A co-loaded drug-targeted mesoporous polydopamine nanoparticle formulation for the treatment of allergic rhinitis, its preparation method and application.

Abstract

This invention discloses a co-loaded, targeted mesoporous polydopamine nanoparticle formulation for treating allergic rhinitis, its preparation method, and its application. The formulation includes a mesoporous polydopamine nanocarrier, an active drug, and a targeting modifying molecule. The active drug comprises budesonide and tofacitinib, which are co-loaded within the mesoporous channels of the mesoporous polydopamine nanocarrier. The targeting modifying molecule is mannose, which is covalently linked to the outer surface of the mesoporous polydopamine nanocarrier. This invention addresses the problems of low drug utilization, poor targeting, and low efficiency of combined drug administration in existing treatments for allergic rhinitis.

Description

Technical Field

[0001] This invention relates to a co-drug-loaded targeted mesoporous polydopamine nanoformulation for the treatment of allergic rhinitis, its preparation method and application, belonging to the field of nanomedicine delivery and biomedical technology. Background Technology

[0002] Currently, glucocorticoids and antihistamines remain the main drugs for the clinical treatment of allergic rhinitis. Budesonide, in particular, has a strong local anti-inflammatory effect and can effectively inhibit the release of inflammatory mediators; tofacitinib, as an inhibitor of the Janus kinase (JAK) signaling pathway, can block signal transduction processes mediated by various inflammatory factors such as IL-4, IL-5, and IL-13. However, both drugs, when used alone, have limited efficacy, low drug utilization, and the potential for side effects with long-term use.

[0003] Recent studies have found that the combined use of budesonide and tofacitinib can synergistically inhibit allergic inflammatory responses through different inflammatory pathways, showing promising therapeutic potential. However, existing combination drug delivery methods mainly rely on simple drug mixing, which suffers from drawbacks such as low drug synergistic efficiency, poor tissue targeting, asynchronous drug release, and increased risk of systemic exposure. Mesoporous polydopamine (MPDA) has advantages such as large specific surface area, strong drug loading capacity, excellent biocompatibility, and easy surface functionalization, making it an ideal drug delivery platform. Meanwhile, macrophages and dendritic cells in inflamed tissues highly express mannose receptors (CD206). Modifying nanoparticles with mannose ligands can achieve active targeted delivery, improving drug accumulation efficiency at inflammatory lesions.

[0004] Therefore, developing a novel nanoformulation that can simultaneously and efficiently load budesonide and tofacitinib and achieve active targeted delivery through mannose modification is of great significance for improving the treatment efficacy of allergic rhinitis and reducing drug side effects. Summary of the Invention

[0005] To address the problems existing in the prior art, this invention provides a co-loaded drug-targeted mesoporous polydopamine nanoparticle formulation for treating allergic rhinitis, its preparation method, and its application, in order to solve the problems of low drug utilization, poor targeting, and low efficiency of combined drug administration in the existing treatment of allergic rhinitis.

[0006] To achieve the above objectives, the present invention employs a co-loaded drug-targeted mesoporous polydopamine nanoparticle formulation for treating allergic rhinitis, comprising a mesoporous polydopamine nanocarrier, an active drug, and a targeting modifying molecule; the active drug comprises budesonide and tofacitinib, wherein budesonide and tofacitinib are co-loaded within the mesoporous channels of the mesoporous polydopamine nanocarrier; the targeting modifying molecule is mannose, wherein mannose is covalently linked to the outer surface of the mesoporous polydopamine nanocarrier.

[0007] Preferably, the mesoporous polydopamine nanocarrier has a particle size of 200–500 nm and an average pore size of 2–20 nm.

[0008] Preferably, the mass ratio of budesonide to tofacitinib is 1:(0.1-10).

[0009] Preferably, the total drug loading of the nano-formulation is 10% to 30% based on the total mass of the nano-formulation, and the encapsulation rates of budesonide and tofacitinib are 50% to 95%, respectively.

[0010] Preferably, the mannose is obtained by modifying with aminomannose, which is covalently bonded to the outer surface of the mesoporous polydopamine nanocarrier via amide bonds.

[0011] A second aspect of the present invention also provides a method for preparing the co-loaded drug-targeted mesoporous polydopamine nanoparticle formulation for treating allergic rhinitis, comprising the following steps:

[0012] (1) The template agent F127 and the pore-expanding agent 1,3,5-trimethylbenzene were dissolved in an ethanol solution, ammonia water was added as a catalyst and stirred evenly, and then dopamine hydrochloride monomer was added to initiate an oxidative polymerization reaction at room temperature; after the reaction was completed, the mixture was centrifuged, washed and freeze-dried to obtain mesoporous polydopamine nanoparticles.

[0013] (2) Dissolve budesonide and tofacitinib in an organic solvent to prepare a drug mixture solution; disperse the mesoporous polydopamine nanoparticles obtained in step (1) in the drug mixture solution, stir at room temperature in the dark to carry out drug adsorption loading, centrifuge and wash to remove free drug on the surface of the particles after the reaction is completed to obtain co-loaded drug nano intermediates.

[0014] (3) Dissolve aminomannose in alkaline buffer to prepare a modification solution, add the co-loaded drug nano intermediate obtained in step (2) to the modification solution, stir at room temperature in the dark to allow the reaction to occur; after the reaction is completed, centrifuge and purify to remove unreacted aminomannose, thereby obtaining the co-loaded drug-targeted mesoporous polydopamine nanoformulation.

[0015] Preferably, in step (2), the organic solvent is any one or a mixture of two of dimethyl sulfoxide and N,N-dimethylformamide; in step (3), the pH range of the alkaline buffer solution is 8-10.

[0016] A third aspect of the present invention also provides the application of the aforementioned drug-loaded targeted mesoporous polydopamine nanoformulation or the drug-loaded targeted mesoporous polydopamine nanoformulation prepared by the aforementioned preparation method in the preparation of a drug for treating allergic rhinitis.

[0017] Preferably, the drug is a nasal topical administration preparation, which is a nasal drop, nasal spray, or nasal gel.

[0018] Mechanism of the invention:

[0019] Mesoporous polydopamine nanocarriers possess the characteristics of large specific surface area, abundant mesoporous structure, good biocompatibility, and easy surface functionalization modification. They can not only efficiently co-load budesonide and tofacitinib, two active drugs with different mechanisms of action, but also regulate drug release behavior through unique mesoporous channel structure, achieving simultaneous and long-acting sustained release of the two active drugs. At the same time, this nanocarrier can effectively prolong the retention time of active drugs on the nasal mucosa surface, improve the problem of poor mucosal permeability and low bioavailability of hydrophobic drugs, and avoid the drawbacks of frequent dosing.

[0020] This invention covalently modifies the surface of mesoporous polydopamine nanocarriers with mannose targeting molecules. Key immune cells such as macrophages and dendritic cells in the inflammatory microenvironment of allergic rhinitis highly express mannose receptors, allowing mannose to specifically bind to them. This mediates an active targeting effect in the nano-formulation, promoting the accumulation of the formulation at the inflammatory lesions in the nasal cavity, reducing non-specific drug distribution in normal tissues, thereby lowering the systemic exposure of the active drug and mitigating systemic adverse reactions caused by long-term administration.

[0021] Furthermore, this invention combines the glucocorticoid budesonide with the JAK inhibitor tofacitinib for combined delivery. The two drugs are released simultaneously at the lesion site, forming a complementary and synergistic anti-inflammatory treatment system: budesonide directly inhibits the massive release of inflammatory mediators, rapidly relieving acute clinical symptoms such as nasal congestion, nasal itching, and runny nose; tofacitinib specifically blocks the JAK-STAT inflammatory signaling pathway, regulating abnormal immune responses and fundamentally inhibiting the allergic inflammatory cascade, reducing the probability of recurrence. The two drugs work synergistically, achieving multi-target, multi-stage combined treatment compared to single-drug administration or simple drug mixing, significantly improving anti-inflammatory efficacy, and allowing for appropriate reduction of individual drug dosages, further enhancing medication safety. The nano-formulation of this invention combines targeting, sustained release, and synergistic anti-inflammatory properties, balancing efficacy and safety, and possesses high industrialization value and clinical application potential in the field of preparing topical nasal treatments for allergic rhinitis.

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

[0023] (1) This invention uses mesoporous polydopamine nanocarriers to co-load budesonide and tofacitinib, two active drugs, and relies on the pore structure of the carrier to achieve simultaneous loading and controlled release of the two drugs. The two drugs act on different pathways of inflammatory response in allergic rhinitis, and can synergistically inhibit the release of inflammatory mediators and block abnormal JAK-STAT signal transduction. Compared with single administration and physical mixed administration, it can significantly improve the overall anti-inflammatory efficacy and effectively improve the clinical symptoms related to allergic rhinitis.

[0024] (2) Mesoporous polydopamine nanocarriers possess a large specific surface area and abundant mesoporous structure, exhibiting excellent loading capacity for hydrophobic budesonide and tofacitinib. Simultaneously, the nanocarriers can prolong the retention time of active drugs on the nasal mucosa surface, improving the shortcomings of traditional free drugs such as easy loss, poor permeability, and short duration of action, effectively enhancing local drug bioavailability. Furthermore, mesoporous polydopamine materials are easy to prepare, readily available from raw materials, have stable overall physicochemical properties, low cytotoxicity, good biocompatibility, and do not irritate nasal mucosa tissues. They are suitable for various nasal delivery formulations such as nasal drops and sprays, have a simple preparation process, and possess good prospects for industrial transformation and clinical application.

[0025] (3) The present invention covalently modifies the surface of the nanocarrier with mannose targeting molecules, which can specifically recognize and bind to immune cells such as macrophages and dendritic cells that highly express mannose receptors in the nasal cavity inflammation site, guide the nano-preparation to be directionally enriched in the inflammatory lesion, reduce the ineffective distribution of drugs in normal nasal mucosa tissue, and improve the targeting accuracy of local drug delivery.

[0026] (4) Based on the active targeting characteristics, this invention can effectively reduce the entry of active drugs into the blood circulation and reduce the degree of systemic drug exposure; at the same time, the synergistic effect of the two drugs can reduce the dosage of a single drug while ensuring the therapeutic effect, avoid systemic toxic side effects caused by long-term and repeated use, and meet the medication needs of long-term treatment of allergic rhinitis. Attached Figure Description

[0027] Figure 1 This is a schematic diagram of the structure of the nano-formulation of the present invention;

[0028] Figure 2 This is a transmission electron microscope (TEM) image of the nano-formulation of the present invention.

[0029] Figure 3 This is a hydration particle size distribution diagram of the nano-formulation of the present invention;

[0030] Figure 4 This is a graph showing the zeta potential changes of the nano-formulation of the present invention;

[0031] Figure 5 This is a bar chart showing the drug loading of budesonide and tofacitinib in the nano-formulation of the present invention.

[0032] Figure 6 A bar chart showing the encapsulation efficiency of budesonide and tofacitinib in the nano-formulation of this invention;

[0033] Figure 7 The above are in vitro drug release curves of the nano-formulation of the present invention under different pH release media.

[0034] Figure 8 This is a bar chart evaluating the cytotoxicity of the nano-formulation of the present invention against nasal mucosal epithelial cells.

[0035] Figure 9 This is a schematic diagram comparing the cell-targeted uptake capabilities of the nano-formulation of the present invention. Detailed Implementation

[0036] To further illustrate the technical means and effects of this invention, the following description, in conjunction with embodiments and accompanying drawings, provides a further explanation of the invention. It is understood that the specific embodiments described herein are merely illustrative of the invention and not intended to limit it.

[0037] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0038] Example 1

[0039] A method for preparing a co-loaded drug-targeted mesoporous polydopamine nanoparticle formulation for treating allergic rhinitis, comprising the following specific steps:

[0040] (1) Synthesis of mesoporous polydopamine nanoparticles

[0041] Prepare 50 mL of a 50% (v / v) ethanol solution. Add 0.25 g of the template agent triblock copolymer F127 (poloxam 407) and 0.25 g of 1,3,5-trimethylbenzene (TMB) sequentially to the solution, and stir at room temperature until completely dissolved. Then add 0.5 mL of ammonia water (28 wt%), stir until homogeneous, and then add 0.2 g of dopamine hydrochloride. Continue stirring the mixture at room temperature for 24 h. After the reaction is complete, centrifuge the resulting product at 10,000 rpm for 10 min and discard the supernatant. Wash the precipitate three times alternately with deionized water and ethanol to thoroughly remove the template agent and unreacted raw materials. Freeze-dry the washed product to obtain pure mesoporous polydopamine nanoparticles (MPDA NPs).

[0042] (2) Total load of drugs

[0043] 10 mg of budesonide and 10 mg of tofacitinib (mass ratio 1:1) were weighed and dissolved together in 5 mL of dimethyl sulfoxide (DMSO). The mixture was sonicated until completely dissolved to obtain a mixed drug solution. 50 mg of MPDA NPs prepared in step (1) was weighed and dispersed in the above mixed drug solution. The mixture was stirred at room temperature in the dark for 24 h to allow the drug to be fully adsorbed into the mesoporous channels of the nanoparticles. The suspension was then centrifuged at 12,000 rpm for 15 min and the precipitate was collected. The precipitate was washed three times with phosphate buffered saline (PBS, pH 7.4) to remove the free drug adhering to the surface. Finally, the solid particles were freeze-dried to obtain MPDA nanoparticles co-loaded with budesonide and tofacitinib (BUD-TOF@MPDA).

[0044] (3) Surface-modified mannose

[0045] 20 mg of aminomannose was dissolved in 20 mL of borate buffer (pH 8.5) to prepare a targeted modification solution; 50 mg of BUD-TOF@MPDA nanoparticles prepared in step (2) were added to the targeted modification solution, and the mixture was stirred at room temperature in the dark for 12 h to allow aminomannose to covalently bind to the surface of the nanoparticles via amide bonds; after the reaction was completed, the reaction solution was centrifuged at 12000 rpm for 15 minutes and the supernatant was discarded; the precipitate was washed three times with PBS (pH 7.4) to remove unreacted aminomannose; the final product can be directly dispersed in PBS buffer for later use, or it can be freeze-dried and stored to obtain a co-loaded targeted mesoporous polydopamine nanoparticle formulation (Man-BUD-TOF@MPDA); its structure is as follows Figure 1 As shown in the figure, the analysis shows that Man-BUD-TOF@MPDA is a spherical nanoparticle carrier with a mesoporous structure. The pores are loaded with two small molecule drugs, budesonide and tofacitinib, and the surface is connected to the target molecule mannose.

[0046] Example 2

[0047] A method for preparing a co-loaded drug-targeted mesoporous polydopamine nanoparticle formulation for treating allergic rhinitis, comprising the following specific steps:

[0048] (1) Synthesis of mesoporous polydopamine nanoparticles: This step is exactly the same as step (1) in Example 1;

[0049] (2) Co-loading of drugs: 15 mg of budesonide and 5 mg of tofacitinib (mass ratio 3:1) were weighed and dissolved together in 5 mL of N,N-dimethylformamide (DMF). The mixture was sonicated to completely dissolve the drugs and a mixed drug solution was obtained. 50 mg of MPDA NPs obtained in step (1) were weighed and dispersed in the above mixed drug solution. The mixture was stirred at room temperature in the dark for 24 h. The subsequent centrifugation, washing and freeze-drying steps were the same as step (2) of Example 1 to obtain the corresponding drug-loaded nanoparticles (BUD-TOF@MPDA).

[0050] (3) Surface modification with mannose: This step is exactly the same as step (3) in Example 1, and finally Man-BUD-(3:1)TOF@MPDA is obtained.

[0051] Example 3

[0052] A method for preparing a co-loaded drug-targeted mesoporous polydopamine nanoparticle formulation for treating allergic rhinitis, comprising the following specific steps:

[0053] (1) Synthesis of mesoporous polydopamine nanoparticles: This step is exactly the same as step (1) in Example 1;

[0054] (2) Co-loading of drugs: 5 mg of budesonide and 15 mg of tofacitinib (mass ratio 1:3) were weighed and dissolved together in 5 mL of a mixed solvent of DMSO and DMF (volume ratio 1:1). The mixture was sonicated to completely dissolve the drugs and obtain a mixed drug solution. 50 mg of MPDA NPs obtained in step (1) were weighed and dispersed in the above mixed drug solution. The mixture was stirred at room temperature in the dark for 24 h. The subsequent centrifugation, washing and freeze-drying steps were the same as step (2) of Example 1 to obtain the corresponding drug-loaded nanoparticles (BUD-TOF@MPDA).

[0055] (3) Surface modification with mannose: This step is exactly the same as step (3) in Example 1, and finally Man-BUD-(1:3)TOF@MPDA is obtained.

[0056] Test case

[0057] The nano-formulation prepared in Example 1 was used as the test sample for performance testing:

[0058] (1) Microscopic morphological characterization

[0059] 5 μL of Man-BUD-TOF@MPDA solution was dropped onto the ultrathin carbon support film, and excess solution was absorbed with filter paper. The film was then allowed to dry naturally at 25°C until the solvent was completely evaporated. The ultrathin carbon support film was then placed under a transmission electron microscope for sample morphology observation. The test results are as follows: Figure 2 As shown, the nano-formulation has a regular spherical structure with uniform particle size, an average particle size of about 300 nm, and a rough particle surface with abundant mesoporous pores, which is consistent with the structural characteristics of mesoporous nano-drug carriers.

[0060] (2) Hydrated particle size and zeta potential test

[0061] The Man-BUD-TOF@MPDA dispersion was diluted to a suitable concentration and added to the sample cell. The hydrated particle size and Zeta potential of the sample were measured using a dynamic light scattering laser particle size analyzer. The particle size test results are as follows: Figure 3 As shown, the hydrated particle size of the sample is approximately 500 nm; the zeta potential test results are as follows. Figure 4 As shown, the sample potential has a high absolute value, indicating that the nano-formulation prepared by this invention has excellent dispersion stability and is not prone to agglomeration and sedimentation.

[0062] (3) Drug loading and encapsulation efficiency test

[0063] 10 mg of lyophilized Man-BUD-TOF@MPDA nanoparticles were weighed and placed in a centrifuge tube. 5 mL of methanol was added, and the mixture was sonicated for 30 min to fully release BUD and TOF from the nanoparticles. The mixture was then centrifuged at 12000 rpm for 10 min, and the supernatant was collected. The standard curves of the two drugs were determined using a UV spectrophotometer, and the drug content was calculated. The detection wavelength for BUD (budesonide) was 244 nm, and the detection wavelength for TOF (tofacitinib) was 287 nm.

[0064] Drug loading capacity is calculated using the following formula: ;

[0065] In the formula, The actual mass (mg) of the drug in the nano-formulation. The total mass (mg) of the lyophilized nano-formulation.

[0066] like Figure 5 As shown, the drug loading capacity of BUD in Man-BUD-TOF@MPDA is 11.8 ± 0.4%, and the drug loading capacity of TOF is 13.0 ± 0.5%, indicating that the nano-formulation of the present invention has excellent drug loading capacity.

[0067] 10 mg of lyophilized Man-BUD-TOF@MPDA nanoparticles were weighed and placed in a centrifuge tube. 5 mL of methanol was added, and the mixture was sonicated for 30 min to fully release BUD and TOF from the nanoparticles. The mixture was then centrifuged at 12000 rpm for 10 min, and the supernatant was collected. The standard curves for both drugs were determined using a UV spectrophotometer, and the drug content was calculated. The detection wavelength for BUD was 244 nm, and for TOF it was 287 nm.

[0068] Encapsulation efficiency is calculated using the following formula: ;

[0069] In the formula, The actual encapsulation mass of the drug in the nano-formulation (mg); The initial mass of the drug (mg) is given.

[0070] like Figure 6 As shown, the encapsulation efficiency of BUD in Man-BUD-TOF@MPDA is 78.3 ± 2.1%, and the encapsulation efficiency of TOF is 86.4 ± 1.8%. The encapsulation efficiency of both drugs exceeds 75%, indicating that the nano-formulation of the present invention can effectively encapsulate BUD and TOF.

[0071] (4) In vitro drug release performance test

[0072] A certain amount of lyophilized Man-BUD-TOF@MPDA nanoparticles was weighed and dispersed in 2 mL of PBS buffer. After being ultrasonically dispersed evenly, the mixture was transferred to a dialysis bag with a molecular weight cutoff of 3500 Da. The dialysis bag was then placed in a centrifuge tube containing 30 mL of release medium and incubated in a constant temperature shaker at 37 °C at a speed of 100 rpm. To simulate the normal physiological environment and the inflammatory microenvironment of allergic rhinitis, pH 7.4 PBS and pH 6.5 PBS were selected as release media, respectively.

[0073] At preset time points of 0, 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours, 1 mL of release medium was collected, and an equal volume of fresh release medium was added simultaneously to maintain a constant volume of the release system. The collected release solutions were centrifuged or filtered, and the contents of BUD and TOF in the release solutions were determined by ultraviolet spectrophotometry. The detection wavelength for BUD was 244 nm, and the detection wavelength for TOF was 287 nm. The drug concentration in the release solutions at each time point was calculated based on a pre-established standard curve.

[0074] In vitro drug release curves are as follows Figure 7 As shown, the nano-formulation exhibits a long-lasting sustained-release effect on both drugs within 48 hours; at pH 7.4, the cumulative release rates of budesonide and tofacitinib are 58% and 70%, respectively; in an acidic inflammatory microenvironment of pH 6.5, the cumulative release rates of the two drugs increase to 75% and 85%, respectively. This demonstrates that the nano-formulation of the present invention possesses significant acidic microenvironment-responsive drug release characteristics, which can meet the targeted drug release requirements of inflammatory lesions.

[0075] (5) Cytotoxicity test

[0076] The biocompatibility of the nano-formulation to nasal mucosal epithelial cells was evaluated using the CCK-8 assay: nasal mucosal epithelial cells were co-incubated with different concentration gradients of Man-BUD-TOF@MPDA nano-formulation for 24 h, and cell viability was detected.

[0077] The results are as follows Figure 8 As shown, when the concentration of the nano-formulation is as high as 1 mg / L, the cell survival rate is still maintained at over 95%, which confirms that the nano-formulation has no obvious toxicity to nasal mucosal epithelial cells, has excellent biocompatibility, and is suitable for local nasal drug delivery.

[0078] (6) Cell-targeted uptake experiment

[0079] The mannose-modified targeted nanoparticles and the unmodified mannose-free non-targeted nanoparticles were labeled with Cy5 fluorescent dye, respectively. Both groups of samples were co-incubated with RAW264.7 macrophages for 4 h, and the fluorescence intensity of the cells was observed using laser confocal microscopy. The experimental results are as follows: Figure 9As shown, the fluorescence intensity of the targeted group cells was significantly higher than that of the non-targeted group, demonstrating that the surface-modified mannose can effectively mediate the specific uptake of the nano-formulation by inflammation-associated macrophages, exhibiting excellent active targeting performance.

[0080] This invention successfully constructed a mannose-modified, dual-drug co-loaded mesoporous polydopamine-targeted nanoformulation using a simple and controllable preparation process. This nanoformulation exhibits uniform particle morphology and strong colloidal stability, enabling efficient simultaneous loading of budesonide and tofacitinib, two active drugs. It also possesses multiple advantages, including long-acting sustained release, acid-responsive drug release, and active targeted enrichment. Multiple in vitro experiments have validated that this nanoformulation demonstrates high biosafety, precisely targeting immune cells at the site of nasal inflammation to achieve synergistic anti-inflammatory effects, effectively improving drug bioavailability and reducing the risk of systemic drug exposure. Therefore, this nanoformulation can serve as a high-performance drug delivery platform for preparing topical nasal treatments for allergic rhinitis, possessing significant clinical translational value and market application prospects.

[0081] It should be noted that the present invention is not limited to the specific embodiments described above. Any modifications, equivalent substitutions, simple improvements, or other technical solutions made by those skilled in the art within the scope of the technology disclosed in the present invention should fall within the protection scope of the present invention.

Claims

1. A co-loaded drug-targeted mesoporous polydopamine nanoformulation for treating allergic rhinitis, characterized in that, The invention comprises a mesoporous polydopamine nanocarrier, an active drug, and a targeted modification molecule; the active drug comprises budesonide and tofacitinib, which are co-loaded within the mesoporous channels of the mesoporous polydopamine nanocarrier; the targeted modification molecule is mannose, which is covalently linked to the outer surface of the mesoporous polydopamine nanocarrier.

2. The co-loaded drug-targeting mesoporous polydopamine nanoformulation according to claim 1, characterized in that, The mesoporous polydopamine nanocarrier has a particle size of 200–500 nm and an average pore size of 2–20 nm.

3. The co-loaded drug-targeting mesoporous polydopamine nanoformulation according to claim 1, characterized in that, The mass ratio of budesonide to tofacitinib is 1:(0.1-10).

4. The co-loaded drug-targeting mesoporous polydopamine nanoformulation according to claim 1, characterized in that, The total drug loading of the nano-formulation is 10% to 30% based on the total mass of the nano-formulation, and the encapsulation efficiency of budesonide and tofacitinib is 50% to 95%, respectively.

5. The co-loaded drug-targeting mesoporous polydopamine nanoformulation according to claim 1, characterized in that, The mannose is obtained by modifying aminomannose, which is covalently bonded to the outer surface of the mesoporous polydopamine nanocarrier via amide bonds.

6. A method for preparing a co-drug-loaded targeted mesoporous polydopamine nanoparticle formulation for treating allergic rhinitis as described in any one of claims 1-5, characterized in that, Includes the following steps: (1) The template agent F127 and the pore-expanding agent 1,3,5-trimethylbenzene were dissolved in an ethanol solution, ammonia water was added as a catalyst and stirred evenly, and then dopamine hydrochloride monomer was added to initiate an oxidative polymerization reaction at room temperature; after the reaction was completed, the mixture was centrifuged, washed and freeze-dried to obtain mesoporous polydopamine nanoparticles. (2) Dissolve budesonide and tofacitinib in an organic solvent to prepare a drug mixture solution; disperse the mesoporous polydopamine nanoparticles obtained in step (1) in the drug mixture solution, stir at room temperature in the dark to carry out drug adsorption loading, centrifuge and wash to remove free drug on the surface of the particles after the reaction is completed to obtain co-loaded drug nano intermediates. (3) Dissolve aminomannose in alkaline buffer to prepare a modification solution, add the co-loaded drug nano intermediate obtained in step (2) to the modification solution, stir at room temperature in the dark to allow the reaction to occur; after the reaction is completed, centrifuge and purify to remove unreacted aminomannose, thereby obtaining the co-loaded drug-targeted mesoporous polydopamine nanoformulation.

7. The preparation method according to claim 6, characterized in that, In step (2), the organic solvent is any one or a mixture of two of dimethyl sulfoxide and N,N-dimethylformamide; in step (3), the pH range of the alkaline buffer solution is 8-10.

8. The use of a co-drug-loaded targeted mesoporous polydopamine nanoformulation as described in any one of claims 1-5 or a co-drug-loaded targeted mesoporous polydopamine nanoformulation prepared by the preparation method described in any one of claims 6-7 in the preparation of a drug for treating allergic rhinitis.

9. The application according to claim 8, characterized in that, The drug is a nasal topical administration preparation, which is a nasal drop, nasal spray, or nasal gel.

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