Drug-loaded ionic gel microsphere, magnetically-driven drug-loaded micro-nano motor, and preparation method and application of drug-loaded ionic gel microsphere and magnetically-driven drug-loaded micro-nano motor

Abstract

The invention provides a drug-loaded ionic gel microsphere, a magnetic-driven drug-loaded micro-nano motor and a preparation method and application of the drug-loaded ionic gel microsphere, the drug-loaded ionic gel microsphere is prepared from a water phase and an oil phase, and controllable response release of a bioactive substance in an inflammatory microenvironment is achieved by introducing a pH-responsive polymer as a drug carrier material; the property of high solubility of the ionic liquid in the carrier is utilized, so that the infiltration capacity of hydrophobic active substances to tissues is enhanced; a bioactive substance is added into a water phase and is mixed and emulsified with a liquid paraffin phase containing an emulsifier, so that the bioactive substance can be loaded in the ionic liquid gel microspheres. According to the magnetically-driven drug-loading micro-nano motor, the surfaces of the drug-loading ionic gel microspheres are modified with the gold nano thorn microstructures, so that anchoring of a bioactive substance carrier at a focus part is facilitated, and the residence of bioactive substances is prolonged; meanwhile, in the aspect of periodontitis treatment, the micro-nano motor can overcome an oral biological barrier to carry out targeted delivery.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of micro-nano materials, and particularly relates to a drug-loaded ionogel microsphere, a magnetically driven drug-loaded micro-nano motor and a preparation method and application thereof. BACKGROUND

[0002] Periodontitis is a chronic inflammatory disease caused by imbalance of periodontal pathogenic bacteria, and is one of the main causes of tooth loss in adults. Its core pathological feature is the continuous destruction of periodontal support tissue, including gingival inflammation, alveolar bone resorption and periodontal attachment loss. With the development of the disease, patients will not only have swollen gums, bleeding, loose teeth, but also may eventually lead to tooth loss. More and more studies have shown that periodontitis is not limited to the oral cavity, and its long-term chronic inflammatory state is also closely related to many systemic diseases, such as cardiovascular disease, diabetes, rheumatoid arthritis and adverse pregnancy outcomes. Therefore, the prevention and treatment of periodontitis not only has significance for oral health, but also has important value for overall health maintenance.

[0003] The current conventional treatment of periodontitis mainly includes basic treatment and surgical treatment. The basic treatment takes mechanical debridement as the core, such as scaling and root planning, aiming to remove plaque and calculus on the surface of the tooth and in the periodontal pocket, so as to control the source of infection; on this basis, local or systemic application of antibacterial drugs can be combined to enhance the anti-infection effect. For moderate and severe patients, flap surgery or regenerative surgery may also be needed to remove deep lesions and attempt to restore some periodontal tissue. However, the existing treatment methods still have significant limitations. First, mechanical debridement depends on the operator's experience, and it is difficult to completely remove pathogenic bacteria in complex root surface anatomy or deep periodontal pockets, which can easily lead to recurrence. Second, long-term or repeated use of antibiotics has the risk of drug resistance and systemic side effects, which is not conducive to the long-term management of chronic diseases. Third, the existing drug carriers mainly rely on passive diffusion, which is difficult to penetrate the dense biofilm in the periodontal pocket and the oral mucus barrier, resulting in insufficient drug concentration in the lesion area and reducing the efficacy. In addition, many drugs with potential therapeutic value, such as antibacterial agents, anti-inflammatory drugs and some natural active substances (such as curcumin, resveratrol, etc.), often have obvious hydrophobicity, which limits their effective release and absorption through aqueous environments, resulting in limited bioavailability in the body.

[0004] Against this backdrop, the development of novel drug delivery systems is particularly necessary. Compared with traditional drug delivery methods, novel delivery systems can maintain stable and efficient drug concentrations in the lesion area through targeted delivery and controlled release mechanisms, reducing non-specific drug distribution in healthy tissues and thus significantly reducing toxic side effects. Simultaneously, by leveraging nanotechnology, micro / nanocarriers, and stimulus-responsive materials, these systems can respond to the characteristics of the periodontal microenvironment (such as acidic pH, reactive oxygen species levels, or enzyme activity), achieving "on-demand release" and improving the selectivity and personalization of treatment. Furthermore, some cutting-edge delivery platforms can be combined with imaging monitoring, tissue regeneration, or immune modulation strategies to construct a comprehensive system integrating diagnosis, treatment, and feedback, providing new directions for the precision treatment and long-term management of periodontitis. Summary of the Invention

[0005] To overcome the problems existing in the prior art, one objective of this invention is to provide a drug-loaded ionogel microsphere. A second objective is to provide a method for preparing the aforementioned drug-loaded ionogel microsphere. A third objective is to provide a magnetically driven drug-loaded micro / nano motor. A fourth objective is to provide a method for preparing the aforementioned magnetically driven drug-loaded micro / nano motor. A fifth objective is to provide the aforementioned composition. A sixth objective is to provide applications of the aforementioned drug-loaded ionogel microsphere, magnetically driven drug-loaded micro / nano motor, or composition.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The first aspect of the present invention provides a drug-loaded ionogel microsphere, the raw materials for which preparation includes an aqueous phase and an oil phase; the aqueous phase includes an ionic liquid, a pH-responsive polymer, a bioactive substance, iron(III) oxide, methanol and water; the oil phase includes an emulsifier and liquid paraffin.

[0007] Preferably, the ionic liquid comprises at least one of N-alkyl-N-methylmorpholinium salt, 1-(ibuprofenyl)-3-hexylimidazolium bromide, 1-butyl-3-methylimidazolium bromide, 1-benzyl-3-methylimidazolium tetrafluoroborate, 1,3-dimethylimidazolium bis(trifluoromethanesulfonyl)imide, 1-dodecyl-3-methylimidazolium salicylate, N-alkylpyridine bromide, cholesterol-trimethylammonium glutamate, 1-ethyl-3-methylimidazolium berberine salt, choline salicylate, choline bis(trifluoromethanesulfonyl)imide, choline glycine salt, 1-ethyl-3-methylimidazolium alanine salt, choline proline salt, tetrabutylammonium serine salt, and N,N-dimethylglycine salt.

[0008] Preferably, the pH-responsive polymer includes at least one of poly(ethyl methacrylate-co-acrylate), poly(hydroxyethyl methacrylate-co-methacrylic acid), poly(methyl methacrylate-co-methacrylic acid), poly(2-(dimethylamino)ethyl methacrylate), poly(N,N-dimethylaminoethyl methacrylate), poly(N-isopropylacrylamide-co-2-aminoethyl methacrylate), poly(caprolactone-co-aminohexanoic acid), and poly(N,N-dimethylaminoethyl methacrylate).

[0009] Stimulus-responsive polymers are a class of intelligent macromolecular systems capable of sensing external environmental stimuli (such as temperature, pH, light, pressure, electric fields, etc.) and altering their own physicochemical properties. This invention introduces pH-responsive polymers as drug carrier materials to achieve controlled release of drugs in an inflammatory microenvironment.

[0010] Preferably, the emulsifier includes at least one of sorbitan monooleate, sorbitan monolaurate, glyceryl monostearate, dehydrated sorbitan fatty acid ester, and polyglycerol-4-isostearate.

[0011] Preferably, the bioactive substance includes polyphenolic compounds or alkaloids.

[0012] The alkaloids mentioned are a class of nitrogen-containing basic organic compounds that exist in nature and have base-like properties. Most of them have complex ring structures, with nitrogen mostly contained within the ring. They have significant biological activity and are one of the important active ingredients in traditional Chinese medicine.

[0013] More preferably, the polyphenolic compound includes at least one of curcumin, resveratrol, baicalin, gallic acid, and quercetin.

[0014] More preferably, the alkaloid includes berberine.

[0015] Preferably, the iron oxide is in the form of nanoparticles.

[0016] Preferably, the mass ratio of the ionic liquid to the pH-responsive polymer is 1:(1-5).

[0017] More preferably, the mass ratio of the ionic liquid to the pH-responsive polymer is 1:(2-4).

[0018] Preferably, the mass ratio of the ionic liquid to the bioactive substance is 1:(0.001-0.03).

[0019] More preferably, the mass ratio of the ionic liquid to the bioactive substance is 1:(0.001-0.005).

[0020] Preferably, the mass ratio of the ionic liquid to iron(III) oxide is 1:(0.1-0.6).

[0021] More preferably, the mass ratio of the ionic liquid to iron(III) oxide is 1:(0.2-0.5).

[0022] Preferably, the mass ratio of the ionic liquid to the emulsifier is 1:(0.2-0.5).

[0023] Preferably, the water and methanol are aqueous solvents, and the ratio of the ionic liquid to the aqueous solvent is 1 g:(5-20) mL.

[0024] More preferably, the methanol has a mass percentage of 50wt%-80wt% in the aqueous solvent.

[0025] Preferably, the volume ratio of the aqueous phase to the oil phase is 1:(2-5).

[0026] A second aspect of the present invention provides a method for preparing the drug-loaded ionospheres described in the first aspect, comprising the following steps: Ionic liquid, pH-responsive polymer, bioactive substance, and iron oxide were mixed in methanol-water solution to obtain an aqueous phase; an emulsifier and liquid paraffin were mixed to obtain an oil phase; the aqueous phase and oil phase were mixed, emulsified, and the solvent was evaporated to obtain drug-loaded ionogel microspheres.

[0027] Preferably, the emulsification reaction time is 10-16 h.

[0028] Preferably, the emulsification reaction temperature is 30-50°C.

[0029] Preferably, the emulsification is carried out under stirring conditions.

[0030] A third aspect of the present invention provides a magnetically driven drug-loaded micro / nano motor, comprising the drug-loaded ion gel microspheres described in the first aspect, wherein a portion of the surface of the drug-loaded ion gel microspheres is coated with a platinum layer, and the surface of the platinum layer has gold nanospikes.

[0031] A fourth aspect of this invention provides a method for preparing the magnetically driven drug-carrying micro / nano motor described in the third aspect, comprising the following steps: The drug-loaded ionogel microspheres described in the first aspect are laid on a substrate, and a platinum layer is deposited on one side of the substrate using ion beam sputtering technology. Then, the drug-loaded ionogel microspheres containing the platinum layer are dispersed in water, and chloroauric acid, silver nitrate and hydrogen peroxide are added in sequence. After an oscillating reaction, gold nanospikes are formed on the surface of the platinum layer to obtain the magnetically driven drug-loaded micro / nano motor.

[0032] Preferably, the concentration of the platinum-layered drug-loaded ionogel microspheres in water is 2-15 mg / mL.

[0033] Preferably, the mass ratio of chloroauric acid to silver nitrate is (6-50):1.

[0034] Preferably, the oscillation reaction time is 60s to 360s.

[0035] A fifth aspect of the present invention provides a composition comprising the magnetically driven drug-carrying micro / nano motor and starch gel described in the third aspect.

[0036] Preferably, the viscosity of the starch gel is 20-100 cP.

[0037] Preferably, the ratio of the magnetically driven drug-loaded micro / nano motor to the starch gel is (2-10) mg:1 mL.

[0038] Preferably, the preparation method of the composition includes the following steps: dispersing a magnetically driven drug-loaded micro / nano motor in a starch gel.

[0039] The sixth aspect of the present invention provides the use of the drug-loaded ionogel microspheres of the first aspect, the magnetically driven drug-loaded micro / nano motor of the third aspect, or the composition of the fifth aspect in the preparation of products for treating chronic inflammatory diseases.

[0040] Preferably, the chronic inflammatory disease is periodontitis.

[0041] The beneficial effects of this invention are: This invention proposes a drug-loaded ionogel microsphere. The raw materials for preparing the drug-loaded ionogel microsphere include an aqueous phase and an oil phase. By introducing a pH-responsive polymer as a drug carrier material, the controlled release of bioactive substances in an inflammatory microenvironment is achieved. Furthermore, the high solubility of the ionic liquid in the carrier enhances the ability of hydrophobic active substances to penetrate into tissues. By mixing and emulsifying the pH-responsive polymer, ionic liquid, bioactive substances, and iron oxide nanoparticles in a methanol aqueous solution as the aqueous phase with a liquid paraffin phase containing an emulsifier, the bioactive substances can be loaded into the ion liquid gel microsphere.

[0042] This invention proposes a magnetically driven drug-carrying micro / nano motor. By modifying the surface of drug-carrying ion gel microspheres with gold nanoparticles, it is beneficial for the bioactive substance carrier to anchor at the lesion site and prolong the residence of the bioactive substance. At the same time, in the treatment of periodontitis, the micro / nano motor can overcome the oral biological barrier for targeted delivery.

[0043] This invention proposes a composition comprising a micro / nano motor and a starch gel. Experiments have shown that the micro / nano motor dispersed in the starch gel exhibits the highest fluorescence intensity in the periodontal tissues of mice after magnetic field treatment, and has the largest retention amount and retention time, indicating that the magnetically driven drug-loaded micro / nano motor and starch gel can be used synergistically for the treatment of periodontitis. Attached Figure Description

[0044] Figure 1 This is a scanning electron microscope image of the magnetically driven drug-carrying micro / nano motor in Example 1; Figure 2 Photographs showing the solubility of curcumin in 1-benzyl-3-methylimidazolium tetrafluoroborate ionic liquid and water; Figure 3 The drug loading and encapsulation efficiency of the ionic liquid gel spheres corresponding to different drug concentrations in Example 2; Figure 4 This is a diagram showing the trajectory of the micro / nano motor following a set route in Example 2. Figure 5 This is a fluorescence image of the magnetic field-driven drug-loaded micro / nano motor residing in the periodontal tissue of mice in Example 3; Figure 6 This is a micro-CT image of mice after treatment with a magnetic field-driven drug-loaded micro / nano motor for periodontitis in Example 3. Detailed Implementation

[0045] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials used in the following embodiments can be obtained from conventional commercial channels or prepared and isolated through simple synthesis; unless otherwise specified, the processes employed are conventional processes in the art.

[0046] The CAS number of poly(methyl methacrylate-co-methacrylic acid) used in the following examples and comparative examples is 25086-15-1; the CAS number of poly(2-(dimethylamino)ethyl methacrylate) used is 25154-86-3.

[0047] Example 1 This embodiment provides a drug-loaded iontophoretic gel microsphere, a magnetically driven drug-loaded micro / nano motor, and a gel composition, the specific preparation method of which is as follows: 1. Preparation of drug-loaded ionogel microspheres: 2g of poly(methyl methacrylate-co-methacrylic acid), 1g of 1-benzyl-3-methylimidazolium tetrafluoroborate and 20mg of flavin were added to 10 mL of methanol aqueous solution of iron oxide nanoparticles with a concentration of 20 mg / mL (60 wt.%). Subsequently, it was mixed and emulsified with 30 mL of liquid paraffin phase containing 0.1~0.3g of sorbitan monooleate. The mixture was then continuously stirred at 40℃ and a stirring speed of 800 rpm for 12 hours to obtain drug-loaded magnetic ionogel microspheres.

[0048] 2. Construction of drug-loaded micro / nanomotors with a spiky structure: The prepared drug-loaded magnetic ion gel microspheres were monolayered on a substrate, and a platinum layer was sputtered on one side of the microspheres for 200 s using an ion beam sputtering device. Subsequently, the microspheres were dispersed in 200 μL of deionized water (particle concentration 5 mg / mL), and 50 μL of 40 mM chloroauric acid, 12 μL of 10 mM silver nitrate, and 80 μL of 2 wt.% hydrogen peroxide were added sequentially. The mixture was shaken and reacted for 100 s. After washing with deionized water and magnetic separation, the microspheres were freeze-dried at -40℃ for at least 12 h to obtain drug-loaded micro / nanomotors with a spiky structure, morphological as shown in the figure. Figure 1 As shown.

[0049] 3. Preparation of the gel composition: 25 g of water-soluble starch was dissolved in 10 mL of distilled water under continuous stirring at 70°C. The starch hydrogel was obtained by naturally cooling the reaction system to room temperature. The above-mentioned spiked structured drug-loaded micro / nanomotor was dispersed in a starch gel with a viscosity of 50 cP (concentration of 2 mg / mL).

[0050] Comparative Example 1 Based on Example 1, the difference in this comparative example is that no ionic liquid is added. Using the method of Example 1, poly(methyl methacrylate-co-methacrylic acid) and curcumin are added to an aqueous solution of iron(III) oxide in methanol, followed by emulsification with a liquid paraffin phase containing sorbitan monooleate. The mixture is then continuously stirred at 800 rpm for 12 hours at 40°C to obtain drug-loaded magnetic polymer microspheres. These polymer microspheres are then monolayered on a substrate, and platinum layer sputtering is performed on one side of the substrate using an ion beam sputtering device. The microspheres are then dispersed in deionized water to prepare a dispersion. Chloroauric acid, silver nitrate, and hydrogen peroxide are added sequentially, followed by shaking and reaction. After washing and magnetic separation, the microspheres are freeze-dried at -40°C for at least 12 hours to obtain a drug-loaded polymer micro / nano motor with a spiky structure. Comparing the ion gel micro / nano motor of Example 1 with the polymer micro / nano motor of Comparative Example 1, curcumin drug can be well dissolved in the ionic liquid (e.g., ...). Figure 2As shown in the figure, it is not easily soluble in deionized water, therefore the ion gel micro-nano motor has significant drug solubility and drug loading capacity.

[0051] Example 2 This embodiment provides a drug-loaded iontophoretic gel microsphere, a magnetically driven drug-loaded micro / nano motor, and a gel composition, the specific preparation method of which is as follows: 1. Preparation of drug-loaded ionogel microspheres: 3g of poly(dimethylamino)ethyl methacrylate, 1g of 1-ethyl-3-methylimidazolium berberine salt, and 30mg (6 mg / mL) of berberine were added to 5 mL of ferric oxide methanol aqueous solution (80 wt.%) with a concentration of 50 mg / mL. This solution was then emulsified with 20 mL of liquid paraffin containing 0.1–0.3g of dehydrated sorbitan fatty acid ester. The mixture was continuously stirred at 1000 rpm for 12 hours at 40°C to obtain drug-loaded magnetic ionogel microspheres. The drug loading was approximately 50 μg / mg, and the encapsulation efficiency was approximately 85% (e.g., ...). Figure 3 (As shown).

[0052] When the amount of berberine added was changed to 10, 20, 40, and 50 mg, the drug loading and encapsulation efficiency of the resulting drug-loaded magnetic ionogel microspheres were as follows: Figure 3 As shown.

[0053] 2. Construction of drug-loaded micro / nanomotors with a spiky structure: The prepared drug-loaded magnetic ionogel microspheres were monolayered on a substrate, and a platinum layer was sputtered on one side of the microspheres for 400 s using an ion beam sputtering device. The microspheres were then dispersed in 500 μL of deionized water (particle concentration 2 mg / mL), and 60 μL of 60 mM chloroauric acid, 10 μL of 15 mM silver nitrate, and 100 μL of 4 wt.% hydrogen peroxide were added sequentially. The mixture was shaken and reacted for 120 s. The microspheres were then washed with deionized water, magnetically separated, and freeze-dried at -40℃ for at least 12 h to obtain drug-loaded micro / nanomotors with a spiky structure.

[0054] Among them, micro-nano motors can perform targeted motion according to a set route under an external magnetic field with an intensity of 500 mT and a frequency of 40 Hz (e.g., Figure 4 (As shown).

[0055] 3. Preparation of gel composition: The above-mentioned spiked structure drug-loaded micro / nano motors were dispersed in starch gel with a viscosity of 80 cP (concentration of 4 mg / mL).

[0056] Example 3 This embodiment provides a drug-loaded iontophoretic gel microsphere, a magnetically driven drug-loaded micro / nano motor, and a gel composition, the specific preparation method of which is as follows: 1. Preparation of drug-loaded ionogel microspheres: 4 g of poly(methyl methacrylate-co-methacrylic acid), 1 g of choline bis(trifluoromethanesulfonyl)imide salt and 36 mg of curcumin were added to 12 mL of ferric oxide methanol aqueous solution (65 wt.%) with a concentration of 40 mg / mL. Then, it was emulsified with 30 mL of liquid paraffin phase containing 0.1~0.3 g of sorbitan monolaurate. The mixture was then stirred continuously at 1200 rpm at 40 °C for 12 hours to obtain drug-loaded magnetic ionogel microspheres. 2. Construction of drug-loaded micro / nanomotors with a spiky structure: The prepared drug-loaded magnetic ionogel microspheres were monolayered on a substrate, and a platinum layer was sputtered on one side of the microspheres for 240 s using an ion beam sputtering device. The microspheres were then dispersed in 400 μL of deionized water (particle concentration 4 mg / mL), and 80 μL of 60 mM chloroauric acid, 20 μL of 12 mM silver nitrate, and 80 μL of 3 wt.% hydrogen peroxide were added sequentially. The mixture was shaken and reacted for 180 s. The microspheres were then washed with deionized water, magnetically separated, and freeze-dried at -40℃ for at least 12 h to obtain drug-loaded micro / nanomotors with a spiky structure.

[0057] 3. Preparation of gel composition: The above-mentioned spiked structure drug-loaded micro / nano motors were dispersed in starch gel with a viscosity of 20 cP (concentration of 5 mg / mL).

[0058] Biological Experimental Analysis A typical ligation-induced periodontitis mouse model was established. Twenty male C57BL / 6 mice (4 weeks old, 20-25g) were randomly assigned to the following five groups: periodontitis control group, starch gel (containing 10% ethanol), curcumin@gel, microrobots@gel, and microrobots@gel with magnetic field. Periodontitis was induced by tying a 5-0 silk suture to the cervical region of the bilateral maxillary second molars. The ligatures were checked every other day to ensure they remained in place during the experiment.

[0059] One week later, the control group (group i) was treated with PBS (50 μL); group ii was treated with starch gel; group iii was treated with curcumin-loaded starch gel (curcumin@gel) (100 μg / mL, 50 μL); group iv was treated with drug-loaded ionogel microrobots@gel (2 mg / mL, 50 μL); and group v was treated with drug-loaded ionogel microrobots@gel (2 mg / mL, 50 μL) + magnetic field drive. The gels were injected into the periodontal pockets, and then the mice in the microrobots@gel + magnetic field group were treated with a portable handheld magnetic controller (under an external magnetic field of 500 mT and 40 Hz) for 30 minutes each time. The procedure was performed every 2 days. After 2 weeks, the mice were sacrificed and tissues were collected to assess the treatment effect.

[0060] The fluorescence intensity of residual drugs in mouse periodontal tissues was analyzed at time intervals using an in vivo animal imaging system. The results showed that the micro-nanomotors dispersed in starch gel exhibited the highest fluorescence intensity in mouse periodontal tissues after magnetic field treatment, indicating that they possessed the largest retention amount and duration (e.g., Figure 5 (As shown).

[0061] Two weeks later, the mice were sacrificed, and maxillary bone tissue was collected for micro-CT to assess the treatment effect. The degree of treatment was evaluated by assessing the distance from the cementoenamel junction to the alveolar ridge crest in the three-dimensional reconstruction of the mouse jawbone using CT. The results showed that the periodontal tissues of mice treated with magnetically driven drug-loaded ionogel micro-nanomotors (group V) showed the fastest recovery (e.g., Figure 6 As shown in the figure, this indicates that magnetically driven drug-loaded micro / nano motors and starch gels can be used synergistically for the treatment of periodontitis.

[0062] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A drug-loaded ionogel microsphere, characterized in that, The raw materials for its preparation include an aqueous phase and an oil phase; the aqueous phase includes ionic liquids, pH-responsive polymers, bioactive substances, iron(III) oxide, methanol, and water; the oil phase includes emulsifiers and liquid paraffin.

2. The drug-loaded ionogel microspheres according to claim 1, characterized in that, The ionic liquid comprises at least one of the following: N-alkyl-N-methylmorpholinium salt, 1-(ibuprofenyl)-3-hexylimidazolium bromide, 1-butyl-3-methylimidazolium bromide, 1-benzyl-3-methylimidazolium tetrafluoroborate, 1,3-dimethylimidazolium bis(trifluoromethanesulfonyl)imide, 1-dodecyl-3-methylimidazolium salicylate, N-alkylpyridine bromide, cholesterol-trimethylammonium glutamate, 1-ethyl-3-methylimidazolium berberine salt, choline salicylate, choline bis(trifluoromethanesulfonyl)imide, choline glycine, 1-ethyl-3-methylimidazolium alanine, choline proline, tetrabutylammonium serine, and N,N-dimethylglycine.

3. The drug-loaded ionogel microspheres according to claim 1, characterized in that, The pH-responsive polymer includes at least one of poly(ethyl methacrylate-co-acrylate), poly(hydroxyethyl methacrylate-co-methacrylic acid), poly(acrylic acid-co-methyl methacrylate), poly(2-diethylaminoethyl methacrylate), poly(N,N-dimethylaminoethyl methacrylate), poly(N-isopropylacrylamide-co-2-aminoethyl methacrylate), poly(caprolactone-co-aminohexanoic acid), and poly(N,N-dimethylaminoethyl methacrylate).

4. The drug-loaded ionogel microspheres according to claim 1, characterized in that, The emulsifier includes at least one of sorbitan monooleate, sorbitan monolaurate, glyceryl monostearate, dehydrated sorbitan fatty acid ester, and polyglycerol-4-isostearate. And / or, the bioactive substance includes polyphenolic compounds or alkaloids.

5. The drug-loaded ionogel microspheres according to claim 1, characterized in that, The proportion of the raw materials used in the preparation satisfies at least one of the following conditions: a) The mass ratio of the ionic liquid to the pH-responsive polymer is 1:(1-5); b) The mass ratio of the ionic liquid to the bioactive substance is 1:(0.001-0.03); c) The water and methanol are aqueous phase solvents, and the ratio of the ionic liquid to the aqueous phase solvent is 1 g:(5-20) mL; d) The volume ratio of the aqueous phase to the oil phase is 1:(2-5).

6. The method for preparing drug-loaded ionogel microspheres according to any one of claims 1-5, characterized in that, Includes the following steps: An aqueous phase was obtained by mixing an ionic liquid, a pH-responsive polymer, a bioactive substance, and iron oxide in a methanol-water solution; an oil phase was obtained by mixing an emulsifier and liquid paraffin; the aqueous and oil phases were mixed and emulsified, and the solvent was evaporated to obtain drug-loaded ionogel microspheres.

7. A magnetically driven drug-carrying micro / nano motor, characterized in that, The drug-loaded ionogel microspheres according to any one of claims 1-5 are wherein a portion of the surface of the drug-loaded ionogel microspheres is coated with a platinum layer, and the surface of the platinum layer has gold nanospikes.

8. The method for preparing the magnetically driven drug-loaded micro / nano motor according to claim 7, characterized in that, Includes the following steps: The drug-loaded ionogel microspheres according to any one of claims 1-5 are laid on a substrate, and a platinum layer is deposited on one side of the substrate using ion beam sputtering technology. Then, the drug-loaded ionogel microspheres containing the platinum layer are dispersed in water, and chloroauric acid, silver nitrate and hydrogen peroxide are added in sequence. After oscillation reaction, gold nanospikes are formed on the surface of the platinum layer to obtain the magnetically driven drug-loaded micro / nano motor.

9. A composition, characterized in that, It includes the magnetically driven drug-carrying micro / nano motor and starch gel as described in claim 7.

10. The use of the drug-loaded ionogel microspheres according to any one of claims 1-5, the magnetically driven drug-loaded micro / nano motor according to claim 7, or the composition according to claim 9 in the preparation of products for treating chronic inflammatory diseases.

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