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] This invention belongs to the field of biomedical materials technology, specifically relating to a glucose-responsive genetic material delivery hydrogel and its applications. Background Technology

[0002] The treatment of chronic diabetic wounds is one of the major challenges in clinical practice. The difficulty in healing stems primarily from a complex set of factors, including persistent inflammation caused by a chronic high-glucose environment, elevated levels of reactive oxygen species (ROS), local hypoxia, and macrophage polarization imbalance. These pathological features lead to impaired local angiogenesis, damaged fibroblast function, and insufficient extracellular matrix (ECM) deposition, thus severely delaying or even hindering normal wound healing. Statistics show that the amputation rate in diabetic wound patients is significantly higher than in non-diabetic patients, and their life expectancy is consequently significantly shortened.

[0003] According to existing literature, miR-146a, as an important regulatory factor, is generally downregulated in diabetic wounds, while maintaining stable expression in normal wounds. Studies have shown that over-delivery of miRNAs may cause non-specific gene interference and even lead to immune and metabolic abnormalities.

[0004] To address the healing challenges of diabetic wounds, numerous treatment strategies have been proposed, including topical anti-inflammatory drugs, antioxidants, dressings, and functional hydrogels. However, these traditional treatments have significant limitations. For instance, the local anti-inflammatory effect is limited: in a high-glucose environment, macrophages struggle to effectively transition from M1 to M2 polarization, leading to persistent inflammation. Furthermore, antioxidant efficiency is insufficient: existing antioxidants cannot rapidly eliminate high concentrations of reactive oxygen species (ROS) in the wound, and the continuous accumulation of ROS further damages tissue. Most critically, there is a lack of intelligent responsiveness: most materials fail to specifically respond to the wound microenvironment (such as high glucose concentrations), resulting in low drug release efficiency. Therefore, in existing diabetic wound treatments, the M1-to-M2 transformation of macrophages is severely inhibited due to factors such as hyperglycemia, ROS accumulation, and immune dysregulation, leading to chronic inflammation and hindering wound healing. Boronate bonds, being dynamic covalent bonds with reversible dynamic properties, can be used to create glucose-responsive genetic material delivery hydrogels for the treatment of diabetic wounds, which holds significant promise. Summary of the Invention

[0005] To address the problems in existing technologies, this invention provides a glucose-responsive genetic material delivery hydrogel and its applications. Utilizing the sensitivity of borate ester bonds to glucose, GOx, MnO2, and miR-146a are loaded into the hydrogel. This combines the glucose-catalyzing degradation of glucose by GOx, the antioxidant and oxygen-generating capabilities of MnO2 nanoparticles, and the precise delivery mechanism of miR-146a to form a glucose-responsive genetic material delivery hydrogel. This invention achieves morphological regulation of the hydrogel under high glucose conditions by introducing borate ester bonds into the hydrogel, and achieves the goal of rapid GOx release under high glucose conditions. It reduces blood glucose levels at the wound site, alleviates oxidative stress caused by hydrogen peroxide accumulation, and promotes the conversion of macrophages to the M2 type through the environmentally responsive release of miR-146a, thereby enhancing anti-inflammatory and tissue repair functions during wound healing. The hydrogel's promoting effect on wound healing is manifested in enhancing M2 macrophage polarization, reducing inflammatory responses, and promoting angiogenesis. Glucose-responsive genetic material delivery hydrogel systems offer an innovative and precise treatment strategy for diabetic wounds by optimizing the structure and function of the hydrogel, demonstrating their great potential in gene therapy and local environmental regulation, and providing strong support for clinical translation.

[0006] The technical problem solved by this invention is achieved by the following technical solution:

[0007] The purpose of this invention is to provide an application of a glucose-responsive genetic material delivery hydrogel in diabetic wound medication, 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 ester bonds.

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

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

[0011] Furthermore, the mass ratio of GOx to 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: hollow MnO2 nanoparticles are added to PEI solution and magnetically stirred for 1.5-3 hours to disperse them evenly. After centrifugation and washing twice with water, HMnO2@PEI is obtained. MicroRNA is dissolved in PBS, and then the solution is added to HMnO2@PEI and stirred. After centrifugation and washing with water, the hollow MnO2@PEI nanoparticles loaded with microRNA are obtained.

[0013] Furthermore, the PEI solution can also be replaced with other cationic polymer solutions.

[0014] Furthermore, the mass ratio of the hollow MnO2 nanoparticles to microRNA is 5–20 mg: 0.5–2 OD.

[0015] Furthermore, the glucose-responsive genetic material delivery hydrogel also includes a hydrogel containing borate ester bonds.

[0016] Furthermore, the hydrogel containing borate ester bonds is a GC-PBA+PAA-DA hydrogel.

[0017] Furthermore, the glucose-responsive genetic material delivery hydrogel is prepared by mixing GC-PBA+PAA-DA hydrogel, GOx, and hollow MnO2@PEI nanoparticles loaded with microRNA.

[0018] Furthermore, the glucose-responsive genetic material delivery hydrogel is prepared by dissolving PAA-DA in PBS, mixing it with a microRNA-loaded complex and GOx to obtain a mixed solution, and then mixing the mixed solution with an equal volume of GC-PBA in PBS to obtain a glucose-responsive genetic material delivery hydrogel.

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

[0020] Furthermore, the GC-PBA is obtained by dissolving 3-carboxyphenylboronic acid (PBA) in MES solution, adding EDC and NHS, stirring until homogeneous, adding chitosan (GC), stirring continuously for 24 hours, dialysis, and freeze-drying.

[0021] Furthermore, the PAA-DA is obtained by adding sodium polyacrylate (PAA) to a MES solution, then adding EDC and NHS, stirring until homogeneous, then adding dopamine hydrochloride (DA), continuing the reaction for 24 hours, and finally dialysis and freeze-drying.

[0022] Furthermore, the diabetic wound includes wounds caused by diabetes or diabetic complications and their treatment.

[0023] Furthermore, the diabetic wound includes ulcers, erosions, gangrene, or diabetic foot caused by diabetes or diabetic complications.

[0024] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0025] This invention utilizes the sensitivity of borate ester bonds to glucose to load GOx, MnO2, and miR-146a into a hydrogel. Combining the glucose-catalyzing degradation of GOx, the antioxidant and oxygen-generating capabilities of MnO2 nanoparticles, and the precise delivery mechanism of miR-146a, this invention is applied to the local treatment of diabetic wounds. By introducing borate ester bonds into the hydrogel, this invention achieves morphological regulation of the hydrogel under high-glucose conditions and enables the rapid release of GOx under high glucose levels.

[0026] By loading GOx into a hydrogel, local glycemic regulation was achieved in a high-glucose environment. GOx catalyzes the conversion of glucose into glucuronic acid and hydrogen peroxide, effectively reducing local blood glucose levels at the wound site and thus alleviating the persistent damage to cell function caused by high glucose. Compared with traditional systemic insulin therapy, this strategy exhibits higher wound targeting and avoids common side effects such as hypoglycemia and insulin resistance.

[0027] This invention introduces MnO2 nanoparticles, utilizing their excellent antioxidant properties to effectively scavenge local ROS, reduce oxidative stress, and decompose hydrogen peroxide produced by GOx, preventing its accumulation in the wound microenvironment. This avoids the potential for oxidative stress caused by hydrogen peroxide generated during the GOx catalysis process, which could negatively impact wound healing. More importantly, MnO2 can also generate oxygen, alleviating the local hypoxia common in diabetic wounds and providing sufficient oxygen support for wound tissue repair. This strategy not only stabilizes the wound microenvironment but also creates favorable conditions for cell metabolism and tissue repair.

[0028] This invention constructs a complex of hollow MnO2 nanoparticles and PEI to ensure that miR-146a is released only in wound environments with high blood glucose levels. MnO2-grafted PEI, acting as a positive charge carrier, effectively adsorbs negatively charged miR-146a. When the local glucose concentration in the wound environment increases, hydrogen peroxide generated by the GOx-catalyzed reaction induces a conformational change in MnO2, thereby promoting the release of miR-146a. This response mechanism ensures the release of more miR-146a in diabetic wounds with high blood glucose levels, avoiding excessive release of miR-146a in diabetic wounds with relatively low blood glucose levels, which could excessively suppress necessary immune responses, leading to delayed wound debridement and repair, or overexpression of miR-146a triggering potential autoimmune or metabolic abnormalities. miR-146a specifically regulates the FAK / NF-κB signaling pathway, promoting the transformation of macrophages from M1 to M2 types, enhancing anti-inflammatory and tissue repair effects. M2 macrophages play a crucial role in the later stages of wound healing, suppressing excessive inflammatory responses and promoting angiogenesis and tissue repair by secreting cytokines such as IL-10 and TGF-β. The macrophage supernatant treated with hydrogel significantly promoted endothelial cell migration and angiogenesis, while also promoting fibroblast migration, indicating that the hydrogel indirectly promotes angiogenesis and tissue repair by regulating macrophage polarization.

[0029] The synergistic effect of oxygen production and macrophage M2 polarization in the hydrogel of this invention promotes angiogenesis in the wound area. The expression levels of type I and type III collagen in the wound area of ​​the hydrogel-treated group were significantly increased, indicating that the hydrogel accelerates collagen synthesis and deposition by promoting fibroblast activation and migration, thereby promoting wound healing. Although the hydrogel system in this study exhibited good biocompatibility.

[0030] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, and in order to make the above and other objects, features and advantages of the present invention more apparent and understandable, specific embodiments of the present invention are described below. Attached Figure Description

[0031] Figure 1 XPS maps of HMnO2, HMnO2@PEI, and HMnO2@PEI@microRNA of this invention.

[0032] Figure 2 This is a transmission electron microscope (TEM) scan of HMnO2@PEI@microRNA obtained in Example 1 of this invention.

[0033] Figure 3This is an EDS elemental analysis diagram of HMnO2@PEI@microRNA obtained in Example 1 of the present invention.

[0034] Figure 4 This is a diagram of the microRNA release experiment in Experiment Example 3 of the present invention.

[0035] Figure 5 This is a diagram of dissolved oxygen experiment in Experiment Example 4 of the present invention.

[0036] Figure 6 These are photographs of the wound healing status of SD rats on days 0, 3, 7, 14, and 21 of each group in Example 5 of the present invention.

[0037] Figure 7 HE staining images of wounds on day 3 and day 14 in Example 6 of the present invention (A is HE staining image on day 3, B is HE staining image on day 21). Detailed Implementation

[0038] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory 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 covered within the scope of protection intended by the present invention.

[0039] In addition, unless otherwise specified, all raw materials, reagents, instruments and equipment used in this invention can be obtained by purchasing them from the market or prepared by existing methods.

[0040] Example 1

[0041] A method for preparing a glucose-responsive genetic material delivery hydrogel includes the following steps:

[0042] 1) Preparation of hollow nanoparticles: Prepare a 50 mg / ml SiO2 aqueous dispersion, add 150 mg KMnO4 to the SiO2 aqueous dispersion, sonicate for 6 h, centrifuge, wash with water 3 times, disperse the obtained precipitate with 20 ml 2 mol / L Na2CO3 solution, stir overnight at 60 °C, centrifuge, wash with water 3 times to obtain hollow MnO2 nanoparticles (HMnO2);

[0043] 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 disperse them evenly. After centrifugation and washing twice with water, HMnO2@PEI was obtained. 1 D of microRNA was dissolved in 1 ml of PBS, and then the solution was added to HMnO2@PEI and stirred for 2 h. After centrifugation and washing with water, the microRNA-loaded complex (HMnO2@PEI@microRNA) was obtained.

[0044] 3) Preparation of hydrogel: 1.5 g of 3-carboxyphenylboronic acid (PBA) was dissolved in 50 ml of MES solution; 2.079 g of EDC and 1.248 g of NHS were added, and the mixture was stirred for 30 min under nitrogen protection. Then 2 g of chitosan (GC) was added, and the mixture was stirred for 24 h. The mixture was then dialyzed and freeze-dried to obtain GC-PBA. 1 g of sodium polyacrylate (PAA) was added to 35 ml of MES solution, and the mixture was stirred evenly under nitrogen protection. 134 mg of EDC and 152 mg of NHS were added, and the mixture was stirred evenly. Then 133 mg of dopamine hydrochloride (DA) was added, and the reaction was continued for 24 h. The mixture was then dialyzed and freeze-dried to obtain PAA-DA.

[0045] 4) Hydrogel and Nanoparticle Composite: 4g of GC-PBA was dissolved in 100mL of 0.1M PBS (pH 8.0) to obtain a 4% (w / v) GC-PBA solution; simultaneously, 4g of PAA-DA was dissolved in 100mL of PBS (pH 7.4), and glucose oxidase (GOx, final concentration 4mg / mL) and hMnO2@PEI@miR-146a (final concentration 10mg / mL) were added to obtain a mixed solution. The mixed solution was then mixed with an equal volume of the GC-PBA solution to obtain a glucose-responsive genetic material delivery hydrogel, HMnO2@PEI@microRNA.

[0046] Example 2

[0047] The Zeta potential was measured using a dynamic light scattering spectrometer (DLS, NanoBrookOmni, UK). The Zeta potential significantly increased from approximately -20 mV (original HMnO2) to approximately -5 mV (PEI modification), and then decreased to approximately -10 mV after microRNA introduction. This indicates that the cationic PEI successfully coated and neutralized the surface negative charge, while microRNA binding reintroduced the negative charge. The synergistic change in particle size and potential not only verified the success of the modification but also reflected the precise regulation of the particle surface environment.

[0048] The HMnO2@PEI@microRNA obtained in Example 1 was scanned using transmission electron microscopy (TEM). During the procedure, ethanol was used for dispersion, and the nanoparticles were dropped onto a copper mesh carbon film. After drying, the morphology of the nanoparticles was observed using TEM. (See Appendix) Figure 2 As can be seen, the particles loaded with microRNA exhibit a distinct solid structure, indicating successful encapsulation. Most of the PEI molecules cover the surface of the nanoparticles, forming a complete protective film.

[0049] The HMnO2@PEI@microRNA hydrogel nanoparticles obtained in Example 1 were analyzed using an EDS mode (JEM-F200, Japan) elemental analysis instrument. See Appendix. Figure 3 As can be seen, almost all elements are distributed around the shell. EDS spectra further validated the distribution of PEI molecules on the particle surface, revealing the characteristic elements of PEI and indicating the uniformity and integrity of the PEI coverage. When the nanoparticles were loaded with miRNA, phosphorus was detected, indicating successful microRNA loading. The miRNA loading process filled the particle cavities, altering their internal and external structural features. The loaded miRNA molecules interacted with the nanoparticle surface or internal cavity, causing the particle morphology to shrink or its structure to change. This is consistent with the TEM images revealing the significant disappearance of the original hollow structure and a marked change in particle morphology.

[0050] XPS analysis was performed on the distribution of HMnO2, HMnO2@PEI, and HMnO2@PEI@microRNA obtained in Example 1. See Appendix. Figure 1 The XPS spectrum of hMnO2 showed major peaks such as Mn 2p and O 1s, indicating the typical chemical composition of manganese dioxide. The hMnO2-PEI sample: Compared to pure hMnO2, the XPS spectrum of hMnO2-PEI showed significant changes after the introduction of PEI (polyethyleneimine). Near the Mn 2p peak, in addition to the Mn signal, a nitrogen (N 1s) signal was also observed, confirming the successful modification by PEI molecules. Furthermore, a slight shift or intensity change in the O 1s peak suggested that the addition of PEI might increase the active sites for surface redox reactions. hMnO2-PEI-microRNA nanoparticles: In the XPS spectrum of hMnO2-PEI-microRNA nanoparticles, in addition to the PEI and Mn signals, a relatively obvious P2p peak was observed, indicating that microRNA molecules played an important role in surface modification. Furthermore, the relative intensity changes of the N 1s and O 1s peaks may also reflect the interaction between microRNA and the PEI and manganese dioxide surfaces, such as hydrogen bonding or ionic bonding.

[0051] Example 3: microRNA release experiment

[0052] A certain mass of the hydrogel loaded with HMnO2@PEI@microRNA from Example 1 was placed into a dialysis bag. The two ends of the dialysis bag were tied tightly and the bag was immersed in 100 ml of PBS buffer containing 1 mg / mL and 4 mg / mL glucose, respectively. The container containing all the dissolution medium was placed on a magnetic stirrer and stirred at 100 rpm under constant temperature of 37°C. At each set time point, 1 mL of dissolution medium was removed and 1 mL of fresh medium was added. The miRNA content was quantitatively detected using RiboGreen RNA assay reagent.

[0053] See appendix Figure 4 Under low glucose concentrations (1 mg / ml), miRNA release was slow, with low initial release followed by a gradual increase over time, but the overall release rate and final release amount were significantly lower than under high glucose conditions. Under higher glucose concentrations (4 mg / ml), miRNA release accelerated significantly, with a rapid initial increase, reaching a high release rate within a short time, and the final cumulative release ratio was significantly higher than under low glucose conditions. This indicates that the hydrogel's network structure, porosity, or cross-linking density is highly sensitive to glucose stimulation. When the external glucose concentration increases, structural loosening, swelling, or changes in dynamic bonding sites occur within the hydrogel, promoting faster and more efficient diffusion of the loaded miRNA molecules. When the external glucose concentration increases, phenylboronic acid forms a reversible complex with glucose, altering the overall cross-linking state of the gel. Simultaneously, if glucose oxidases are present in the hydrogel, they catalyze the glucose conversion process, altering local pH or ionic strength, inducing gel swelling or shrinkage. These structural changes alter porosity and diffusion pathways, thereby accelerating miRNA release.

[0054] Example 4 Dissolved Oxygen Experiment

[0055] A certain amount of hydrogel loaded with HMnO2@PEI@microRNA was placed in 50 ml of glucose solutions containing 1 mg / mL and 4 mg / mL, respectively. The probe was fixed in a certain position, and the dissolved oxygen content in the solution was detected at different time points using a JPSJ605F dissolved oxygen analyzer (Yitian Scientific Instruments Co., Ltd., Shanghai).

[0056] See appendix Figure 5Under 1 mg / mL glucose conditions, the dissolved oxygen level starts from a low value and gradually increases over time, but the rate of increase is relatively slow, eventually reaching a high but limited equilibrium value. Under 4 mg / mL glucose conditions, the increase in dissolved oxygen is more rapid and significant. At the same time point, the total dissolved oxygen under high glucose conditions is much higher than under low glucose conditions. Dissolved oxygen rises rapidly and continuously until it reaches a higher equilibrium value. Glucose oxidase (GOx), in the presence of sufficient glucose, oxidizes glucose to glucuronic acid, consuming oxygen to generate H2O2. H2O2 is further decomposed into water and oxygen under the action of manganese dioxide, leading to an increase in the local oxygen concentration in the solution. When the external glucose concentration is high (4 mg / mL), this enzymatic reaction rate is faster, resulting in more O2 being generated and dissolved in the aqueous phase, thus causing a rapid increase in dissolved oxygen concentration.

[0057] Example 5 Healing Experiment

[0058] 1. Animal selection:

[0059] SD rats aged 6-8 weeks were selected. A diabetic SD rat model was established using streptozotocin (STZ) solution.

[0060] 2. Wound model establishment:

[0061] A full-thickness acute wound model was established on the back of a rat by using a punch to create a circular skin wound with a diameter of about 1 cm on the rat's back.

[0062] 3. Use of glucose-responsive genetic material delivery hydrogels for wound treatment

[0063] The experimental animals were randomly divided into two groups:

[0064] Control group: No wound treatment (control group);

[0065] GMR group: treated with hydrogel loaded with miR-146a.

[0066] 4. Experimental Results:

[0067] Photos of the backs of SD rats were taken on days 0, 3, 7, 14, and 21 of wound healing. The wound area at different time points was compared. (See Appendix) Figure 6 :

[0068] Control group: On day 3, the wound healed slowly, with no obvious contraction, significant exudate, and a slow healing process. On days 14 and 21, the wound gradually contracted, but some areas remained incompletely healed, indicating a slower healing rate.

[0069] GMR group (miR-146a hydrogel loaded group): The GMR group showed significant wound healing by day 3. Wound healing in the GMR group was significantly better than in the control group, with rapid wound contraction, faster wound surface coverage, and good repair of surrounding tissues. By days 14 and 21, the wound in the GMR group was almost completely healed, with complete wound closure and no obvious inflammatory reaction on the wound surface. Compared with the control group, the GMR group healed faster and with better healing quality.

[0070] Example 6 Histological Evaluation

[0071] The skin at the wound edge of the four groups of experimental animals in Example 5 was fixed with 4% paraformaldehyde on the 3rd and 21st days after wound healing. The tissue fixative was then changed, and the samples were decalcified, paraffin-coated, sectioned, and stained with eosin (HE).

[0072] See appendix Figure 7 The images show HE staining on day 3 and day 21 of wound healing, indicating that wound healing gradually improved and the differences between groups became more pronounced.

[0073] Day 3:

[0074] Contro group: The wound showed more severe inflammatory cell infiltration.

[0075] GMR group: The infiltration of inflammatory cells in the wound was significantly reduced in the GMR group.

[0076] Day 21:

[0077] Contro group: Partial wound healing and disordered epidermal hyperplasia structure.

[0078] GMR group: The wound in the GMR group was completely closed, the epidermal layer proliferated completely, there was no obvious inflammatory response in the wound, and the blood vessels and fibroblasts in the dermis proliferated, resulting in better healing quality than the Control group.

[0079] The results, including improvements in healing time, wound contraction rate, and tissue repair, demonstrate that the glucose-responsive genetic material delivery hydrogel of this invention is superior to other groups in promoting wound healing, reducing inflammation, and accelerating angiogenesis. The glucose-responsive hydrogel automatically releases miR-146a based on local blood glucose levels at the wound site, thereby accelerating wound healing by regulating the inflammatory response and promoting the polarization of M2 macrophages. miR-146a also accelerates wound repair by inhibiting the expression of inflammatory factors, reducing inflammation in the wound area, and promoting the proliferation of fibroblasts and vascular endothelial cells, resulting in significant therapeutic effects.

[0080] The sequence numbers of the above embodiments of the present invention are for descriptive purposes only and do not represent the superiority or inferiority of the embodiments.

[0081] The embodiments of the present invention have been described above with reference to the accompanying drawings. However, the present invention is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of the present invention without departing from the spirit and scope of the claims. All of these forms are within the protection scope of the present invention.

Claims

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

2. The application as described in claim 1, characterized in that: The microRNA is miR-146a.

3. The application as described in claim 1, characterized in that: The glucose-responsive genetic material delivery hydrogel promotes macrophage polarization from M1 to M2.

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

5.

5. The application as described in claim 1, characterized in that, The method for preparing the hollow MnO2@PEI nanoparticles loaded with microRNA is as follows: hollow MnO2 nanoparticles are added to a PEI solution and magnetically stirred for 1.5–3 h to disperse them evenly. After centrifugation and washing twice with water, HMnO2@PEI is obtained. MicroRNA is dissolved in PBS, and then the solution is added to HMnO2@PEI and stirred. After centrifugation and washing with water, the hollow MnO2@PEI nanoparticles loaded with microRNA are obtained.

6. The application as described in claim 1, characterized in that: The glucose-responsive genetic material delivery hydrogel also includes a hydrogel containing borate ester bonds, wherein the hydrogel containing borate ester bonds is a GC-PBA+PAA-DA hydrogel.

7. The application as described in claim 6, characterized in that: The glucose-responsive genetic material delivery hydrogel is prepared by dissolving PAA-DA in PBS, mixing it with a microRNA-loaded complex and GOx to obtain a mixed solution, and then mixing the mixed solution with an equal volume of GC-PBA in PBS to obtain a glucose-responsive genetic material delivery hydrogel.

8. The application as described in claim 1, characterized in that: The diabetic wounds include wounds caused by diabetes or diabetic complications and their treatment.

9. The application as described in claim 8, characterized in that: The diabetic wounds include ulcers, erosions, gangrene, or diabetic feet caused by diabetes or diabetic complications.

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