A pharmaceutical composition targeting neuroinflammation and uses thereof

Abstract

The present application provides a kind of drug composition and its application for targeting neuroinflammation, the composition is composed of active ingredient and natural nanometer delivery carrier for encapsulating active ingredient, the active ingredient includes fisetin, pyrrole quinoline quinone, resveratrol, bauhinia A, apigenin, saffron, quercetin and hair monkey element;The natural nanometer delivery carrier is the plant source extracellular vesicle of surface modification brain targeting molecule.The composition of the present application realizes the intervention to vascular cognitive impairment by multi-component scientific compatibility, combined with two-stage brain targeting delivery design, solves the pain points of low blood-brain barrier penetration rate and poor bioavailability of natural active ingredient, has the effect of strong anti-inflammatory and significantly improving cognitive function, excellent safety, can be used for preparing the medicine for preventing or adjuvant therapy neuroinflammation related vascular cognitive impairment, has very high clinical conversion value.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a pharmaceutical composition targeting neuroinflammation and its application. Background Technology

[0002] Vascular cognitive impairment (VCI) is a large category of syndromes ranging from mild cognitive impairment to dementia caused by cerebrovascular risk factors (such as hypertension, hyperlipidemia, cerebral infarction, cerebral hypoperfusion, etc.) and overt or covert cerebrovascular diseases. It is the second leading cause of dementia after Alzheimer's disease, and its incidence is rising year by year, making it a major global public health problem.

[0003] Currently, there are no effective disease-modifying drugs for vascular cognitive impairment in clinical practice. Existing treatment options are mainly symptomatic, such as cholinesterase inhibitors and NMDA receptor antagonists. These can only temporarily improve cognitive symptoms and cannot stop disease progression. Furthermore, they have drawbacks such as large peripheral side effects and poor long-term tolerability.

[0004] Studies have confirmed that neuroinflammation is the core driving pathological mechanism in the development of vascular cognitive impairment: cerebrovascular injury leads to insufficient brain perfusion, causing disruption of the blood-brain barrier integrity, which in turn induces excessive activation of central microglia and abnormal activation of the NLRP3 inflammasome, resulting in the release of large amounts of pro-inflammatory factors such as IL-1β, TNF-α, and IL-6, forming a neuroinflammatory cascade. Ultimately, this leads to oxidative stress damage, synaptic loss, and neuronal apoptosis in hippocampal and cortical neurons, causing progressive cognitive decline. Simultaneously, pathological damage to the blood-brain barrier further blocks the brain pathway for peripheral drug administration, resulting in extremely low brain tissue accumulation of most drugs, rendering them ineffective.

[0005] Current interventions for neuroinflammation face several insurmountable technical bottlenecks: First, single-target anti-inflammatory drugs cannot cover the multiple pathological links in vascular cognitive impairment, namely "blood-brain barrier damage-neuroinflammatory cascade-mitochondrial dysfunction-neuronal loss," resulting in weak in vivo efficacy and easy drug resistance. Second, natural plant-derived components with anti-inflammatory and neuroprotective activities, such as flavonoids and polyphenols, generally suffer from high lipid solubility, low oral bioavailability, insufficient blood-brain barrier penetration, and short in vivo half-life, making it difficult to achieve effective therapeutic concentrations at central lesions. Third, existing synthetic nanodelivery carriers, such as liposomes and polymer nanoparticles, suffer from poor biocompatibility, strong in vivo immunogenicity, difficulty in industrial scale-up, and rapid in vivo clearance, hindering clinical translation. Fourth, the application of existing plant-derived extracellular vesicles mostly involves unmodified natural vesicles, lacking active brain-targeting design, resulting in low brain penetration efficiency and failing to form a systematic compatibility and synergistic effect with natural active ingredients, thus failing to specifically address the core pathological problems of vascular cognitive impairment. Summary of the Invention

[0006] In view of this, the present invention proposes a pharmaceutical composition targeting neuroinflammation and its application, thereby solving the above-mentioned problems.

[0007] The technical solution of the present invention is achieved as follows: a pharmaceutical composition targeting neuroinflammation, the composition comprising an active ingredient and a natural nano-delivery carrier for encapsulating or loading the active ingredient, the active ingredient comprising the following raw materials in parts by weight: 20-30 parts of flavin, 2-5 parts of pyrroloquinoline quinone, 10-20 parts of resveratrol, 5-8 parts of phloroglucinol A, 10-15 parts of apigenin, 1-3 parts of crocin, 2-5 parts of quercetin, and 0.3-0.8 parts of citronellol.

[0008] Furthermore, the active ingredients include the following raw materials in parts by weight: 25 parts of flavin, 3 parts of pyrrolidone, 15 parts of resveratrol, 6 parts of phloroglucinol A, 12 parts of apigenin, 2 parts of crocin, 3 parts of quercetin, and 0.5 parts of citronellol.

[0009] Furthermore, the natural nanodelivery carrier is a plant-derived extracellular vesicle, and the total mass of the active ingredient to the mass of the plant-derived extracellular vesicle is 1:(5~20).

[0010] Furthermore, the plant-derived extracellular vesicles are any one or more combinations of ginger-derived extracellular vesicles, broccoli-derived extracellular vesicles, and ginseng-derived extracellular vesicles, and the particle size of the plant-derived extracellular vesicles is 30~150nm.

[0011] Furthermore, the surface of the plant-derived extracellular vesicles is modified to connect to a brain-targeting molecule, which is selected from any one of lactoferrin, rabies virus glycoprotein-derived peptide RVG29, and transferrin receptor single-domain antibody.

[0012] The method for preparing the pharmaceutical composition targeting neuroinflammation of the present invention includes the following steps:

[0013] S1. Extraction and purification of plant-derived extracellular vesicles: Take ginger, broccoli or ginseng raw materials, wash, disinfect and crush them, and then homogenize them with isotonic PBS buffer at 2~6℃ at a material-to-liquid ratio of 1:(2~4)g / mL; centrifuge the homogenate sequentially at 2~6℃ at 1000×g for 15min, 4000×g for 25min, and 12000×g for 45min, collect the supernatant, filter it and concentrate it using a tangential flow ultrafiltration system with a molecular weight cutoff of 100kD to obtain vesicle concentrate, purify and remove impurities, collect the vesicle characteristic peak eluent to obtain plant-derived extracellular vesicle solution;

[0014] S2, Brain-targeted modification: The vesicle solution obtained in step S1 was adjusted to a phospholipid concentration of 2-6 mg / mL with isotonic PBS buffer (pH 7.2-7.4). The brain-targeting molecule solution was added at a mass ratio of total vesicle phospholipids to brain-targeting molecules of 100:(2-6). The solution was pre-incubated at 2-8°C in the dark for 10 min. After sonication with a probe, the modification was completed by stirring at 100-150 rpm at 2-8°C in the dark for 20-40 min.

[0015] S3. Drug loading: The targeted modified vesicles obtained in step S2 are mixed with the active ingredient, and drug loading is performed by low-temperature incubation-ultrasound method. The mixture is then filtered through a 0.22μm filter membrane for sterilization to obtain the drug composition, or freeze-dried to prepare lyophilized powder.

[0016] Furthermore, in step S2, the probe ultrasonic power is 50~80W, and a pulse working mode is adopted. The working cycle is 1~3 seconds of ultrasound with an interval of 2~4 seconds. The total ultrasonic processing time is 1~3 minutes, and the ultrasonic process is carried out under ice bath conditions.

[0017] Furthermore, in step S3, the temperature of the low-temperature incubation-ultrasound is as follows: the low-temperature incubation is carried out at 2~8℃ for 1~4 hours; the ultrasound is pulsed ultrasound with a power of 20~100W, the working cycle is 2~5 seconds on and 5~10 seconds off, the total ultrasound time is 1~3 minutes, and the ultrasound process is carried out under ice bath conditions.

[0018] The dosage form of the pharmaceutical composition of the present invention is any one of oral nanosuspension, oral soft capsule, nasal brain-targeting spray, and intravenous lyophilized powder injection.

[0019] The use of the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or adjunctive treatment of neuroinflammatory-related vascular cognitive impairment.

[0020] Compared with the prior art, the beneficial effects of the present invention are:

[0021] This invention, based on the core pathological mechanism of vascular cognitive impairment, constructs a full-chain intervention system through the scientific formulation of multiple components, encompassing "upstream inflammation blocking, midstream mitochondrial repair, and downstream blood-brain barrier repair." The synergistic effect of each active component achieves potent anti-inflammatory and neuroprotective effects, breaking through the efficacy ceiling of single-target drugs. Combining the natural delivery advantages of plant-derived extracellular vesicles with active brain-targeting modification, a dual-level brain-targeting delivery system is formed, significantly improving the central lesion enrichment efficiency of active ingredients. This overcomes the industry's core pain points of low blood-brain barrier penetration and poor oral bioavailability of natural flavonoids and polyphenols. In classic animal models of vascular cognitive impairment, the composition of this invention has been demonstrated to significantly improve cognitive function, reverse core pathological changes such as neuroinflammation and blood-brain barrier damage, with cognitive improvement effects superior to first-line clinical symptomatic drugs, exhibiting a clear disease-modifying effect. Furthermore, the composition is entirely derived from natural sources, has no significant toxic side effects, excellent safety, and its preparation process can be linearly scaled up industrially with strong batch stability, possessing extremely high clinical translational and commercial application value. Detailed Implementation

[0022] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate the invention.

[0023] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0024] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0025] Unless otherwise specified, all excipients used in the formulations of this invention are pharmaceutical grade excipients, and their dosage can be reasonably adjusted within the conventional pharmaceutical range in this field according to the formulation specifications and clinical dosage.

[0026] Example 1

[0027] The pharmaceutical composition of this embodiment consists of an active ingredient and a natural nanodelivery carrier for encapsulating and loading the active ingredient.

[0028] The active ingredient is composed of the following raw materials in parts by weight: 25 parts of flavin, 3 parts of pyrroloquinoline quinone, 15 parts of resveratrol, 6 parts of phloroglucinol A, 12 parts of apigenin, 2 parts of crocin, 3 parts of quercetin, and 0.5 parts of citronellol.

[0029] The natural nanodelivery carrier is a ginger-derived extracellular vesicle with surface-modified lactoferrin;

[0030] The total mass ratio of the active ingredients to the plant-derived extracellular vesicles is 1:10.

[0031] Its preparation method includes the following steps:

[0032] S1. Extraction and purification of plant-derived extracellular vesicles:

[0033] (1) Take fresh ginger raw material, rinse with sterile water, disinfect the surface with sodium hypochlorite solution with a volume fraction of 0.8% for 2 minutes, rinse with sterile water until there is no disinfectant residue, remove the outer skin and coarse fiber tissue, and chop to obtain plant tissue fragments with a particle size ≤2mm.

[0034] (2) Mix the plant tissue fragments with isotonic PBS buffer pre-cooled at 4℃ at a ratio of 1:3 g / mL and homogenize at 4℃ in the dark to obtain a homogenate. The homogenate is then centrifuged at 4℃ for 15 min at 1000×g, 25 min at 4000×g, and 45 min at 12000×g. The supernatant is collected each time to remove impurities and obtain a crude supernatant.

[0035] (3) After the crude supernatant was filtered through a 0.45 μm hydrophilic microporous membrane, it was concentrated and replaced with isotonic PBS buffer at 4 °C using a tangential flow ultrafiltration membrane system with a molecular weight cutoff of 100 kD to obtain vesicle concentrate.

[0036] (4) The vesicle concentrate was purified by agarose gel size exclusion chromatography with isotonic PBS buffer at pH 7.4 as the mobile phase and a flow rate of 0.8 mL / min. The characteristic elution peaks of exosomes were collected to obtain the purified ginger-derived extracellular vesicle solution.

[0037] The vesicles were found to have a diameter of 82 nm, a zeta potential of -22.3 mV, and a phospholipid concentration of 4.2 mg / mL.

[0038] S2, Brain-targeted modification: The vesicle solution obtained in step S1 was adjusted to a phospholipid concentration of 4 mg / mL with isotonic PBS buffer (pH 7.4). Lactoferrin solution was added at a mass ratio of total phospholipids to lactoferrin of 100:4. The solution was pre-incubated at 4°C in the dark for 10 min. Probe sonication was then performed under ice bath conditions at a power of 60 W using a pulsed mode, with sonication for 2 seconds followed by a 3-second interval, for a total sonication time of 2 min. The modification was then completed by incubation at 4°C in the dark with stirring at 120 rpm for 30 min.

[0039] After incubation, the unbound free lactoferrin was removed by agarose gel size exclusion chromatography to obtain ginger-derived extracellular vesicles with surface-modified lactoferrin.

[0040] The modification efficiency was 87.2%, the vesicle size was 95 nm, the PDI was 0.182, and the zeta potential was -18.6 mV.

[0041] S3. Drug loading: The targeted modified vesicles obtained in step S2 are mixed with the active ingredient at a mass ratio of 10:1. The mixture is incubated at 4°C in the dark with stirring at 120 rpm for 2 hours. Then, pulsed ultrasound treatment is performed in an ice bath in the dark. The ultrasound power is 80W, the working cycle is 3 seconds on and 6 seconds off, and the total ultrasound time is 2 minutes. After ultrasound treatment, the mixture is incubated at 4°C in the dark for 30 minutes to complete the encapsulation. The mixture is then filtered through a 0.22μm sterile filter membrane to obtain the drug composition.

[0042] The test results showed that the total encapsulation rate of the active ingredients was 82.5%, the drug loading was 8.9%, the particle size was 102 nm, and the PDI was 0.195, which met the requirements for pharmaceutical preparations.

[0043] Example 2

[0044] The pharmaceutical composition of this embodiment consists of an active ingredient and a natural nanodelivery carrier for encapsulating and loading the active ingredient.

[0045] The active ingredient is composed of the following raw materials in parts by weight: 20 parts of flavin, 2 parts of pyrrolidone, 10 parts of resveratrol, 5 parts of phloroglucinol A, 10 parts of apigenin, 1 part of crocin, 2 parts of quercetin, and 0.3 parts of citronellol.

[0046] The natural nanodelivery carrier is a broccoli-derived extracellular vesicle with a surface-modified RVG29 peptide; the total mass ratio of the active ingredients to the plant-derived extracellular vesicles is 1:5.

[0047] The difference between its preparation method and Example 1 is that: the raw material in step S1 (1) is fresh broccoli, the brain-targeting molecule in step S2 is rabies virus glycoprotein-derived peptide RVG29, the mass ratio of total phospholipids in vesicles to RVG29 is 100:2, and the remaining process parameters are the same as in Example 1.

[0048] According to the test results, the total encapsulation efficiency of the active ingredient in the pharmaceutical composition prepared in this embodiment is 78.3%, the drug loading is 8.1%, the vesicle size is 88 nm, the PDI is 0.203, and the targeting modification efficiency is 89.6%.

[0049] Example 3

[0050] The pharmaceutical composition of this embodiment consists of an active ingredient and a natural nanodelivery carrier for encapsulating and loading the active ingredient.

[0051] The active ingredient is composed of the following raw materials in parts by weight: 30 parts of flavin, 5 parts of pyrrolidone, 20 parts of resveratrol, 8 parts of phloroglucinol A, 15 parts of apigenin, 3 parts of crocin, 5 parts of quercetin, and 0.8 parts of citronellol.

[0052] The natural nanodelivery carrier is a ginseng-derived extracellular vesicle with a surface-modified transferrin receptor single-domain antibody; the total mass ratio of the active ingredient to the plant-derived extracellular vesicle is 1:20.

[0053] The difference between its preparation method and Example 1 is that: the raw material in step S1 (1) is fresh ginseng, the brain-targeting molecule in step S2 is transferrin receptor single-domain antibody, the mass ratio of total phospholipids in vesicles to single-domain antibody is 100:6, and the remaining process parameters are the same as in Example 1.

[0054] According to the test results, the total encapsulation efficiency of the active ingredient of the pharmaceutical composition prepared in this embodiment is 76.9%, the drug loading is 8.3%, the vesicle size is 112 nm, the PDI is 0.215, and the targeting modification efficiency is 85.7%.

[0055] Example 4: Preparation of oral soft capsules

[0056] The pharmaceutical composition obtained in Example 1 was mixed with 85 parts of injection-grade soybean oil, 2 parts of beeswax, and 1.5 parts of injection-grade lecithin by mass ratio. The mixture was prepared uniformly under light-protected conditions below 35°C to form a uniform and stable soft capsule contents. The gelatin-glycerin mixture was prepared with a mass ratio of 1:0.4. The gelatin was then pelletized, shaped, and dried to obtain oral soft capsules, each containing 10 mg of total active ingredients.

[0057] Example 5: Preparation of lyophilized powder for intravenous injection

[0058] The pharmaceutical composition prepared in Example 1 was mixed with mannitol for injection to a final concentration of 5% (w / v) as a lyophilization protectant. After sterilization by filtration through a 0.22 μm sterile filter membrane, the mixture was dispensed into sterile vials at 1 mL / vial. The mixture was then subjected to a vacuum freeze-drying process: pre-freezing at -45°C for 4 hours, followed by sublimation drying at -20°C for 12 hours, and then desorption drying at 25°C for 6 hours to prepare a lyophilized powder for intravenous injection. The powder was then sealed and stored at 2-8°C.

[0059] Example 6: Preparation of a nasal brain-targeting spray

[0060] The pharmaceutical composition prepared in Example 1 was adjusted to isotonicity by adding sodium chloride for injection to a final concentration of 0.9% (w / v), and benzalkonium chloride was added to a final concentration of 0.01% (w / v) as an antibacterial agent. The volume was adjusted to a final concentration by sterile isotonic PBS buffer at pH 7.4. After sterilization by filtration through a 0.22 μm sterile filter membrane, the solution was dispensed into quantitative nasal spray bottles at 10 mL / bottle to prepare a nasal brain-targeting spray containing 0.5 mg of total active ingredient per spray.

[0061] Experiment Example 1: In vitro anti-inflammatory activity verification experiment

[0062] The in vitro anti-inflammatory activity of the composition of this invention was verified using an LPS-induced BV2 microglia activation model. The experimental groups are as follows:

[0063] Blank control group: BV2 cells cultured normally, without LPS induction;

[0064] Model group: BV2 cells induced by LPS (1 μg / mL) for 24 h;

[0065] Free drug group: Free active ingredients with the same ratio as in Example 1, administered at a concentration (based on total active ingredients) of 10 μg / mL;

[0066] Unmodified vesicle group: Ginger-derived vesicles without targeted modification loaded with the same dose of active ingredients;

[0067] The composition group of this invention: The composition obtained in Example 1 was administered at a concentration (based on total active ingredient) of 10 μg / mL. After 24 hours of administration to each group, the levels of IL-1β, TNF-α, and IL-6 in the cell supernatant were detected using ELISA. The results are shown in Table 1 below:

[0068] Table 1 Comparison of pro-inflammatory cytokine levels in each group (x±s, n=6)

[0069]

[0070] Experimental results show that the composition of the present invention can significantly inhibit the release of pro-inflammatory factors induced by LPS in BV2 microglia, and the inhibition rates of IL-1β, TNF-α and IL-6 reached 87.2%, 85.8% and 87.0% respectively. The anti-inflammatory effect is significantly better than that of the free drug group and the unmodified vesicle group, which confirms the potent anti-inflammatory activity of the composition and the synergistic effect of the delivery carrier.

[0071] Experiment Example 2: In vivo pharmacodynamic verification experiment

[0072] The in vivo cognitive improvement effect of the composition of the present invention was verified using a classic vascular cognitive impairment model of bilateral common carotid artery permanent ligation (2VO) in SD rats.

[0073] 1. Experimental grouping: Sixty SPF-grade male SD rats were randomly divided into 6 groups, with 10 rats in each group:

[0074] Sham surgery group: Only the bilateral common carotid arteries were separated without ligation, and an equal volume of normal saline was administered by gavage;

[0075] Model group: After successful 2VO modeling, the model was given an equal volume of physiological saline by gavage;

[0076] Positive drug group: After successful 2VO modeling, donepezil (1 mg / kg·d) was administered by gavage;

[0077] Free drug group: After successful 2VO modeling, the same ratio of free active ingredient as in Example 1 was administered by gavage at a dose of 50 mg / kg·d (based on total active ingredient).

[0078] The low-dose group of the present invention: After successful 2VO modeling, the composition prepared in Example 1 was administered by gavage at a dose of 10 mg / kg·d (based on total active ingredients).

[0079] In the high-dose group of this invention: after successful 2VO modeling, the composition prepared in Example 1 was administered by gavage at a dose of 50 mg / kg·d (based on total active ingredients).

[0080] Rats in each group were given medication one week after modeling and continued for four weeks. After the medication was administered, the Morris water maze test was performed to assess the rats' cognitive function. After the experiment, the rats were sacrificed and hippocampal tissue was collected to detect relevant indicators.

[0081] 2. Experimental Results

[0082] (1) Morris water maze test results: As shown in Table 2, the escape latency of rats in the model group was significantly longer than that in the sham-operated group, and the number of platform crossings was significantly less than that in the sham-operated group (P<0.01), confirming the successful establishment of the model; the escape latency of rats in the high-dose group of this invention was shortened by 62.8% compared with the model group, and the number of platform crossings was increased by 2.7 times compared with the model group, and the cognitive improvement effect was significantly better than that in the positive drug group and the free drug group (P<0.05).

[0083]

[0084] (2) Results of hippocampal inflammatory factor detection: As shown in Table 3, the contents of IL-1β and TNF-α in the hippocampus of rats in the high-dose group of the present invention were reduced by 78.2% and 76.5% respectively compared with the model group, and the anti-inflammatory effect was significantly better than that of the positive drug group and the free drug group (P<0.05); at the same time, the expression level of BDNF protein in the hippocampus was increased by 2.3 times compared with the model group, which confirmed the neuroprotective and synaptic repair effects of the composition.

[0085] Table 3 Comparison of relevant indicators of hippocampal tissue in rats of different groups (x±s, n=10)

[0086]

[0087] Test Example 3 Safety Verification Experiment

[0088] 1. Acute toxicity test: 20 SPF-grade ICR mice, half male and half female, were administered the composition prepared in Example 1 of this invention by gavage at a dose of 2000 mg / kg (200 times the clinical dose based on total active ingredients). The mice were observed for 14 consecutive days, and their general condition, diet, and weight changes were recorded. After 14 days, the mice were sacrificed for gross necropsy and observation.

[0089] The results showed that none of the mice died or exhibited abnormal behavior after administration. Their diet and weight gain were normal, and gross anatomical examination revealed no obvious abnormalities in any of the organs, confirming that the composition of the present invention has no acute toxicity.

[0090] 2. Long-term toxicity test: Forty SD rats were randomly divided into a control group and a treatment group, with 20 rats in each group, half male and half female. The treatment group was given the composition prepared in Example 1 of this invention by gavage at a dose of 100 mg / kg·d (10 times the clinical dose based on total active ingredients). The control group was given an equal volume of physiological saline. The administration was carried out for 90 consecutive days.

[0091] The results showed that the rats in each group were in good general condition during the administration period. There were no significant differences in diet, weight, blood routine, and blood biochemical indicators compared with the control group. The organ coefficients and histopathological examinations of the major organs (heart, liver, spleen, lung, kidney, and brain) showed no obvious abnormalities, confirming that the composition of the present invention has no obvious toxic side effects and excellent safety with long-term administration.

[0092] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A pharmaceutical composition targeting neuroinflammation, characterized in that, The composition comprises an active ingredient and a natural nano-delivery carrier for encapsulating or loading the active ingredient. The active ingredient comprises the following raw materials in parts by weight: 20-30 parts of flavin, 2-5 parts of pyrroloquinoline quinone, 10-20 parts of resveratrol, 5-8 parts of phloroglucinol A, 10-15 parts of apigenin, 1-3 parts of crocin, 2-5 parts of quercetin, and 0.3-0.8 parts of citronellol.

2. The pharmaceutical composition targeting neuroinflammation as described in claim 1, characterized in that, The active ingredients include the following raw materials in parts by weight: 25 parts of flavin, 3 parts of pyrrolidone, 15 parts of resveratrol, 6 parts of phloroglucinol A, 12 parts of apigenin, 2 parts of crocin, 3 parts of quercetin, and 0.5 parts of citronellol.

3. The pharmaceutical composition targeting neuroinflammation as described in claim 1, characterized in that, The natural nanodelivery carrier is a plant-derived extracellular vesicle, and the total mass ratio of the active ingredient to the plant-derived extracellular vesicle is 1:(5~20).

4. The pharmaceutical composition targeting neuroinflammation as described in claim 3, characterized in that, The plant-derived extracellular vesicles are any one or more combinations of ginger-derived extracellular vesicles, broccoli-derived extracellular vesicles, and ginseng-derived extracellular vesicles, and the particle size of the plant-derived extracellular vesicles is 30~150nm.

5. The pharmaceutical composition targeting neuroinflammation as described in claim 3, characterized in that, The surface of the plant-derived extracellular vesicles is modified to connect to a brain-targeting molecule, which is selected from any one of lactoferrin, rabies virus glycoprotein-derived peptide RVG29, and transferrin receptor single-domain antibody.

6. A method for preparing a pharmaceutical composition targeting neuroinflammation as described in any one of claims 1 to 5, characterized in that, Includes the following steps: S1. Extraction and purification of plant-derived extracellular vesicles: Take ginger, broccoli or ginseng raw materials, wash, disinfect and crush them, and then homogenize them with isotonic PBS buffer at 2~6℃ at a material-to-liquid ratio of 1:(2~4)g / mL; centrifuge the homogenate sequentially at 2~6℃ at 1000×g for 15min, 4000×g for 25min, and 12000×g for 45min, collect the supernatant, filter it and concentrate it using a tangential flow ultrafiltration system with a molecular weight cutoff of 100kD to obtain vesicle concentrate, purify and remove impurities, collect the vesicle characteristic peak eluent to obtain plant-derived extracellular vesicle solution; S2, Brain-targeted modification: Adjust the phospholipid concentration of the vesicle solution obtained in step S1 to 2-6 mg / mL with isotonic PBS buffer at pH 7.2-7.4, add brain-targeted molecule solution at a mass ratio of total phospholipids in vesicles to brain-targeted molecules of 100:(2-6), and pre-incubate at 2-8°C in the dark for 10 min. The modification was completed by ultrasonic treatment with a probe, followed by incubation at 2-8°C in the dark with stirring at 100-150 rpm for 20-40 minutes. S3. Drug loading: The targeted modified vesicles obtained in step S2 are mixed with the active ingredient, and drug loading is performed by low-temperature incubation-ultrasound method. The mixture is then filtered through a 0.22μm filter membrane for sterilization to obtain the drug composition, or freeze-dried to prepare lyophilized powder.

7. The preparation method according to claim 6, characterized in that, In step S2, the probe ultrasonic power is 50~80W, and a pulse working mode is adopted. The working cycle is 1~3 seconds of ultrasound with an interval of 2~4 seconds. The total ultrasonic processing time is 1~3 minutes, and the ultrasonic process is carried out under ice bath conditions.

8. The preparation method according to claim 6, characterized in that, In step S3, the temperature of the low-temperature incubation-ultrasound is as follows: the low-temperature incubation is carried out at 2~8℃ for 1~4 hours; the ultrasound is pulsed ultrasound with a power of 20~100W, the working cycle is 2~5 seconds on and 5~10 seconds off, the total ultrasound time is 1~3 minutes, and the ultrasound process is carried out under ice bath conditions.

9. The pharmaceutical composition according to claim 1, characterized in that, The dosage form of the composition is any one of oral nanosuspension, oral soft capsule, nasal brain-targeting spray, and intravenous lyophilized powder injection.

10. The use of the pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a medicament for the prevention or adjunctive treatment of neuroinflammatory-related vascular cognitive impairment.

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