes, i.e., Exo-RD; and

[0014] (2) Encapsulating oxaliplatin into the Exo-RD to obtain OXA@Exo-RD.

[0015] According to an embodiment of the present invention, the preparation method further comprises the step of preparing or preparing RGD engineered exosomes Exo-R.

[0016] According to an embodiment of the present invention, the step (1) comprises: adding DSPE-PEG 2000 -DQA, PBS buffer and Exo-R were mixed to obtain Exo-RD.

[0017] According to an embodiment of the present invention, step (1) comprises:

[0018] (1a) DSPE-PEG 2000 -DQA is mixed with PBS buffer to obtain a mixed solution;

[0019] (1b) Mixing Exo-R with the mixed solution of step (1a).

[0020] Preferably, the Exo-R is added to the mixed solution of step (1a) in the form of a suspension thereof. For example, the Exo-R suspension is a PBS suspension of Exo-R.

[0021] According to an embodiment of the present invention, in step (1a), DSPE-PEG 2000 - The temperature of mixing DQA and PBS buffer is 30-70°C; and / or the mixing time is 10-30 min.

[0022] According to an embodiment of the present invention, the mixing temperature in step (1b) is 30-50° C.; and / or the mixing time is 1-4 h.

[0023] According to an embodiment of the present invention, in step (1b), the concentration of the Exo-R suspension is 100-300 μg / mL, preferably 150-200 μg / mL, for example, 150 μg / mL, 160 μg / mL, 170 μg / mL, 180 μg / mL, 190 μg / mL or 200 μg / mL.

[0024] According to an embodiment of the present invention, in step (1a), DSPE-PEG in the mixed solution 2000 - The concentration of DQA is 20-100 μg / mL, preferably 20-60 μg / mL, for example 20 μg / mL, 30 μg / mL, 40 μg / mL, 50 μg / mL or 60 μg / mL.

[0025] According to an embodiment of the present invention, in step (1b), the Exo-R surface protein is reacted with DSPE-PEG 2000 -DQA has a mass ratio of 5:1 to 1:15, for example, 5:1, 1:1, 1:5, 1:10 or 1:15.

[0026] According to an embodiment of the present invention, in step (2), the mass ratio of Exo-RD surface protein to oxaliplatin is 10:1 to 1:10, for example, 10:1, 8:1, 6:1, 5:1, 4:1, 2:1, 1:1, 1:2, 1:4, 1:5, 1:6, 1:8 or 1:10.

[0027] According to an embodiment of the present invention, step (2) specifically comprises: encapsulating oxaliplatin (OXA) into Exo-RD using an electroporation method (such as X-Porator H1 electroporation system).

[0028] According to an embodiment of the present invention, the DSPE-PEG 2000 -DQA is prepared by methods known in the art, such as by mixing DSPE-PEG 2000 -COO-NHS reacts with dequalinium chloride to obtain DSPE-PEG 2000 -DQA. As an example, the DSPE-PEG 2000 The preparation method of -DQA comprises the following steps:

[0029] (S1) 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 -Carboxyl (DSPE-PEG 2000 -COOH), N-hydroxysulfosuccinimide (NHS), carbodiimide hydrochloride (EDC-HCl) and triethylamine were mixed to obtain DSPE-PEG 2000 -COO-NHS;

[0030] (S2) DSPE-PEG 2000 -COO-NHS reacts with dequalinium chloride (DQA) to obtain the DSPE-PEG 2000 -DQA.

[0031] Preferably, step (S1) is carried out in the presence of an organic solvent, for example, the organic solvent is chloroform.

[0032] Preferably, step (S2) is carried out in the presence of an organic solvent, for example, the organic solvent is DMSO.

[0033] The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the bionic nanomedicine.

[0034] The present invention also provides application of the bionic nano drug in cancer treatment.

[0035] The present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of the bionic nanomedicine to a patient in need.

[0036] The present invention also provides a method for reducing tumor growth, comprising administering a therapeutically effective amount of the above bionic nanomedicine to a patient in need.

[0037] According to an embodiment of the present invention, the cancer may be colon cancer and / or rectal cancer, such as colorectal cancer.

[0038] According to an embodiment of the present invention, the tumor may be a colon tumor and / or a rectal tumor, such as a colorectal tumor.

[0039] Beneficial Effects

[0040] The inventors were surprised to find that the bionic nanomedicine (OXA@Exo-RD) provided by the present invention can increase the accumulation of mitochondrial function-interfering drugs dequalinium chloride (DQA) and oxaliplatin (OXA) by sequentially targeting resistant colorectal cancer cells and mitochondria, thereby inducing mitochondrial-mediated apoptosis and mitochondrial dysfunction, synergistically improving the drug resistance of colorectal cancer, and inhibiting the metastasis of cancer cells. In addition, the bionic nanomedicine of the present invention can protect the "cargo" (i.e., DQA and OXA) that induces mitochondrial disorders during blood circulation. Among them, cargo 1 (DQA) induces oxidative stress, triggers mitochondrial-mediated apoptosis and mitochondrial dysfunction; cargo 2 (OXA) destroys mitochondrial DNA, prevents DNA repair from starting, and thus improves chemotherapy resistance.

[0041] Moreover, the bionic nanomedicine of the present invention has the advantages of good biocompatibility, high stability, long circulation time, low immunogenicity, etc., and can significantly avoid the problem of adverse reactions caused by nonspecific distribution. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 This is a flow chart of the preparation of OXA@Exo-RD of the present invention.

[0043] Figure 2 It is a transmission electron microscopy characterization image of Exo in comparative example 1 and OXA@Exo-RD nanoparticles in example 1.

[0044] Figure 3 This is the anticancer activity test result of HCT116 and HCT116 / OXA cells treated with OXA, OXA@Exo, OXA@Exo-R, OXA@Exo-D and OXA@Exo-RD for 24 hours.

[0045] Figure 4 It is a graph of the in vivo anticancer results of PBS, OXA, OXA@Exo, OXA@Exo-R, OXA@Exo-D, and OXA@Exo-RD.

[0046] Figure 5 These are the anti-metastasis results of PBS, OXA, OXA@Exo, OXA@Exo-R, OXA@Exo-D, and OXA@Exo-RD. DETAILED DESCRIPTION

[0047] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0048] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0049] DSPE-PEG 2000 -cRGD and DSPE-PEG 2000 -COOH was purchased from Xi'an Ruixi Biotechnology Co., Ltd., DQA was purchased from Sigma-Aldrich, oxaliplatin, N-hydroxysulfosuccinimide (NHS) and carbodiimide hydrochloride (EDC) were purchased from MacLean Chemical Reagent Co., Ltd., and 4- to 6-week-old female BALB / c nude mice used in animal experiments were obtained from Vital River (Beijing).

[0050] Example 1: Preparation of OXA@Exo-RD

[0051] Figure 1 OXA@Exo-RD preparation process of the present invention is shown in FIG. Figure 1 As shown, first, Exo-R was purified from the culture supernatant, then Exo-RD was obtained by conjugation with DQA through post-insertion treatment, and finally OXA was encapsulated in Exo-RD by electroporation to form a sequential targeting and mitochondrial dysfunction drug delivery system OXA@Exo-RD. The specific preparation method is as follows:

[0052] 1.1 DSPE-PEG 2000 - Preparation of DQA

[0053] 50mg 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 -Carboxyl (DSPE-PEG 2000 -COOH), 2 mg N-hydroxysulfosuccinimide (NHS) and 6.8 mg EDC-HCl were dissolved in 4 mL chloroform, and then three drops of triethylamine were added. The reaction mixture was reacted at room temperature in the dark for 3 hours to obtain DSPE-PEG. 2000 -COO-NHS.

[0054] Then, 9.2 mg of dequalinium chloride (DQA) dissolved in DMSO (4 mL) was added to the DSPE-PEG 2000 -COO-NHS and stirred for 1 hour. After removing chloroform by rotary evaporation, 20 mL of deionized water was added. The crude product was dialyzed against deionized water for 72 hours using a 3000Da MWCO regenerated cellulose dialysis tube to remove uncoupled reactants, and then freeze-dried to obtain a dry powder.

[0055] 1.2 Preparation of OXA@Exo-RD

[0056] First, RGD-engineered exosomes (Exo-R) were obtained from cell culture supernatants using gradient centrifugation. Specifically, hUMSCs were cultured in DMEM containing 10% exosome-free FBS and 1% penicillin-streptomycin for 24 h. The culture medium was replaced with DSPE-PEG 2000 -cRGD (100 μg / mL) in DMEM and continue to culture for 24 hours. When the cells reach 80-90% confluence, the culture medium is collected with a pipette. The obtained supernatant is subjected to gradient ultracentrifugation to obtain Exo-R. The obtained Exo-R is resuspended in PBS and stored at -80°C for further analysis. All centrifugations are performed at 4°C.

[0057] Next, DQA was incorporated into Exo-R by post-insertion method to prepare Exo-RD. 2000 -DQA PBS buffer was heated at 60°C for 15 minutes to obtain solution A. Then 200 μg / mL Exo-R suspension was mixed with solution A at 40°C for 3 hours. After the crude product was cooled to room temperature, exosomes co-modified with cRGD and DQA (Exo-RD) were obtained. Finally, 20 μg / mL oxaliplatin (OXA) was encapsulated into 200 μg / mL Exo-RD to obtain OXA@Exo-RD. Specifically, the purified Exo-RD (or Exo-RD PBS solution) (200 μg / mL) and oxaliplatin (or oxaliplatin PBS solution) (20 μg / mL) were mixed and electroporated at 200V and 100 μF on the X-Porator H1 electroporation system; thereafter, the prepared OXA@Exo-RD was collected by centrifugation and stored at 4°C for later use.

[0058] In OXA@Exo-RD, the content of dequalinium chloride (DQA) on the surface of the carrier Exo-RD is 7.3wt%; the content of oxaliplatin (OXA) inside the carrier Exo-RD is 5.8wt%.

[0059] Comparative Example 1: Preparation of OXA@Exo

[0060] The preparation method of OXA@Exo is as follows:

[0061] First, exosomes (Exo) were obtained from the cell culture supernatant using gradient centrifugation. Specifically, hUMSCs were cultured in DMEM containing 10% exosome-free FBS and 1% penicillin-streptomycin. When the cells reached 80-90% confluence, the culture medium was collected with a pipette. Exo was obtained by gradient ultracentrifugation of the obtained supernatant. The obtained Exo was resuspended in PBS and stored at -80°C for further analysis. All centrifugations were performed at 4°C.

[0062] Next, oxaliplatin (OXA) was encapsulated into Exo to obtain OXA@Exo. Specifically, purified Exo (200 μg / mL) and oxaliplatin (20 μg / mL) were mixed and electroporated at 200 V and 100 μF on an X-Porator H1 electroporation system, and the prepared OXA@Exo was collected by centrifugation and stored at 4 °C for later use.

[0063] Comparative Example 2: Preparation of OXA@Exo-R

[0064] The preparation method of OXA@Exo-R is as follows:

[0065] The preparation of Exo-R was the same as in Example 1.

[0066] Next, oxaliplatin (OXA) was encapsulated into Exo-R to obtain OXA@Exo-R. Specifically, purified Exo-R (200 μg / mL) and oxaliplatin (20 μg / mL) were mixed and electroporated at 200 V and 100 μF on an X-Porator H1 electroporation system, and the prepared OXA@Exo-R was collected by centrifugation and stored at 4 °C for later use.

[0067] Comparative Example 3: Preparation of OXA@Exo-D

[0068] The preparation method of OXA@Exo-D is as follows:

[0069] DSPE-PEG 2000 - The preparation of DQA is the same as in Example 1.

[0070] Exosomes (Exo) were obtained from the cell culture supernatant using gradient centrifugation. The preparation of Exo was the same as that in Comparative Example 1.

[0071] Next, DQA was incorporated into Exo by post-insertion method to prepare Exo-D. Specifically, 40 μg / mL DSPE-PEG 2000 -DQA was dissolved in PBS buffer and heated at 60°C for 15 minutes to obtain solution A. Then, 200 μg / mL Exo suspension was mixed with solution A at 40°C for 3 hours. After the crude product was cooled to room temperature, DQA co-modified exosomes (Exo-D) were obtained.

[0072] Finally, oxaliplatin (OXA) was encapsulated into Exo-D to obtain OXA@Exo-D. Specifically, purified Exo-D (200 μg / mL) and oxaliplatin (20 μg / mL) were mixed and electroporated at 200 V and 100 μF on an X-Porator H1 electroporation system, and the prepared OXA@Exo-D was collected by centrifugation and stored at 4 °C for later use.

[0073] Test Example 1

[0074] Figure 2 Figure 1 is a transmission electron microscope characterization image of Exo in Comparative Example 1 and OXA@Exo-RD nanoparticles in Example 1. Figure 2 As shown in the figure, through TEM observation, the morphology of Exo and OXA@Exo-RD are both disc-shaped, which is the typical morphology of Exo, indicating that Exo was successfully extracted and its integrity was maintained after post-modification and drug loading.

[0075] Test Example 2

[0076] The CCK-8 assay was used to evaluate the cytotoxicity of OXA, OXA@Exo (Comparative Example 1), OXA@Exo-R (Comparative Example 2), OXA@Exo-D (Comparative Example 3), and OXA@Exo-RD (Example 1) against OXA-sensitive and resistant HCT116 cells.

[0077] The specific experimental process is as follows: First, HCT116 and HCT116 / OXA cells were inoculated in 96-well plates (1×10 4 / well) and cultured overnight. Then OXA, OXA@Exo, OXA@Exo-R, OXA@Exo-D, and OXA@Exo-RD containing 0.01-20μg / mL Pt were added to the culture plate and incubated for 24h. After adding 10μL CCK-8 solution to each well and incubating for 2h, the absorbance at 450nm was recorded with an ELISA reader. The IC was calculated by the dose-effect curve after serial dilution of different drugs 50 .

[0078] The results of the anticancer activity analysis of HCT116 and HCT116 / OXA cells after 24 h of treatment with OXA, OXA@Exo, OXA@Exo-R, OXA@Exo-D, and OXA@Exo-RD are shown in Figure 2. Figure 3 shown. Figure 3 The results showed that compared with OXA, OXA@Exo-RD showed stronger cytotoxicity against HCT116 / OXA cells, and IC 50 This was also confirmed by the decrease in the index (0.87 μg / mL vs 8.09 μg / mL).

[0079] Furthermore, HCT116 / OXA and HCT116 IC 50 The (resistance factor) ratio decreased from 3.50 for OXA to 1.21 for OXA@Exo-RD, indicating that OXA@Exo-RD can alleviate the resistance of OXA.

[0080] Test Example 3

[0081] In view of the fact that OXA@Exo-RD had a significant inhibitory effect on OXA-resistant HCT116 cells in the in vitro experiment of Test Example 2, this test example further evaluated the in vivo anti-tumor therapeutic effect of OXA@Exo-RD in an OXA-resistant colorectal cancer subcutaneous tumor model.

[0082] BALB / c nude mice bearing HCT116 / OXA tumors were randomly divided into 6 groups (n=6) and intravenously injected with PBS, OXA, OXA@Exo, OXA@Exo-R, OXA@Exo-D and OXA@Exo-RD every other day. Based on OXA, the equivalent doses of OXA, OXA@Exo, OXA@Exo-R, OXA@Exo-D and OXA@Exo-RD were all 2 mg / kg, for a total of 5 times.

[0083] The anti-tumor efficacy was reflected by monitoring the changes in tumor volume in different treatment groups within 21 days. Figure 4 The in vivo anticancer results of PBS, OXA, OXA@Exo, OXA@Exo-R, OXA@Exo-D and OXA@Exo-RD are shown, where V represents the volume of the tumor at different treatment days, and V0 represents the initial volume of the tumor. Figure 4 It was shown that OXA@Exo-RD had the best growth inhibitory effect on subcutaneous OXA-resistant CRC and the smallest tumor volume.

[0084] Test Example 4

[0085] Liver metastasis is the leading cause of death in colorectal cancer patients. Given the key role of mitochondria in cancer metastasis, this test case further investigated the anti-metastatic effect of OXA@Exo-RD in the HCT116 / OXA metastasis model.

[0086] To establish the liver metastasis model, the mouse spleen was tied and divided into two segments, each with intact vascular pedicles. 2×10 6 HCT116 / OXA cells were injected into the distal part of the spleen. The spleen was gently massaged at the injection site for 5 minutes with a cotton swab to avoid tumor cell extravasation and promote tumor cell migration to the liver. 5 minutes after inoculation, when tumor cells entered the portal vein, half of the spleen containing the injected cells was removed to simulate primary tumor resection.

[0087] On the first day after spleen injection, mice were randomly divided into 6 groups (n=3 mice in each group) and intravenously injected with PBS, OXA, OXA@Exo, OXA@Exo-R, OXA@Exo-D and OXA@Exo-RD every other day. The equivalent dose of OXA was 2 mg / kg for 5 times. Based on OXA, the equivalent doses of OXA@Exo, OXA@Exo-R, OXA@Exo-D and OXA@Exo-RD were all 2 mg / kg. The body weight and activity of mice were recorded during the administration period.

[0088] On day 21, mice were killed, liver metastases were counted, and the level of colorectal cancer liver metastasis was evaluated. The livers after treatment were taken, fixed with 4% paraformaldehyde, and embedded in paraffin. The paraffin-embedded tumors were then cut into 4 μm sections and stained with hematoxylin-eosin (H&E) for histopathological analysis.

[0089] Figure 5 The anti-metastasis results of PBS, OXA, OXA@Exo, OXA@Exo-R, OXA@Exo-D and OXA@Exo-RD are shown below:

[0090] A is a representative image of the liver after different treatments;

[0091] B is the number of liver metastases in each group at the end of the study;

[0092] C is a representative H&E staining image of liver tissue in each group.

[0093] like Figure 5 As shown in Figures A and C, the livers of mice treated with PBS showed diffuse metastatic lesions, with the highest tumor burden based on liver weight; whereas OXA alone had little effect on liver metastases. Figure 5 As shown in Figure B, the number of liver metastases was the least after OXA@Exo-RD treatment. Compared with the PBS group, the metastasis inhibition rates of the OXA group, OXA@Exo group, and OXA@Exo-R group were 31.9%, 51.2%, and 66.3%, respectively. In addition, OXA@Exo-D and OXA@Exo-RD increased the inhibition rates to 80.7% and 86.6%, respectively, which were nearly 1.5 times and 1.7 times that of the OXA group, confirming that OXA@Exo-RD has a more excellent anti-metastasis ability.

[0094] The above examples are used to illustrate the specific implementation of the present invention. However, the protection scope of this application is not limited to the above implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included in the protection scope of the claims of this application.

Claims

1. A bionic nanomedicine, characterized in that: The bionic nanomedicine comprises RGD engineered exosomes as a carrier, dequalinium chloride modified on the surface of the carrier, and oxaliplatin encapsulated inside the carrier.

2. The bionic nano drug according to claim 1, characterized in that: The surface of the carrier is modified with dequalinium chloride. Preferably, the dequalinium chloride is inserted into the surface of the carrier.

3. The bionic nano drug according to claim 1, characterized in that: The content of dequalinium chloride on the surface of the carrier is 5-10wt%. Preferably, the content of oxaliplatin in the carrier is 5-10 wt %.

4. The method for preparing the bionic nano drug according to any one of claims 1 to 3, characterized in that: The method comprises: (1) preparing dequalinium-modified RGD engineered exosomes, i.e., Exo-RD; and (2) Encapsulating oxaliplatin into the Exo-RD to obtain OXA@Exo-RD.

5. The method according to claim 4, characterized in that The step (1) comprises: adding DSPE-PEG 2000 -DQA, PBS buffer and Exo-R were mixed to obtain Exo-RD. Preferably, step (1) comprises: (1a) adding DSPE-PEG 2000 -DQA is mixed with PBS buffer to obtain a mixed solution; (1b) Mixing Exo-R with the mixed solution of step (1a). Preferably, in step (1b), the concentration of the Exo-R suspension is 100-300 μg / mL. Preferably, in step (1a), DSPE-PEG in the mixed solution 2000 - The concentration of DQA is 20-100 μg / mL.

6. The method according to claim 4, characterized in that In step (1b), Exo-R surface protein and DSPE-PEG 2000 -The mass ratio of DQA is 5:1 to 1:

15. Preferably, in step (2), the mass ratio of Exo-RD surface protein to oxaliplatin is 10:1 to 1:

10.

7. The method according to claim 4, characterized in that Step (2) specifically includes: encapsulating oxaliplatin into Exo-RD by electroporation.

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the bionic nanomedicine according to any one of claims 1 to 3.

9. Use of the bionic nanomedicine according to any one of claims 1 to 3 in cancer treatment.

10. A method for treating cancer, characterized in that: The method comprises administering a therapeutically effective amount of the bionic nanomedicine according to any one of claims 1 to 3 to a patient in need. Preferably, a method for reducing tumor growth is characterized by comprising administering a therapeutically effective amount of the biomimetic nanomedicine according to any one of claims 1-3 to a patient in need. Preferably, the cancer is colon cancer and / or rectal cancer, such as colorectal cancer. Preferably, the tumor is a colon tumor and / or a rectal tumor, such as a colorectal tumor.

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