Glucose response type genetic material delivery hydrogel and application thereof

Abstract

The invention provides glucose response type genetic material delivery hydrogel and application of the glucose response type genetic material delivery hydrogel in diabetes wound surface drugs. The glucose response type genetic material delivery hydrogel comprises GOx and hollow MnO2-coated PEI nanoparticles loaded with microRNA (Ribonucleic Acid). According to the invention, GOx, MnO2 and miR-146a are loaded in hydrogel by utilizing the sensitivity of a borate bond to glucose, and accurate regulation and control of a local microenvironment of a wound surface are successfully realized by combining the blood glucose regulation and control function of glucose oxidase (GOx), the oxidation resistance and oxygen generation capacity of MnO2 nanoparticles and the gene regulation and control function of miR-146a.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical materials, and in particular relates to a glucose-responsive genetic material delivery hydrogel and an application thereof. Background Art

[0002] The treatment of chronic diabetic wounds is one of the major challenges in clinical treatment. The difficulty in healing is mainly due to a series of complex factors such as persistent inflammatory response caused by chronic high-sugar environment, increased reactive oxygen species (ROS) levels, local hypoxia, and imbalance of macrophage polarization. These pathological characteristics lead to local angiogenesis obstruction, impaired fibroblast function, and insufficient deposition of extracellular matrix (ECM), which seriously delays or even hinders the normal healing of wounds. According to statistics, the amputation rate of patients with diabetic wounds is much higher than that of non-diabetic patients, and the life expectancy of these patients is significantly shortened.

[0003] According to existing literature, miR-146a, as an important regulatory factor, is generally downregulated in diabetic wounds, while it remains stably expressed in normal wounds. Studies have shown that excessive delivery of miRNA may cause nonspecific gene interference and even lead to immune and metabolic abnormalities.

[0004] To solve the problem of diabetic wound healing, many treatment strategies have been proposed, such as the topical use of anti-inflammatory drugs, antioxidants, topical dressings or functional hydrogels. However, these traditional treatments have significant shortcomings. For example, the local anti-inflammatory effect is limited: in a high-sugar environment, it is difficult for macrophages to effectively transform from M1 polarization to M2 polarization, and inflammation persists for a long time. In addition, the antioxidant efficiency is insufficient: existing antioxidants cannot quickly remove high concentrations of ROS in the wound, and the continuous accumulation of ROS will further damage the tissue. The most critical thing is the lack of intelligent responsiveness: most materials are difficult to respond specifically to the wound microenvironment (such as high concentrations of glucose), resulting in low drug release efficiency. Therefore, in the prior art diabetic wound, due to factors such as high blood sugar, ROS accumulation and immune disorders, the transformation of macrophages from M1 to M2 is severely inhibited, resulting in long-term inflammatory response and hindering wound healing. The boronate bond is a dynamic covalent bond with dynamic reversibility. It uses its sensitivity to glucose to form a glucose-responsive genetic material delivery hydrogel for the treatment of diabetic wounds, which has positive significance. Summary of the invention

[0005] In order to solve the problems in the prior art, the present invention provides a glucose-responsive genetic material delivery hydrogel and its application. The sensitivity of the boronate bond to glucose is utilized to load GOx, MnO2, and miR-146a in the hydrogel, and the catalytic degradation of glucose by GOx, the antioxidant and oxygen generation ability of MnO2 nanoparticles, and the precise delivery mechanism of miR-146a are combined to form a glucose-responsive genetic material delivery hydrogel. The present invention realizes the morphological regulation of the hydrogel in a high-sugar environment by introducing a boronate bond into the hydrogel, and achieves the purpose of rapid release of GOx in high sugar. The blood sugar level of the wound surface is reduced, the oxidative stress caused by the accumulation of hydrogen peroxide is reduced, and the environmental responsive release of miR-146a is used to promote the transformation of macrophages to the M2 type, thereby enhancing the anti-inflammatory and tissue repair functions in the wound healing process. The promotion effect of the hydrogel on wound healing shows the effects of enhancing the polarization of M2 macrophages, reducing inflammatory responses, and promoting angiogenesis. The glucose-responsive genetic material delivery hydrogel system provides an innovative precision treatment strategy for diabetic wound treatment by optimizing the structure and function of the hydrogel, demonstrating its great application potential in gene therapy and local environment regulation, and providing strong support for clinical transformation.

[0006] The present invention solves the technical problem by adopting the following technical solutions:

[0007] The object of the present invention is to provide a glucose-responsive genetic material delivery hydrogel for use in diabetic wound medicine, wherein the glucose-responsive genetic material delivery hydrogel comprises GOx and hollow MnO2@PEI nanoparticles loaded with microRNA.

[0008] Furthermore, the glucose-responsive genetic material delivery hydrogel contains borate bonds.

[0009] Furthermore, the microRNA is miR-146a.

[0010] Furthermore, the glucose-responsive genetic material delivery hydrogel promotes the polarization of macrophages from M1 type to M2 type.

[0011] Furthermore, the mass ratio of the GOx to the hollow MnO2@PEI nanoparticles loaded with microRNA is 2:5.

[0012] Furthermore, the preparation method of the hollow MnO2@PEI nanoparticles loaded with microRNA is as follows: adding the hollow MnO2 nanoparticles to the PEI solution and magnetically stirring for 1.5 to 3 hours to make them evenly dispersed, and then centrifuging and washing with water twice to obtain HMnO2@PEI; dissolving the microRNA with PBS, and then adding the solution to the HMnO2@PEI and stirring, and then centrifuging and washing with water to obtain the hollow MnO2@PEI nanoparticles loaded with microRNA.

[0013] Furthermore, the PEI solution may be replaced by other cationic polymer solutions.

[0014] Furthermore, the particle size of the hollow MnO2 nanoparticles is 150 to 250 nm.

[0015] Furthermore, the mass ratio of the hollow MnO2 nanoparticles to microRNA is 5-20 mg: 0.5-2 OD.

[0016] Furthermore, the glucose-responsive genetic material delivery hydrogel also includes a hydrogel containing borate bonds.

[0017] Furthermore, the hydrogel containing borate ester bonds is GC-PBA+PAA-DA hydrogel.

[0018] Furthermore, the preparation method of the glucose-responsive genetic material delivery hydrogel is to mix GC-PBA+PAA-DA hydrogel, GOx, and hollow MnO2@PEI nanoparticles loaded with microRNA.

[0019] Furthermore, the mass ratio of GC-PBA to PAA-DA in the GC-PBA+PAA-DA hydrogel is 1:1.

[0020] Furthermore, the diabetic wounds include wounds caused by diabetes or diabetic complications and their treatment.

[0021] Furthermore, the diabetic wound surface includes ulcers, erosions, gangrene or diabetic foot caused by diabetes or diabetic complications.

[0022] Compared with the prior art, the beneficial technical effects of the present invention are:

[0023] The present invention utilizes the sensitivity of boronate bonds to glucose, loads GOx, MnO2, and miR-146a in hydrogels, combines GOx catalytic degradation of glucose, the antioxidant and oxygen generation capabilities of MnO2 nanoparticles, and the precise delivery mechanism of miR-146a, and is used for local treatment of diabetic wounds. The present invention achieves morphological regulation of hydrogels in a high-sugar environment by introducing boronate bonds in the hydrogel, and achieves the purpose of rapid release of GOx in high-sugar environments.

[0024] By loading GOx in the hydrogel, local blood sugar regulation in a high-sugar environment is achieved. GOx catalyzes the conversion of glucose into glucuronic acid and hydrogen peroxide, effectively reducing the local blood sugar level on the wound surface, thereby alleviating the continuous damage of high sugar to cell function. Compared with traditional systemic insulin therapy, this strategy shows higher wound targeting and avoids common side effects such as hypoglycemia and insulin resistance.

[0025] The present invention introduces MnO2 nanoparticles, which utilize their excellent antioxidant properties to effectively remove local ROS, reduce oxidative stress, and decompose the hydrogen peroxide produced by GOx to prevent its accumulation in the wound microenvironment, thereby avoiding the possibility that hydrogen peroxide produced during the GOx catalytic process may induce oxidative stress and have a negative impact on wound healing. More importantly, MnO2 can also produce oxygen, alleviate the common local hypoxia problem in diabetic wounds, and provide sufficient oxygen support for the repair of wound tissue. This strategy not only stabilizes the wound microenvironment, but also creates favorable conditions for cell metabolism and tissue repair.

[0026] The present invention ensures that miR-146a is released only in the wound environment with high blood sugar level by constructing a complex of hollow MnO2 nanoparticles and PEI. MnO2-grafted PEI can effectively adsorb negatively charged miR-146a as a positive charge carrier. When the sugar concentration in the local environment of the wound increases, the hydrogen peroxide generated by the GOx catalytic reaction will cause MnO2 to undergo conformational changes, thereby promoting the release of miR-146a. This response mechanism ensures that more miR-146a is released in diabetic wounds with high blood sugar, and avoids excessive release of miR-146a in diabetic wounds with relatively low blood sugar levels, excessively inhibiting necessary immune responses, resulting in delayed wound debridement and repair, or overexpression of miR-146a causing potential autoimmunity or metabolic abnormalities. MiR-146a promotes the transformation of macrophages from M1 to M2 by specifically regulating the FAK / NF-κB signaling pathway, thereby enhancing anti-inflammatory and tissue repair effects. M2 macrophages play an important role in the late stage of wound healing. They can inhibit excessive inflammatory responses and promote angiogenesis and tissue repair by secreting cytokines such as IL-10 and TGF-β. The supernatant of macrophages treated with hydrogel can significantly promote the migration and angiogenesis of endothelial cells, as well as the migration of fibroblasts, indicating that the hydrogel indirectly promotes angiogenesis and tissue repair by regulating macrophage polarization.

[0027] The dual synergistic effect of the hydrogel of the present invention on oxygen production and macrophage M2 polarization promoted angiogenesis in the wound area. The expression of type I and type III collagen in the wound area of ​​the hydrogel-treated group increased significantly, indicating that the hydrogel accelerated the synthesis and deposition of collagen by promoting the activation and migration of fibroblasts, thereby promoting wound healing. Although the hydrogel system in this study showed good biocompatibility

[0028] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention, it can be implemented according to the contents of the specification. In order to make the above and other purposes, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are listed below. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The particle size analysis diagram of HMnO2, HMnO2@PEI and HMnO2@PEI@microRNA obtained in Example 1 of the present invention.

[0030] Figure 2 This is a transmission electron microscope scanning image of HMnO2@PEI@microRNA obtained in Example 1 of the present invention.

[0031] Figure 3This is the EDS elemental analysis diagram of HMnO2@PEI@microRNA obtained in Example 1 of the present invention.

[0032] Figure 4 This is a diagram of the microRNA release experiment in Experimental Example 3 of the present invention.

[0033] Figure 5 This is a diagram of the dissolved oxygen experiment in Experimental Example 4 of the present invention.

[0034] Figure 6 These are photographs of the wound healing degree of SD rats in each group in Example 5 of the present invention on the 3rd, 7th, 14th and 21st days.

[0035] Figure 7 These are the hematoxylin and HE staining images of the wound surfaces of each group in Example 6 of the present invention on the 14th day. DETAILED DESCRIPTION

[0036] The technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments. It should be understood that the following embodiments are only exemplary illustrations 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 of protection that the present invention is intended to protect.

[0037] In addition, unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0038] Example 1

[0039] A method for preparing a glucose-responsive genetic material delivery hydrogel comprises the following steps:

[0040] 1) Preparation of hollow nanoparticles: Prepare 50 mg / ml SiO2 aqueous dispersion, add 150 mg KMnO4 to the SiO2 aqueous dispersion, ultrasonicate for 6 h, centrifuge, and wash with water three times, then disperse the obtained precipitate with 20 ml 2 mol / L Na2CO3 solution, stir overnight at 60°C, centrifuge, and wash with water three times to obtain hollow MnO2 nanoparticles (HMnO2);

[0041] 2) Preparation of microRNA-loaded complex: 10 mg of HMnO2 nanoparticles obtained in step 1) were added to 4 ml of 0.5 mg / ml PEI solution and magnetically stirred for 2 h to make them dispersed evenly, and then centrifuged and washed twice to obtain HMnO2@PEI; 1 OD of microRNA was dissolved in 1 ml of PBS, and then the solution was added to HMnO2@PEI and stirred for 2 h, and then centrifuged and washed to obtain a microRNA-loaded complex (HMnO2@PEI@microRNA);

[0042] 3) Preparation of hydrogel: 1 g of hydroxyethyl chitosan (GC) and 0.85 g of 3-carboxyphenylboronic acid (PBA) were dissolved in 400 ml of PBS solution at pH = 5.5, and then 30 mg of EDC and 50 mg of NHS were added, stirred for 24 h, dialyzed, and freeze-dried to obtain GC-PBA; 1 g of sodium polyacrylate (PAA) was added to 50 ml of PBS solution at pH = 5.5, and then 10 mg of EDC and 8 mg of NHS were added, stirred evenly, and then 50 mg of dopamine hydrochloride (DA) was added, and the reaction was continued for 24 h, dialyzed, and freeze-dried to obtain PAA-DA; GC-PBA and PAA-DA obtained in a mass ratio of 1:1 were mixed with 0.1 M PBS to prepare a 2% GC-PBA + 2% PAA-DA hydrogel;

[0043] 4) Hydrogel and nanoparticle composite: 5 mg HMnO2@PEI@microRNA obtained in step 2), 2% GC-PBA+2% PAA-DA hydrogel obtained in step 3), and 2 mg GOx were mixed to obtain a glucose-responsive genetic material delivery hydrogel.

[0044] Example 2

[0045] The particle size of HMnO2, HMnO2@PEI and HMnO2@PEI@microRNA obtained in Example 1 was analyzed by NanoBrook Omni (Brookhaven Instruments, UK) particle size analyzer, see Appendix Figure 1 . It can be seen that the particle size of the unmodified HMnO2 particles is 189.57±5.32nm and the PDI is 0.18. After modification, the particle size of HMnO2@PEI and HMnO2@PEI@microRNA gradually increases to 220.81±5.25nm, and the PDI of the modified HMnO2@PEI@microRNA drops to 0.09. It can be seen that the stability and controllability of the particles are improved through the modification process. The Zeta potential increased significantly from -19.83±1.53mV to -4.69±1.03mV (PEI modification), and dropped to -10.54±1.31mV after the introduction of microRNA, indicating that the cationic PEI was successfully coated to neutralize the surface negative charge, while the microRNA binding re-increased the negative charge. The coordinated changes in particle size and potential not only verify the successful modification, but also reflect the precise regulation of the particle surface environment.

[0046] The HMnO2@PEI@microRNA obtained in Example 1 was scanned using a transmission electron microscope. During the operation, ethanol was used for dispersion and then dropped onto the copper mesh carbon film. After drying, the morphology of the nanoparticles was observed using a transmission electron microscope. Figure 2It can be seen that there are PEI genes attached around the nanoparticles.

[0047] The HMnO2@PEI@microRNA hydrogel nanoparticles obtained in Example 1 were detected using an elemental analysis device in EDS mode (JEM-F200, Japan). Figure 3 It can be seen that all elements are almost distributed around the shell, and most of the PEI molecules cover the surface of the nanoparticles, forming a complete protective film.

[0048] Example 3 microRNA release experiment

[0049] A certain mass of the HMnO2@PEI@microRNA-loaded hydrogel of Example 1 was loaded into a dialysis bag, and the two ends of the dialysis bag were tied and immersed in 100 ml of PBS buffer containing 1 mg / L and 4 mg / L glucose respectively. The container containing all the dissolution medium was placed on a magnetic stirrer and stirred at a speed of 100 r / min at a constant temperature of 37°C. According to the set time node, 1 mL of dissolution medium was taken out each time and then 1 mL of fresh medium was added, and the miRNA content was quantitatively detected using RiboGreen RNA detection reagent (Maokang Biotechnology Co., Ltd., Shanghai).

[0050] See attached Figure 4 Under the condition of low glucose concentration (1 mg / ml), the miRNA release rate is relatively slow, the initial release is low, and the release rate gradually increases with time, but the overall release rate and the final release amount are significantly lower than those under high glucose conditions. Under the condition of high glucose concentration (4 mg / ml), the miRNA release is significantly accelerated, the initial release increases sharply, and a higher release rate is reached in a short time. The final cumulative release ratio is significantly higher than that under low glucose conditions. This means that the network structure, porosity or cross-linking density of the hydrogel is very sensitive to glucose stimulation. When the external glucose concentration rises, the structure loosens, the swelling changes or the dynamic bonding points change inside the hydrogel, thereby promoting the loaded miRNA molecules to diffuse out faster and more efficiently. When the glucose concentration in the external solution increases, phenylboronic acid forms a reversible complex with glucose, which changes the cross-linking state of the entire gel. At the same time, if there are enzymes similar to glucose oxidase in the hydrogel, they will catalyze the glucose conversion process, change the local pH value or ionic strength, and induce the gel to swell or shrink. These structural changes will change the porosity and diffusion path, thereby accelerating the release of miRNA.

[0051] Example 4 Dissolved oxygen experiment

[0052] A certain amount of HMnO2@PEI@microRNA-loaded hydrogel was placed in 50 ml of glucose solution containing 1 mg / L and 4 mg / L concentrations, respectively. The probe was fixed at a certain position, and a JPSJ605F dissolved oxygen analyzer (Yitian Scientific Instrument Co., Ltd., Shanghai) was used to detect the dissolved oxygen content in the solution at different time points.

[0053] See attached Figure 5 , under 1mg / L glucose conditions, the dissolved oxygen level starts from a low value and gradually increases over time, but the growth rate is relatively slow, and finally reaches a higher but limited equilibrium value. Under 4mg / L glucose conditions, the increase in dissolved oxygen is more rapid and obvious. At the same time point, the total amount of dissolved oxygen under high glucose conditions is much higher than that under low glucose conditions. Dissolved oxygen rises rapidly and continuously until it reaches a higher equilibrium value. Glucose oxidase (GOx), when there is enough glucose, oxidizes glucose into glucuronic acid, while consuming oxygen to generate H2O2, which is further decomposed into water and oxygen under the action of manganese dioxide, resulting in an increase in the oxygen concentration in the local solution. When the external glucose concentration is high (4mg / L), the rate of this enzymatic reaction is faster, resulting in more O2 being generated and dissolved in the water phase, so the dissolved oxygen concentration rises rapidly.

[0054] Example 5 Healing Experiment

[0055] 1. Animal selection:

[0056] 6-8 weeks old SD rats were selected and streptozotocin (STZ) solution was used to establish a diabetic SD rat model.

[0057] 2. Wound model establishment:

[0058] A full-thickness acute wound model was established on the back of rats. A circular skin wound with a diameter of approximately 1 cm was created on the back of the rats using a punch.

[0059] 3. Use of glucose-responsive genetic material delivery hydrogel for wound treatment

[0060] The experimental animals were randomly divided into 4 groups:

[0061] Control group: no wound treatment (control group);

[0062] GM group: treated with blank hydrogel without miR-146a loading;

[0063] GMN group: treated with blank hydrogels containing miR-146a-loaded NCs;

[0064] GMM group: treated with hydrogel loaded with miR-146a.

[0065] 4. Experimental results:

[0066] The backs of SD rats were photographed on the 0th, 3rd, 7th, 14th and 21st days of wound healing, and the wound areas at different time points were compared. Figure 6 :

[0067] Control group: On the 7th day, the wound of the control group healed slowly, the wound did not shrink significantly, there was obvious secretion on the wound, and the healing process was slow. On the 14th and 21st days, the wound gradually shrank, but there were still some areas that were not completely healed, showing a slower healing speed.

[0068] GM group (blank hydrogel group): After using blank hydrogel without miR-146a loading, wound healing improved on the 7th day, with obvious wound contraction and reduced secretions, but the wound healing speed was slightly increased compared with the control group. On the 14th and 21st days, the wound healed gradually and the wound area was significantly reduced, but there was still a certain healing lag.

[0069] GMN group (NC group loaded with miR-146a): The blank hydrogel group of NC loaded with miR-146a showed a similar healing process to that of the GM group.

[0070] GMM group (miR-146a hydrogel group): The GMM group had obvious wound healing on the 3rd day, while the other groups did not have obvious wound healing; on the 7th day, the wound healing in the GMM group was significantly better than that in the other groups, the wound shrank rapidly, the wound surface was covered quickly, and the tissue around the wound was well repaired. On the 14th and 21st days, the wound healing in the GMM group was almost complete, the wound was completely closed, there was no obvious inflammatory reaction on the wound surface, and almost no scar formation. Compared with other groups, the GMM group had the fastest healing speed and the best healing quality.

[0071] Example 6 Histological Evaluation

[0072] The wound edge skin of the four groups of experimental animals in Example 5 was fixed with 4% paraformaldehyde for 7 days on the 7th, 14th and 21st day of wound healing, and then the tissue samples were changed, and then the tissue fixative was changed twice. The samples were then decalcified, paraffinized, sliced ​​and stained with hematoxylin and eosin (HE).

[0073] See attached Figure 7 , which are hematoxylin and HE staining pictures on the 14th day of wound healing. The wound healing gradually improved, and the difference between the groups became more obvious.

[0074] Contro group: There was still a relatively obvious inflammatory reaction on the wound surface, some areas were not completely healed, the epidermis proliferated relatively slowly, and there was still a lot of necrotic tissue in the center of the wound surface.

[0075] In the GM and GMN groups, fibroblast proliferation was obvious, and the epidermal hyperplasia at the edge of the wound was relatively abundant, but there was still local inflammatory cell infiltration, the healing speed was slow, and it was not completely closed.

[0076] GMM group: The wound surface of the GMM group was almost completely closed, the epidermis was fully hyperplastic, there was no obvious inflammatory reaction on the wound surface, the blood vessels and fibroblasts in the dermis were evenly distributed, and the healing quality was better than that of other groups. The speed of cell proliferation and tissue repair was faster, and angiogenesis was significant.

[0077] From the aspects of healing time, wound contraction rate, tissue repair, etc., it can be seen that the wound surface treated with the glucose-responsive genetic material delivery hydrogel of the present invention is superior to other groups in promoting wound healing, reducing inflammatory response, and accelerating angiogenesis. The glucose-responsive hydrogel can automatically release miR-146a according to the local blood glucose level of the wound surface, and accelerate wound healing by regulating the inflammatory response and promoting the polarization of M2 macrophages. MiR-146a inhibits the expression of inflammatory factors, reduces the inflammatory response in the wound area, and promotes the proliferation of fibroblasts and vascular endothelial cells, thereby accelerating wound repair, and the application effect is significant.

[0078] The serial numbers of the above embodiments of the present invention are only for description and do not represent the advantages or disadvantages of the embodiments.

[0079] The embodiments of the present invention are described above in conjunction with the accompanying drawings, but the present invention is not limited to the above-mentioned specific implementation modes, which are merely illustrative rather than restrictive. Under the guidance of the present invention, ordinary technicians in this field can also make many forms without departing from the scope of protection of the present invention and the claims, all of which are within the protection of the present invention.

Claims

1. Application of a glucose-responsive genetic material delivery hydrogel in diabetic wound medicine, wherein the glucose-responsive genetic material delivery hydrogel comprises GOx and hollow MnO2@PEI nanoparticles loaded with microRNA.

2. The use according to claim 1, characterized in that: The microRNA is miR-146a.

3. The use according to claim 1, characterized in that: The glucose-responsive genetic material delivery hydrogel promotes the polarization of macrophages from M1 type to M2 type.

4. The use according to claim 1, characterized in that: The mass ratio of the GOx to the hollow MnO2@PEI nanoparticles loaded with microRNA is 2:

5.

5. The use according to claim 1, characterized in that: The preparation method of the hollow MnO2@PEI nanoparticles loaded with microRNA is as follows: adding the hollow MnO2 nanoparticles to the PEI solution and magnetically stirring for 1.5 to 3 hours to make them evenly dispersed, and then centrifuging and washing with water twice to obtain HMnO2@PEI; dissolving the microRNA with PBS, and then adding the solution to the HMnO2@PEI and stirring, and then centrifuging and washing with water to obtain the hollow MnO2@PEI nanoparticles loaded with microRNA.

6. The use according to claim 5, characterized in that: The particle size of the hollow MnO2 nanoparticles is 150-250nm.

7. The use according to claim 1, characterized in that: The glucose-responsive genetic material delivery hydrogel also includes a hydrogel containing borate ester bonds, and the hydrogel containing borate ester bonds is a GC-PBA+PAA-DA hydrogel.

8. The use according to claim 7, characterized in that: The preparation method of the glucose-responsive genetic material delivery hydrogel is to mix GC-PBA+PAA-DA hydrogel, GOx, and hollow MnO2@PEI nanoparticles loaded with microRNA.

9. The use according to claim 1, characterized in that: The diabetic wounds include wounds caused by diabetes or diabetic complications and their treatment.

10. The use according to claim 9, characterized in that: The diabetic wound surface includes ulcers, erosions, gangrene or diabetic foot caused by diabetes or diabetic complications.

Images