Conductive hydrogel microneedle for multi-target nerve repair and preparation method of conductive hydrogel microneedle

Abstract

The invention discloses a conductive hydrogel microneedle for multi-target nerve repair and a preparation method thereof, and relates to the field of traditional Chinese medicine, and the conductive hydrogel microneedle comprises the following main medicine components: astragaloside, ligustrazine, gastrodin, tenuigenin and edaravone. The preparation method comprises the following steps: preparing soybean lecithin, cholesterol and astragaloside into a lipid membrane; adding edaravone, ligustrazine and selenium nanoparticles to obtain a liposome; the preparation method comprises the following steps: biologically coupling liposome and a TfR-mAb solution to obtain a chitosan coating layer; the preparation method comprises the following steps: preparing gastrodin and tenuigenin into microspheres; uniformly mixing GelMA, SBMA, carboxylated nanocellulose, the chitosan coating layer and the microspheres, and then adding an LAP photoinitiator to prepare a mixed solution; and cleaning and blow-drying the filiform needle, placing the filiform needle in a PDMS mold, adding the mixed solution, carrying out vacuum defoaming, and then carrying out UV curing and packaging. According to the traditional Chinese medicine composition, qi deficiency and blood stasis and phlegm and blood stasis are integrated into the same prescription, and the limitation of traditional typing treatment is solved through ligustrazine and gastrodin.

Description

Technical Field

[0001] The present invention belongs to the field of traditional Chinese medicine, and particularly relates to a conductive hydrogel microneedle for multi-target nerve repair and a preparation method thereof. Background Art

[0002] Drug-loaded acupuncture needles are a novel medical tool that blends traditional acupuncture therapy with modern drug delivery technology. By integrating drug carriers on or within the needles, they achieve the dual therapeutic effects of physical acupoint stimulation and precise drug release. Modern drug-loaded acupuncture needles emerged in the 21st century, leveraging the intersection of nanotechnology, materials science, and Traditional Chinese Medicine theory to gradually transition from the laboratory to the clinic. Through nanostructure design, drugs can be released at specific times and locations. For example, drug-loaded press-fit patches deliver sustained drug release subcutaneously for 14 days for chronic disease management. Compared to traditional acupoint injections, they reduce drug dosage by 50%-70%, minimizing systemic toxicity and side effects. For example, drug-loaded press-fit needles stimulate the Zusanli acupoint and, in combination with sustained-release metformin, achieve synergistic regulation of blood sugar and body weight. Acupuncture needles loaded with anti-inflammatory drugs (such as diclofenac sodium) deliver directly to the site of pain, reducing oral medication dosage. The drug-loaded acupuncture needles developed by Zhang Chunyan's team are used to treat endometriosis, delivering blood-activating and blood-stasis-removing Chinese medicinal ingredients through acupuncture points to relieve dysmenorrhea and shrink cysts.

[0003] Neurological diseases include neurosis (including anxiety disorder, obsessive-compulsive disorder, etc.), neurasthenia, neurodermatitis, diabetic peripheral neuropathy, depressive neurosis, polyneuropathy, etc. According to TCM syndrome differentiation, diabetic peripheral neuropathy is divided into:

[0004] Qi deficiency and blood stasis syndrome: numbness, pain, abnormal sensation in the limbs, fatigue, shortness of breath, laziness to speak, sweating when moving, diarrhea or constipation, pale tongue, or with petechiae, thin white tongue coating, and thready and wiry pulse.

[0005] Yin deficiency and blood stasis syndrome: numbness, pain, and abnormal sensation in the limbs, especially at night, hot flashes in the five hearts, insomnia and nightmares, dry skin, dry mouth and throat, soreness of the waist and knees, dizziness and tinnitus, constipation, tender or dark red tongue, peeled tongue coating with little moisture, and thin and rapid or fine and wiry pulse.

[0006] Phlegm and blood stasis blocking the meridians syndrome: numbness and tingling in the limbs, often in a fixed location, purple and swollen skin, drowsiness in the limbs, heavy head, confusion, obesity, sticky and tasteless mouth, chest tightness and poor appetite, abdominal distension and discomfort, sticky stools, purple and dark tongue, enlarged tongue with teeth marks, thick white and greasy tongue coating, and deep and slippery or deep and wiry pulse.

[0007] Qi deficiency and blood stasis syndrome is currently treated primarily with tonifying qi, activating blood circulation, and unblocking the collaterals. Common prescriptions include Buyang Huanwu Decoction and Huangqi Guizhi Wuwu Decoction. These can also be combined with Chinese herbal fumigation or acupoint application. Yin deficiency and blood stasis syndrome focuses on nourishing yin, clearing heat, and activating blood circulation and unblocking the collaterals. Liuwei Dihuang Wan combined with Taohong Siwu Decoction is commonly used. Phlegm and blood stasis obstructing the collaterals focuses on resolving phlegm, removing blood stasis, and unblocking the collaterals. Erchen Decoction combined with Xuefu Zhuyu Decoction is commonly used.

[0008] The practice of acupuncture for neurological diseases can be traced back to the classic Chinese medicine text, the Yellow Emperor's Classic of Internal Medicine. Its core concept is to "regulate the spirit and regulate qi." By stimulating meridian acupoints, it regulates the flow of qi and blood, as well as the function of internal organs, thereby achieving the effects of "unblocking the meridians, activating the collaterals, and awakening the mind and opening the orifices." In the field of neurodegenerative diseases, Traditional Chinese Medicine believes that diseases such as Alzheimer's disease (AD) stem from "marrow deficiency" and "phlegm and blood stasis blocking the orifices." Acupuncture exerts its therapeutic effects by "tonifying the kidneys and filling the marrow" and "resolving phlegm and removing blood stasis." Existing drug-loaded acupuncture needles mostly utilize surface coatings or microporous drug delivery (such as diclofenac sodium and liraglutide). However, for neurological diseases, optimization is required for blood-brain barrier (BBB) penetration and neuronal targeting. For example, while conventional drug-loaded acupuncture needles using nanotube or polymer membrane delivery technologies can achieve sustained drug release, they lack a release mechanism responsive to the brain microenvironment. Furthermore, the drug's short half-life at the local acupoint requires frequent treatment (e.g., multiple acupuncture sessions per week), leading to low patient compliance. Existing studies have mostly used single traditional Chinese medicines or Western medicines as carriers, lacking the design of compound prescriptions based on TCM syndrome differentiation. For example, acupuncture needles often use Western medicines (such as diclofenac) without integrating the holistic regulatory effects of traditional Chinese medicine prescriptions (such as tonifying qi and promoting blood circulation, unblocking meridians and opening the orifices).

[0009] CN105169100B, invention name "a kind of ointment for coordinating acupuncture therapy to treat numbness of limbs", adopts Gastrodia elata, Agkistrodon murrill, Black red mushroom, Morus alba, Saffron, Summer no, Scorpion, Arisaema preparata, Perennial Cortex, Niu Dali, Coix seed, Bombyx batryticatus, Snake lady, Chuanxiong, the ointment obtained by adopting the above-mentioned medicament is coordinated with acupuncture therapy to treat the numbness of limbs caused by each cause of disease such as nerve blockage, wind evil entering the collaterals, numbness due to deficiency of qi, numbness due to deficiency of blood, numbness due to stagnation of qi, blood stasis blocking the collaterals and damp phlegm blocking the collaterals. However, this patented drug relies on passive diffusion, is difficult to penetrate the blood-brain barrier (BBB), and has limited regulation on central nervous system diseases (such as spinal cord injury). Based on dispelling wind and dampness, promoting the flow of meridians, lacks nerve repair (such as axon regeneration, myelin remodeling) and microcirculation bidirectional regulatory effect, and drug utilization rate is low.

[0010] CN104971204B, the invention name is "A kind of kidney-tonifying and awakening pill and medicine strip for treating neurological tinnitus in combination with acupuncture", is made of Astragalus and Rehmannia root as the main drugs, supplemented by 17 other Chinese herbal medicines; the medicine strip is made of Angelica dahurica as the main drug, and Asarum, Borneol, Gelsemium elegans, and Angelica dahurica are ground into powder, and wrapped with Rehmannia root slices or gauze into strips; scalp acupuncture adopts the method of equal tonification and equal drainage, and abdominal acupuncture adopts the method of guiding Qi back to the origin, for the comprehensive treatment of neurological tinnitus. The use of acupuncture to treat neurological tinnitus cannot treat both the symptoms and the root cause, and the recovery is unstable and the recurrence rate is high. This patent focuses on tonifying the kidney and replenishing essence, and has weak regulation on neuroinflammation (such as microglial activation) and mitochondrial energy metabolism disorders. The medicine strip plugs the ear and relies on passive absorption. The drug concentration in the cochlea is insufficient, and it cannot accurately regulate the ion channels of the auditory pathway. Summary of the Invention

[0011] In order to solve the above problems, the present invention provides a conductive hydrogel microneedle for multi-target nerve repair and a preparation method thereof.

[0012] The present invention provides a conductive hydrogel microneedle for multi-target nerve repair. The main medicinal ingredients of the conductive hydrogel microneedle for multi-target nerve repair are composed of 30% to 40% of astragaloside IV, 20% to 30% of ligustrazine, 15% to 25% of gastrodin, 10% to 20% of polygala saponin and 5% of edaravone in terms of mass percentage.

[0013] Furthermore, the main medicinal ingredients of the conductive hydrogel microneedle for multi-target nerve repair are composed of 35% astragaloside IV, 25% ligustrazine, 20% gastrodin, 15% polygala saponin and 5% edaravone in terms of mass percentage.

[0014] The method for preparing conductive hydrogel microneedles for multi-target nerve repair is as follows:

[0015] 1) Dissolve soybean lecithin, cholesterol, and astragaloside IV in chloroform and rotary evaporate to form a lipid film;

[0016] 2) mixing the lipid film, phosphate buffer, edaravone, ligustrazine, and selenium nanoparticles, and filtering to obtain liposomes;

[0017] 3) The liposomes and chitosan solution were mixed and stirred evenly, and the TfR-mAb solution was added to obtain a chitosan coating layer using a biocoupling method;

[0018] 4) dissolving poly(lactic acid-co-glycolic acid), gastrodin, and polygalaenoside in dichloromethane, adding polyvinyl alcohol solution, homogenizing, stirring to evaporate the organic solvent, centrifuging, and collecting to obtain microspheres;

[0019] 5) GelMA, SBMA, and carboxylated nanocellulose were dissolved in PBS, chitosan coating layer and microspheres were added and mixed, and then LAP photoinitiator was added and stirred in the dark to obtain a mixed solution;

[0020] 6) After cleaning and drying the needles, place them in a PDMS mold, pour in the mixed solution from step 5), vacuum degas, and then perform UV curing and encapsulation.

[0021] Furthermore, the mass ratio of the soybean lecithin to cholesterol is 2 to 3:1.

[0022] Furthermore, the amount of selenium nanoparticles added is 0.5% to 1.0% of the mass of the lipid membrane.

[0023] Furthermore, the volume ratio of the liposome to chitosan is 1:2-3.

[0024] Furthermore, the mass concentration of the TfR-mAb solution is 0.1-0.2 mg / mL.

[0025] Furthermore, the biocoupling method is an EDC / NHS coupling method, and the reaction conditions of the EDC / NHS coupling method are to react overnight at a temperature of 4° C., pH=6.0, and a rotation speed of 200-300 rpm.

[0026] Furthermore, the mass percentage of the GelMA is 8-12%, the mass concentration of SBMA is 0.5-0.6 mg / mL, and the mass percentage of the carboxylated nanocellulose is 1.5-2.0%.

[0027] Furthermore, the UV curing conditions are: wavelength 365nm, intensity 10-15mW / cm 2 , time 5 to 10 minutes.

[0028] The Astragalus root of the present invention has the effects of replenishing Qi and strengthening the foundation. Replenishing Qi: directly improves the state of Qi deficiency, enhances the driving force of Qi, and provides power for promoting blood circulation and removing blood stasis. Strengthening the foundation: by improving immunity, it reduces the invasion of external evils caused by Qi deficiency. Chuanxiong has the effects of promoting blood circulation and removing blood stasis. Promoting blood circulation: dredges blood vessels and improves pain and numbness caused by blood stasis. Promoting Qi: synergistically with Astragalus root, the movement of Qi leads to the movement of blood, and the effect of removing blood stasis is enhanced. Gastrodia elata has the effects of calming wind and resolving phlegm. Calming wind: calms liver wind and relieves dizziness and headache caused by wind-phlegm disturbance. Resolving phlegm: by improving microcirculation, it promotes the metabolism of phlegm turbidity. Polygala tenuifolia resolves phlegm and opens the orifices. Resolving phlegm: directly decomposes phlegm turbidity and improves phlegm-dampness stagnation. Opening the orifices: by enhancing the function of the cholinergic system, it restores clear orifices and unblocks.

[0029] The present invention has the following beneficial effects:

[0030] The present invention is the first to incorporate "Qi deficiency and blood stasis" and "mutual binding of phlegm and blood stasis" into the same prescription. "Qi deficiency and blood stasis" uses Astragalus membranaceus to replenish Qi as the main ingredient, and Chuanxiong to promote blood circulation as the secondary ingredient; "Phlegm turbidity blocking the orifices" uses Gastrodia elata to calm the wind and Polygala tenuifolia to resolve phlegm as the auxiliary ingredients. The limitations of traditional classification treatment are solved by using Chuanxiongzine (to promote blood circulation) + Gastrodia elata (to resolve phlegm). The present invention integrates three mechanisms: brain energy metabolism (astragaloside IV), ALP pathway (Gastrodia elata), and anti-inflammatory (Polygala tenuifolia saponins), breaking through the limitations of single ingredient effects. pH-responsive hydrogels combined with targeted nanocarriers can achieve precise drug release in the brain, significantly improving the utilization rate compared to traditional decoctions.

[0031] Astragaloside IV activates the AMPK pathway, reversing the mitochondrial damage associated with diabetic neuropathy. Gastrodin and edaravone form a dual "scavenging-protecting" cycle. Activating TFEB with gastrodin can reverse the excessive inhibition of autophagy potentially induced by astragaloside IV, creating a dynamic equilibrium. Polygala tenuifolia saponins inhibit the nephrotoxicity of edaravone. This invention overcomes the existing therapeutic bottlenecks in complex neurological diseases. DETAILED DESCRIPTION

[0032] In order to make the objectives, technical solutions and advantages of the embodiments of the present invention more clearly understood, the spirit of the contents disclosed in the present invention will be described in detail below. After understanding the embodiments of the contents of the present invention, any technician in the relevant technical field can change and modify the contents of the present invention based on the techniques taught by the contents of the present invention without departing from the spirit and scope of the contents of the present invention.

[0033] The exemplary embodiments of the present invention and the description thereof are used to explain the present invention but are not intended to limit the present invention.

[0034] Example 1

[0035] The preparation of a conductive hydrogel microneedle for multi-target nerve repair in this embodiment is as follows:

[0036] 1) 70 mg of soybean lecithin, 30 mg of cholesterol, and 5 mg of astragaloside IV were mixed and dissolved in 10 mL of chloroform. The mixture was rotary evaporated at 40°C and 0.1 MPa vacuum to form a lipid film.

[0037] 2) Add 10 mL of phosphate buffer (pH = 7.4), 5 mg of edaravone, 25 mg of ligustrazine, and 0.6 mg of selenium nanoparticles (particle size <50 nm) to the lipid film. Ultrasonicate at 300 W for 15 min to form a liposome suspension, which is then extruded through a 0.2 μm polycarbonate membrane to obtain liposomes of uniform particle size.

[0038] 3) The resulting liposomes were mixed with 20 mL of chitosan solution (1% w / v, pH 5.0) and magnetically stirred at 500 rpm for 4 h. Then, 3 mg of TfR-mAb solution, 28.76 mg of EDC (5 mM), and 16.28 mg of Sulfo-NHS (2.5 mM) were added, and the mixture was reacted overnight at 4°C, pH 6.0, and 200 rpm to obtain a chitosan coating.

[0039] 4) Dissolve 100 mg of poly(lactic-co-glycolic acid), 20 mg of gastrodin, and 15 mg of polygalaenoside in 10 mL of dichloromethane. Add 20 mL of polyvinyl alcohol solution (0.5% w / v) and homogenize at 10,000 rpm to form a W / O emulsion. Stir at room temperature to evaporate the organic solvent, and collect the microspheres by centrifugation.

[0040] 5) Dissolve 10 g of GelMA, 57 mg of SBMA monomer, and 1.5 g of carboxylated nanocellulose in PBS and stir magnetically until dissolved. Then, add 30 mL of chitosan coating and 10 mL of microspheres and mix well. Then, add 0.1 g of LAP photoinitiator and stir in the dark for 10 minutes to obtain a mixed solution.

[0041] 6) Soak the needles in 0.1M PBS for 30 minutes to remove the oxides, then clean them with 75% ethanol ultrasonically and blow dry.

[0042] Place the microneedle at the bottom of the PDMS mold with the tip facing upward, pour the mixed solution from step 5), vacuum degas for 5 minutes, and then perform UV curing (wavelength 365nm, intensity 10mW / cm 2 , time 5min), and after encapsulation, the conductive hydrogel microneedles for multi-target nerve repair were obtained.

[0043] The conductive hydrogel microneedles for multi-target nerve repair in this embodiment contain astragaloside IV (35%), ligustrazine (25%), gastrodin (20%), polygala root saponin (15%), and edaravone (5%) by weight.

[0044] Example 2

[0045] Example 1 Conductive hydrogel microneedles for multi-target nerve repair were prepared and then subjected to animal experimental studies

[0046] 1. Establishment of animal model

[0047] Animals: Male SD rats (weight 200-250 g, n=40) were randomly divided into 4 groups:

[0048] Blank control group (n=10): normal diet, no diabetes induction.

[0049] Model group (n=10): STZ-induced diabetes + high-fat diet (12 weeks).

[0050] Positive control group (n=10): model group + methylcobalamin.

[0051] Experimental group (n=10): model group + conductive hydrogel microneedles for multi-target nerve repair.

[0052] 2. Neuropathy Induction

[0053] Chronic Sciatic Nerve Compression (CCI):

[0054] The sciatic nerve of the anesthetized rats was exposed and ligated four times with 4-0 chromic gut at 1 mm intervals to simulate chronic nerve injury.

[0055] 3. Experimental methods

[0056] Experimental group: The rats' back hair was shaved, and filiform needles were placed in the lumbar sacral region (covering the L4-L6 ganglia). The rats were connected to a low-frequency pulse electroacupuncture device (10 Hz continuous wave + 0.2-0.5 ms pulse width). The stimulation time was 30 minutes / time for 6 consecutive weeks.

[0057] Positive control group: rats were gavaged with 0.5 mg / kg / d methylcobalamin daily.

[0058] 4. Evaluation Metrics

[0059] 4.1 Behavioral Assessment

[0060] The mechanical pain threshold was assessed using the Von Frey method, and the thermal pain threshold was assessed using the Hargreaves method.

[0061] 4.2 Neuroelectrophysiological testing

[0062] Sciatic nerve conduction velocity:

[0063] After anesthesia, the proximal sciatic nerve was stimulated, the distal compound muscle action potential (CMAP) was recorded, and the conduction velocity (m / s) was calculated.

[0064] 4.3 Histopathology and Molecular Mechanism Analysis

[0065] The sciatic nerve was removed, fixed with 4% paraformaldehyde, and sectioned into paraffin (5 μm). The myelinated nerve fibers were stained with toluidine blue and the density of myelinated nerve fibers (number of fibers / mm) was counted under a microscope. 2 ).

[0066] Serum TNF-α, IL-6 levels, and AMPKα1 concentration were measured by ELISA. Serum MDA and SOD were detected by colorimetry, and the proportion of nuclear localization-positive cells (co-localization of DAPI and TFEB signals) was calculated by immunofluorescence.

[0067] Dorsal root ganglion (DRG) tissues were collected to detect the expression of AMPK, PGC-1α (mitochondrial metabolism), NF-κB p65 (inflammation), LC3-II (autophagy), and p-AMPK (Thr172) proteins, and the ratio of p-AMPK (Thr172) to total AMPK was calculated.

[0068] 5. Results

[0069] 5.1 Behavioral Results

[0070] Group Mechanical pain threshold (g) Heat pain latency (s) Nerve conduction velocity (m / s) Blank control group 15.2±1.8 12.5±1.2 48.3±3.5 Model Group 4.5±0.6* 5.2±0.8* 16.8±2.1* Positive control group 9.8±1.2# 8.3±1.1# 28.4±2.8# Experimental group 18.3±2.2 14.0±1.5 44.5±4.2

[0071] (*P<0.01 vs blank group; #P<0.05 vs model group; no significant difference between the experimental group and the blank group)

[0072] 5.2 Histopathology and Molecular Mechanism Results

[0073]

[0074]

[0075] (**P<0.01 vs blank group; ##P<0.01 vs model group)

[0076] The above results show that through the synergistic effect of TfR-mAb, conductive gel and ligustrazine, the mechanical pain threshold of the experimental group increased by about 4 times compared with the model group, the thermal pain latency was extended by about 60%, and the nerve conduction velocity was 44.5m / s, which is close to the healthy level.

[0077] The nerve conduction velocity of the experimental group increased by about 165% compared with the model group, indicating that TfR-mAb-modified ligustrazine increased the drug concentration in the brain. In response to "Qi deficiency", the nerve conduction velocity of the experimental group recovered to 44.5m / s due to the use of astragaloside IV, which was close to the 48.3m / s of the blank group and significantly better than the positive control group (28.4m / s), indicating that astragaloside IV activated the AMPK / PGC-1α pathway and repaired mitochondrial function. Compared with the TNF-α85.6pg / mL in the model group, the experimental group was 18.3pg / mL, indicating that the experimental group promoted blood circulation and removed blood stasis, and inhibited the NF-κB inflammatory pathway. It can be seen that the experimental group dynamically associated "Qi deficiency and blood stasis" (AMPK / PGC-1α energy metabolism disorder) with "mutual entanglement of phlegm and turbidity" (TFEB autophagy imbalance, NF-κB inflammation), forming a "Qi tonifying, blood stasis-removing phlegm and unblocking collaterals" closed loop.

[0078] The experimental group containing gastrodin showed a 4.5-fold increase in the LC3-II / LC3-I ratio compared to the model group, while the experimental group containing edaravone showed a 76% decrease in MDA compared to the model group. This results in a "scavenging-protecting" closed loop in the experimental group, transcending the single mode of action of traditional antioxidants. Edaravone scavenges ROS and also blocks oxidative stress caused by AMPK overactivation. The experimental group forms a closed-loop regulation by combining astragaloside IV (an AMPK activator) with gastrodin (a TFEB autophagy activator), preventing the energy depletion caused by AMPK overactivation while also overcoming the limitations of traditional single-pathway drugs. Compared to the model group, the experimental group showed a 3.75-fold increase in BDNF, a 3.17-fold increase in myelinated nerve fiber density, and a 3.0-fold increase in AMPK activation. The experimental group, through the combination of electrical stimulation and astragaloside IV, synergistically promoted axonal regeneration. The TfR-mAb-modified ligustrazine vector can penetrate the blood-nerve barrier, increasing AMPKα1 concentrations to 43.1 ng / mL in dorsal root ganglia, achieving precise activation within the lesion. From the serum creatinine data, the experimental group was about 27% lower than the model group, indicating that the polygala saponins in the experimental group inhibited the nephrotoxicity of edaravone and played a role in protecting the kidneys.

[0079] The above results indicate that the experimental group controlled the release of gastrodin through chitosan-microspheres. When AMPK was overactivated and caused intracellular acidification, TFEB activation was accelerated to clear metabolic waste. Selenium nanoparticles released edaravone when ROS was excessive, neutralizing oxidative stress. Carboxylated nanocellulose gel sustained-released the drug, maintaining AMPK activity within a safety window of 0.8-1.2.

Claims

1. A conductive hydrogel microneedle for multi-target nerve repair, characterized by The main medicinal components of the conductive hydrogel microneedle for multi-target nerve repair are composed of 30% to 40% of astragaloside IV, 20% to 30% of ligustrazine, 15% to 25% of gastrodin, 10% to 20% of polygala saponin and 5% of edaravone in terms of mass percentage.

2. The conductive hydrogel microneedle for multi-target nerve repair according to claim 1, characterized in that The main medicinal components of the conductive hydrogel microneedle for multi-target nerve repair are composed of 35% astragaloside IV, 25% ligustrazine, 20% gastrodin, 15% polygala saponin and 5% edaravone in terms of mass percentage.

3. The method for preparing the conductive hydrogel microneedle for multi-target nerve repair according to claim 1, characterized in that The conductive hydrogel microneedle preparation method is as follows: 1) Dissolve soybean lecithin, cholesterol, and astragaloside IV in chloroform and rotary evaporate to form a lipid film; 2) mixing the lipid film, phosphate buffer, edaravone, ligustrazine, and selenium nanoparticles, and filtering to obtain liposomes; 3) The liposomes and chitosan solution were mixed and stirred evenly, and the TfR-mAb solution was added to obtain a chitosan coating layer using a biocoupling method; 4) dissolving poly(lactic acid-co-glycolic acid), gastrodin, and polygalaenoside in dichloromethane, adding polyvinyl alcohol solution, homogenizing, stirring to evaporate the organic solvent, centrifuging, and collecting to obtain microspheres; 5) GelMA, SBMA, and carboxylated nanocellulose were dissolved in PBS, chitosan coating layer and microspheres were added and mixed, and then LAP photoinitiator was added and stirred in the dark to obtain a mixed solution; 6) After cleaning and drying the needles, place them in a PDMS mold, pour in the mixed solution from step 5), vacuum degas, and then perform UV curing and encapsulation.

4. The preparation method according to claim 3, characterized in that The mass ratio of the soybean lecithin to cholesterol is 2-3:

1.

5. The preparation method according to claim 3, characterized in that The added amount of the selenium nanoparticles is 0.5% to 1.0% of the mass of the lipid membrane.

6. The preparation method according to claim 3, characterized in that The volume ratio of the liposome to chitosan is 1:2-3.

7. The preparation method according to claim 3, characterized in that The mass concentration of the TfR-mAb solution is 0.1-0.2 mg / mL.

8. The preparation method according to claim 3, characterized in that The biocoupling method is an EDC / NHS coupling method, and the reaction conditions of the EDC / NHS coupling method are: reacting overnight at a temperature of 4° C., pH=6.0, and a rotation speed of 200-300 rpm.

9. The preparation method according to claim 8, characterized in that The mass percentage of the GelMA is 8-12%, the mass concentration of the SBMA is 0.5-0.6 mg / mL, and the mass percentage of the carboxylated nanocellulose is 1.5-2.0%.

10. The preparation method according to claim 3, characterized in that The UV curing conditions are: wavelength 365nm, intensity 10-15mW / cm 2 , time 5 to 10 minutes.

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