A black phosphorus nanosheet drug delivery system for improving the half-life of resveratrol and a preparation method thereof

Abstract

The application provides a black phosphorus nanosheet drug delivery system for improving the half-life of resveratrol and a preparation method thereof.The black phosphorus nanosheet drug delivery system has good drug loading capacity and photothermal effect, and has good drug release capacity under acidic conditions and near-infrared light irradiation conditions.The black phosphorus nanosheet drug delivery system is modified by polydopamine, so that the stability of the black phosphorus nanosheet is improved, and the black phosphorus nanosheet drug delivery system has good stability.The black phosphorus nanosheet drug delivery system can effectively increase the molecular exclusion volume and reduce the renal clearance rate, significantly prolong the in-vivo half-life of resveratrol, and improve the drug bioavailability.The black phosphorus nanosheet drug delivery system does not produce hemolysis effect at a therapeutic concentration, and has good biocompatibility and low toxicity.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a black phosphorus nanosheet drug delivery system for improving the half-life of resveratrol and its preparation method. Background Technology

[0002] Stroke is a neurological deficit syndrome caused by acute vascular or blood abnormalities leading to impaired blood circulation in the brain. It is characterized by high morbidity, high recurrence rate, high disability rate, and high mortality rate. Stroke is one of the leading causes of death and long-term disability worldwide, and the third leading cause of death in China, after malignant tumors and heart disease. Clinically, stroke is divided into ischemic stroke (IS) and hemorrhagic stroke (HS), with IS accounting for up to 70% and being the main type of stroke, primarily caused by cerebral artery embolism. Although the survival rate of stroke patients has exceeded 50% with advancements in medical science, IS remains a major cause of physical injury, leading to neurological disorders and impairing physical and mental functions, including cognition, learning, and memory.

[0003] Only a limited number of drugs have shown real progress in the treatment of ischemic stroke (IS). Intravenous injection of recombinant tissue plasminogen activator (t-PA) or endovascular therapy is currently the only available treatment for acute ischemic stroke, but its narrow therapeutic window and side effects limit its clinical application. While most natural active drugs have shown potential in stroke treatment, they generally suffer from rapid metabolism, short half-life, poor stability, and low bioavailability, making it difficult to maintain effective concentrations in vivo and meet the needs of long-term treatment. Nanocarriers have been studied as drug delivery carriers for treating related diseases and have many advantages, such as good biocompatibility, low toxicity, the ability to load multiple therapeutic drugs, protection of therapeutic drugs from in vivo degradation, and the ability to achieve long-term controlled drug release and improve in vivo pharmacokinetic behavior.

[0004] Among emerging two-dimensional nanomaterials, black phosphorus (BP) is used in various biomedical applications, including photothermal therapy, drug delivery, biosensing, and bioimaging. In the biomedical field, its honeycomb-like, wrinkled structure can effectively increase the loading capacity of drugs, biomolecules, and contrast agents. Moreover, BP is easily degraded in physiological environments and does not cause toxicity to the body. After loading drugs, targeting molecules, and fluorescent molecules, BP nanosheets achieve targeted detection-treatment combined performance and photocontrolled drug release capabilities.

[0005] Black phosphorus (BP) exhibits excellent biocompatibility and biodegradability. Furthermore, under near-infrared laser irradiation, it generates a large number of oxygen free radicals and produces heat, making it a promising candidate for photothermal and photodynamic therapy. With drug loading and surface functionalization, BP nanosheets can achieve stable delivery, long-lasting circulation, and controlled drug release. Therefore, BP can be used as a promising nanomaterial for improving the in vivo behavior of short-half-lived drugs.

[0006] Resveratrol (Res) is a natural polyphenolic active compound widely found in plants such as grapes, Japanese knotweed, and peanuts. It has significant antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective effects, showing good application potential in the prevention and treatment of ischemic stroke. However, resveratrol has prominent drawbacks in vivo, such as a short elimination half-life, rapid metabolism, poor in vivo stability, and low bioavailability. It is easily and rapidly eliminated, making it difficult to maintain effective drug concentrations in the bloodstream and at the lesion site, which seriously limits its long-term efficacy and clinical translation in stroke treatment.

[0007] Black phosphorus (BP) exhibits poor stability. When exposed to air or placed in aqueous solution under light conditions, BP degrades to form non-toxic PxOy oxides, which further react with water in the environment to form phosphoric acid, thus losing its properties and limiting its applications. Therefore, methods are needed to protect its special functions; for example, the surface of BP can be coated to isolate it from air and prevent oxidation. Mussel-inspired polydopamine (PDA) combines biocompatibility and unique adhesive properties. Utilizing a simple self-polymerization-based preparation method, it has the potential to develop into a simple, rapid, and economical nanoparticle platform. PDA exhibits good pH responsiveness, remaining stable under neutral pH conditions (such as blood and tissue fluid), while degrading under slightly acidic microenvironments to release drugs and achieve therapeutic effects. Therefore, PDA can be used as a material to encapsulate black phosphorus, successfully enhancing its stability and allowing for the modification of more functional groups.

[0008] In summary, this invention prepares uniformly sized black phosphorus nanosheets, modifies them with polyethylene glycol (PEG) to reduce renal clearance, loads them with resveratrol, and then modifies their surface with polydopamine (PDA), constructing a black phosphorus nanosheet drug delivery system with excellent stability and significantly improved resveratrol half-life. Using a mouse middle cerebral artery embolism-reperfusion model, the drug content of resveratrol in the brain at different time points after cerebral ischemia / reperfusion in mice under different dosage forms was investigated, providing new insights for the clinical application of resveratrol. Summary of the Invention

[0009] The purpose of this invention is to overcome the shortcomings of the prior art and provide a black phosphorus nanosheet drug delivery system for improving the half-life of resveratrol and its preparation method. The black phosphorus nanosheet drug delivery system of this invention has good photothermal effect, stability, blood-brain barrier permeability and low toxicity, and has good application prospects in the treatment of nervous system diseases and drug delivery.

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows: a black phosphorus nanosheet drug delivery system for improving the half-life of resveratrol and its preparation method. The black phosphorus nanosheet drug delivery system has a sheet-like layered structure. The black phosphorus nanosheets are modified with polyethylene glycol (PEG) to form BP-PEG. The model drug resveratrol (Res) binds to the black phosphorus nanosheets through electrostatic adsorption. Polydopamine (PDA) is coated on the surface of the black phosphorus nanosheets, which is the black phosphorus nanosheet drug delivery system (BP-Res@PDA).

[0011] In some embodiments of the present invention, the mass ratio of the black phosphorus nanosheets to the polyethylene glycol is 1:10.

[0012] In some preferred embodiments of the present invention, the mass ratio of BP-PEG to Res is 1:6.

[0013] In some more preferred embodiments of the present invention, the mass ratio of the BP-Res to the PDA is 1:7.5.

[0014] In some more preferred embodiments of the present invention, the average size of the black phosphorus nanosheets is 100~200 nm.

[0015] In some more preferred embodiments of the present invention, the particle size of the black phosphorus nanosheet-loaded resveratrol composite material is 200~250 nm.

[0016] In some more preferred embodiments of the present invention, the particle size of the polydopamine-modified black phosphorus nanosheet drug delivery system is 250-300 nm.

[0017] This invention proposes a method for preparing a black phosphorus nanosheet drug delivery system for improving the half-life of resveratrol, comprising the following steps:

[0018] Dissolve an appropriate amount of resveratrol in an equal volume of solvent. Centrifuge the polyethylene glycol-modified black phosphorus nanosheet suspension at high speed and low temperature for 30 min, remove the supernatant, add the resveratrol solution, shake under low temperature and in the dark, and centrifuge again at high speed and low temperature to obtain a precipitate. Dissolve an appropriate amount of dopamine hydrochloride in an appropriate amount of pure water, add it to the above precipitate, adjust the pH to 8.5, shake under low temperature and in the dark, centrifuge again at high speed and low temperature, and resuspend the precipitate in ultrapure water to obtain the solution of polydopamine-modified black phosphorus nanosheet drug delivery system (BP-Res@PDA).

[0019] In some embodiments of the present invention, the solvent is selected from at least one of PEG400, ethanol, and DMSO.

[0020] In some preferred embodiments of the present invention, the high-speed low-temperature centrifugation conditions are 12000 rpm, 4℃, and the shaking time in the dark is 48 h.

[0021] In some preferred embodiments of the present invention, the preparation method of the black phosphorus nanosheets includes: weighing black phosphorus powder and dispersing it in an organic solvent, placing it in a mortar, and grinding it at low temperature in the dark; transferring the entire suspension after grinding to an EP tube and adding ice-cold organic solvent; sonicating the resulting black phosphorus suspension in an ice-water bath in the dark, changing the water continuously to maintain the low temperature, and then continuing sonication in a cell disruptor; after completion, removing the suspension and letting it stand overnight at 4 ℃; taking the upper layer of the standing suspension, centrifuging it at low speed and low temperature for 5 min, taking the upper layer liquid, and then centrifuging it twice at high speed and low temperature, replacing NMP with an equal volume of ultrapure water to obtain the black phosphorus nanosheet suspension solution.

[0022] In some preferred embodiments of the present invention, the organic solvent is selected from any one of N-methylpyrrolidone (NMP), dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

[0023] In some preferred embodiments of the present invention, the grinding time is 1 h, the ultrasonic power is 500 W, the ice water bath ultrasonic time is 6 h, and the cell disruptor ultrasonic time is 1 h.

[0024] In some preferred embodiments of the present invention, the low-speed low-temperature centrifugation conditions are 2000 rpm and 4 ℃, and the high-speed low-temperature centrifugation conditions are 15000 rpm and 4 ℃.

[0025] In some more preferred embodiments of the present invention, the method for preparing the polyethylene glycol-modified black phosphorus nanosheets includes: taking a black phosphorus nanosheet (BP) suspension, adding polyethylene glycol (PEG-NH2), sonicating, vortexing and mixing, shaking under low temperature conditions in the dark, centrifuging at high speed and low temperature for 30 min, and removing the supernatant to obtain the PEG-modified black phosphorus nanosheets (BP-PEG).

[0026] In some more preferred embodiments of the present invention, the polyethylene glycol (PEG-NH2) has a molecular weight of 3400.

[0027] In some more preferred embodiments of the present invention, the ultrasonic power is 500 W and the ultrasonic time is 30 min.

[0028] In some more preferred embodiments of the present invention, the light-shielding shaking time is 12 hours, and the high-speed low-temperature centrifugation conditions are 12,000 rpm and 4 °C.

[0029] This invention proposes a stable formulation that can cross the blood-brain barrier, comprising the aforementioned polydopamine-modified black phosphorus nanosheet drug delivery system.

[0030] In this invention, the black phosphorus nanosheet drug delivery system can improve the half-life of resveratrol.

[0031] This invention proposes a black phosphorus nanosheet drug delivery system for improving the half-life of resveratrol, wherein the black phosphorus nanosheet drug delivery system is the aforementioned black phosphorus nanosheet drug delivery system.

[0032] The beneficial effects of this invention are as follows:

[0033] This invention utilizes the principle of electrostatic adsorption to functionalize Res and PEG molecules onto the surface of negatively charged black phosphorus nanosheets, followed by PDA surface modification. This significantly increases the exclusion volume of nanoparticles, reduces renal filtration clearance, achieves stable loading and slow controlled release of resveratrol, effectively prolongs the drug's in vivo half-life, improves bioavailability and cyclic stability, reduces medication risks, and has a therapeutic effect superior to direct administration.

[0034] The black phosphorus nanosheet drug delivery system of the present invention exhibits good stability due to the modification with polydopamine.

[0035] The black phosphorus nanosheet drug delivery system of the present invention may serve as a drug carrier for treating other diseases, thereby enabling targeted therapy of the target disease and becoming a new strategy for treating other neurological diseases. Detailed Implementation

[0036] To better illustrate the purpose, technical solution, and advantages of this invention, the invention will be further described below.

[0037] Unless otherwise specified, the experimental methods used in the embodiments of this invention are conventional methods; the materials and reagents used are commercially available unless otherwise specified.

[0038] In this embodiment of the invention, the preparation method of the polydopamine-modified black phosphorus nanosheet drug delivery system is as follows:

[0039] S1: Preparation of black phosphorus nanosheets (BP):

[0040] BP was prepared using a liquid-phase exfoliation method. 0.1 g of BP was thoroughly ground in a mortar, then treated with an ultrasonic cleaner (500 W) at a constant temperature of 10 °C for 48 h using a circulating water cooler, followed by rotation at 2000 rpm / min for 5 min. The supernatant was collected, and the mixture was rotated again at 15000 rpm for 5 min. The precipitate was collected, and 1 ml of NMP was added. The resulting black phosphorus nanosheet suspension was stored at 4 °C.

[0041] S2: Preparation of resveratrol-loaded black phosphorus nanosheets (BP-Res) composite material

[0042] Take 5 mL of black phosphorus nanosheet (BP) suspension after 6 h of sonication, weigh 10 times the weight of PEG-NH2 (MW: 3400) and add it to the suspension. Sonicate at 500 W for 30 min, vortex for 5 min, and shake at 300 rpm and 4 ℃ in the dark for 12 h. After completion, centrifuge at 12000 rpm and 4 ℃ for 30 min and remove the supernatant. Take 2, 4, 6, 8, and 10 times the weight of resveratrol, respectively, and dissolve them in an equal volume of anhydrous ethanol. Add the resveratrol solution to the BP-PEG precipitate, shake at 300 rpm and 4 ℃ in the dark for 24 h, and centrifuge at 12000 rpm and 4 ℃ for 20 min. Resuspend the precipitate in ultrapure water to obtain the black phosphorus-loaded resveratrol (BP-Res) solution.

[0043] S3: Preparation of a polydopamine-modified black phosphorus nanosheet drug delivery system

[0044] Adjust the pH of the BP-Res solution to 8.5, add 7.5 times the weight of dopamine hydrochloride (based on the weight of black phosphorus), and shake at room temperature in the dark for 12 hours. Centrifuge the sample at 12,000 rpm, 4°C, for 20 minutes, and discard the supernatant. Wash the sample twice with PBS under the same centrifugation conditions, collect the precipitate, and resuspend it in ultrapure water to obtain the polydopamine-modified black phosphorus nanosheet drug delivery system (BP-Res@PDA) solution.

[0045] Experimental Example 1

[0046] This experimental example analyzes the structural characteristics and properties of intermediates and products prepared in the example preparation process.

[0047] Electron microscopy was performed on black phosphorus nanosheets, black phosphorus nanosheets loaded with resveratrol (BP-Res), and polydopamine-modified black phosphorus nanosheets (BP-Res@PDA).

[0048] Black phosphorus crystals have a low-layered, plate-like structure with good dispersibility. After drug loading, it is clear that the drug has been successfully loaded. Polydopamine uniformly encapsulates the black phosphorus nanosheets, with an average overall size and no change in the layered structure.

[0049] To investigate the effect of different drug-to-black phosphorus ratios on the overall drug loading rate, drug loading was achieved by administering Res doses of 2, 4, 6, 8, and 10 times the mass of black phosphorus nanosheets.

[0050] When BP:Res = 1:6 (w / w%), the drug loading rate is 89.5%, reaching its maximum. When BP:Res = 1:6, the absorption peak of the full wavelength spectrum is the highest.

[0051] Particle size distribution and potential distribution of black phosphorus nanosheets, black phosphorus nanosheets loaded with resveratrol (BP-Res), and polydopamine-modified black phosphorus nanosheets (BP-Res@PDA) were analyzed.

[0052] The dimensions of black phosphorus nanosheets were 255.7 ± 3.9 nm, BP-Res were 263.1 ± 2.3 nm, and BP-Res@PDA were 277.9 ± 7.8 nm. No significant volume change was observed in the black phosphorus nanosheets after drug loading and PDA modification. The Zeta potential of black phosphorus nanosheets was -22.9 ± 1.2 mV, that of BP-Res was -17.6 ± 0.7 mV, and that of BP-Res@PDA was -20.5 ± 2.0 mV. The absolute values ​​of the Zeta potentials of drug-loaded BP-Res and polydopamine-modified BP-Res@PDA were lower than those of pure black phosphorus nanosheets.

[0053] To compare the photothermal effects of black phosphorus nanosheets and polydopamine-modified black phosphorus nanosheet composites, the temperature changes of PBS, black phosphorus nanosheet solutions, and polydopamine-modified black phosphorus nanosheet drug delivery system solutions under near-infrared laser irradiation were investigated. The effects of different power near-infrared laser irradiations on the temperature of the polydopamine-modified black phosphorus nanosheet drug delivery system solution were also examined. Furthermore, the temperature changes of polydopamine-modified black phosphorus nanosheet drug delivery system solutions with different concentrations under near-infrared laser irradiation were investigated, as well as the temperature changes of the polydopamine-modified black phosphorus nanosheet drug delivery system solution during five cycles of near-infrared light switching.

[0054] Compared to the PBS group, the temperature change of the black phosphorus nanosheet drug delivery system was smaller than that of the polydopamine-modified black phosphorus nanosheet drug delivery system. With increasing power, the temperature of the polydopamine-modified black phosphorus nanosheet drug delivery system solution increased significantly after 10 minutes of irradiation. With increasing solution concentration, the temperature of the polydopamine-modified black phosphorus nanosheet drug delivery system solution also increased significantly after 10 minutes of irradiation. In the five cycles of near-infrared laser irradiation, the temperature rose gradually with no significant difference in the maximum temperature, indicating good stability.

[0055] To investigate the stability of black phosphorus nanosheets, black phosphorus nanosheets loaded with resveratrol composites, and polydopamine-modified black phosphorus nanosheet drug delivery system solutions, changes were compared at 1, 4, and 7 days using ultraviolet light across the entire wavelength range.

[0056] Black phosphorus nanosheets exhibited significant changes across the entire wavelength range over a week, indicating relative instability. The resveratrol-loaded black phosphorus nanosheet composite showed a higher wavelength across the entire wavelength range on day 7 compared to day 4, but both were lower than on day 1, suggesting further instability. The drug delivery system solution based on polydopamine-modified black phosphorus nanosheets showed a gradual increase in the entire wavelength range, demonstrating better stability. This is attributed to the polydopamine modification on the black phosphorus surface, which enhances the stability of the black phosphorus nanosheets.

[0057] Experimental Example 2

[0058] This study evaluates the biosafety of polydopamine-modified black phosphorus nanosheet drug delivery systems (BP-Res@PDA) at different concentrations.

[0059] To investigate the hemolysis rate of polydopamine-modified black phosphorus nanosheet drug delivery systems (BP-Res@PDA) at different concentrations, a hemolysis experiment was conducted. Mouse blood was collected in heparin sodium EP tubes and centrifuged at 1500 rpm, 4°C for 10 min. The supernatant was discarded to obtain mouse red blood cells, which were washed 2-3 times with physiological saline until the supernatant was clear. The purified red blood cells were prepared into a 4% red blood cell suspension, and appropriate amounts of the suspension were transferred to EP tubes for later use. The hemolysis experiment consisted of 6 groups: negative group (100 μL of physiological saline was added to the tube); positive group (100 μL of ultrapure water was added to the tube); and different concentrations of BP-Res@PDA groups (100 μL of BP-Res@PDA (50, 100, 150, 200 μg / ml) PBS suspension was added to the tube. All groups were incubated simultaneously in a 37 ℃ incubator for 3 h. After incubation, the samples were centrifuged at 2500 rpm and 4 ℃ for 5 min. 200 μL of each sample was accurately pipetted into a 96-well plate, and the OD value at 540 nm was measured. The hemolysis rate was then calculated.

[0060] The hemolysis rate of BP-Res@PDA did not exceed 5% with increasing concentration, and it did not show obvious hemolysis.

[0061] Experimental Example 3

[0062] This study evaluated the drug content in the blood and brain of mice in the resveratrol administration group and the near-infrared irradiation polydopamine-modified black phosphorus nanosheet drug delivery system group to assess whether it could cross the blood-brain barrier.

[0063] To investigate the blood-brain barrier permeability of the polydopamine-modified black phosphorus nanosheet drug delivery system, UPLC was used to measure the drug content. For the preparation of the Res standard curve: 10.0 mg of Res was accurately weighed and placed in a 10 ml volumetric flask. Methanol was added to dissolve the Res and the solution was diluted to the mark, resulting in a stock solution concentration of 1.0 mg / ml. Corresponding series of Res concentrations (5, 10, 20, 40, 60, 90 μg / ml) were prepared, resulting in a tissue drug concentration gradient of 0.5, 1, 2, 4, 6, and 9 μg / ml. The preparation of the Res gradient concentrations should be performed at room temperature, under which Res exhibits good stability. A linear regression was performed on the peak area (Y, A) of the Res standard reference against the corresponding concentration (X, μg / ml) to obtain the tissue standard curve equation. Determination of Res drug concentration in blood and brain tissue: Mice were divided into two groups (n=3): ① Res group; ② BP-Res@PDA+NIR irradiation group. All mice were injected with the drug via the tail vein, and group ② was irradiated with an 808 nm laser (1 W cm²) for 10 min. Plasma samples were collected from the tail vein at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 h after drug administration. Brain samples were collected after cardiac perfusion at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h. Tissue homogenates were prepared and proteins were removed. The Res content in all samples was measured using UPLC. Pharmacokinetic parameters, including peak concentration of Res in plasma or brain (Cmax), elimination half-life (T1 / 2), area under the Res concentration-time curve in plasma or brain (AUC0-t), and mean residence time (MRT0-t), were calculated using DAS (Drug and Statistics) 2.0 software.

[0064] The Res content in plasma of the monotherapy group was higher than that of the formulation group, and the pharmacokinetic parameters were also higher in the monotherapy group. In brain tissue, the Res content of the formulation group was significantly higher than that of the monotherapy group, and the pharmacokinetic parameters also indicate that more Res can be delivered to the brain from the formulation. Therefore, it can be concluded that, compared with monotherapy, the polydopamine-modified black phosphorus nanosheet drug delivery system can cross the blood-brain barrier to reach the brain and release the drug.

Claims

1. A black phosphorus nanosheet drug delivery system for improving the half-life of resveratrol, characterized in that... Black phosphorus nanosheets with a sheet-like structure, after being modified with polyethylene glycol (PEG), bind to the model drug resveratrol via electrostatic adsorption. Polydopamine (PDA) is then used to further modify the surface of the black phosphorus nanosheets. This black phosphorus nanosheet drug delivery system exhibits good stability. Due to the steric hindrance of the PEG chains, the molecular exclusion volume of the modified molecules significantly increases, resulting in a significant reduction in renal filtration clearance and thus increasing the half-life of resveratrol.

2. The black phosphorus nanosheet drug delivery system as described in claim 1, characterized in that: The black phosphorus nanosheets have a particle size of 100~200 nm.

3. The black phosphorus nanosheet drug delivery system as described in claim 1, characterized in that: The particle size of the black phosphorus nanosheets loaded with resveratrol composite material is 200~250 nm.

4. The black phosphorus nanosheet drug delivery system as described in claim 1, characterized in that: The particle size of the polydopamine-modified black phosphorus nanosheet composite material is 250~300 nm.

5. The black phosphorus nanosheet drug delivery system as described in claim 1, characterized in that: The mass ratio of the black phosphorus nanosheets to the PEG is 1:

10.

6. The black phosphorus nanosheet drug delivery system as described in claim 1, characterized in that: The mass ratio of the black phosphorus nanosheets to the resveratrol is 1:6, and the mass ratio of the resveratrol to the polydopamine is 1:7.

5.

7. A method for preparing a black phosphorus nanosheet drug delivery system as described in claims 1-6, characterized in that: The preparation method of the polydopamine-modified black phosphorus nanosheet drug delivery system is as follows: Take an appropriate amount of black phosphorus nanosheet solution, centrifuge, and collect the supernatant. Take an appropriate amount of polyethylene glycolamine, dissolve it in pure water, add it to the black phosphorus nanosheet precipitate, shake it in the dark under low temperature conditions, and then centrifuge it at high speed and low temperature to obtain the precipitate. Take an appropriate amount of resveratrol, dissolve it in an equal volume of solvent, add the resveratrol solution to the polyethylene glycol-modified black phosphorus nanosheet precipitate, shake it in the dark under low temperature conditions, and then centrifuge it at high speed and low temperature to obtain the precipitate. Take an appropriate amount of dopamine hydrochloride, dissolve it in an appropriate amount of pure water, add it to the above precipitate, adjust the pH to 8.5, shake it in the dark under low temperature conditions, centrifuge it at high speed and low temperature, and then resuspend the precipitate in ultrapure water to obtain the solution of the polydopamine-modified black phosphorus nanosheet drug delivery system (BP-Res@PDA).

8. The method for preparing the black phosphorus nanosheet drug delivery system as described in claim 7, characterized in that: The solvent is selected from at least one of PEG400, ethanol, and dimethyl sulfoxide (DMSO).

9. The preparation method of the black phosphorus nanosheet drug delivery system as described in claim 7, characterized in that: The high-speed low-temperature centrifugation conditions are 12000 rpm and 4 ℃, and the shaking time in the dark is 12 h or 48 h.

10. The application of a polydopamine-modified black phosphorus nanosheet drug delivery system as described in any one of claims 1 to 6 in improving the half-life of resveratrol.