Preparation method of polysaccharide-modified metal organic framework carrier of pH-responsive nutritional factor-loaded liposome

Abstract

The invention belongs to the technical field of biological materials, and provides a preparation method of a polysaccharide modified metal organic framework carrier of pH response type trophic factor-loaded liposome. Comprising the following steps: preparing a lipidosome carrier loaded with nutritional factors through a film hydration method, and combining the lipidosome carrier with a metal organic framework to obtain a metal organic framework loaded with nutritional factor lipidosome; the preparation method comprises the following steps: dispersing the metal organic framework loaded with the nutritional factor liposome into a polysaccharide composite solution, slowly stirring, centrifuging, washing and drying to obtain the polysaccharide modified metal organic framework carrier of the pH response type nutritional factor liposome, so that adverse effects on a human body due to excessive intake of cholesterol can be avoided; meanwhile, under the synergistic interaction of the lipidosome, the metal organic framework and the polysaccharide, the stability of the nutritional factors in the gastrointestinal tract environment is improved, and the biological accessibility of the nutritional factors is improved.

Description

Technical Field

[0001] This invention belongs to the field of biomaterials technology, and particularly relates to a method for preparing a polysaccharide-modified metal-organic framework carrier for pH-responsive nutrient factor liposomes. Background Technology

[0002] Nutritional factors possess powerful physiological functions such as anti-inflammation, anti-oxidation, anti-tumor, and lipid-lowering effects, and various delivery systems have been developed to package, protect, and release them. However, some nutritional factors face challenges such as strong hydrophobicity, poor stability, off-flavors and unpleasant sensory properties, and low oral bioavailability, which affect their application.

[0003] The nutrient carriers prepared by related technologies are very fragile in the face of gastric acid and bile salts. The metal-organic framework is structurally unstable in acidic gastric juice and will decompose rapidly. At the same time, the bioavailability of nutrient factors is low after digestion in the gastrointestinal tract. Furthermore, excessive intake of cholesterol, a common raw material for liposomes, will increase the risk of cardiovascular and cerebrovascular diseases and atherosclerosis. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing a polysaccharide-modified metal-organic framework carrier for pH-responsive liposomes carrying nutrients, in order to solve the problems that existing metal-organic frameworks are structurally unstable in acidic gastric juice, decompose rapidly, and have low bioavailability of nutrients after gastrointestinal digestion.

[0005] The objective of this invention is achieved as follows: In a first aspect, a method for preparing a polysaccharide-modified metal-organic framework carrier for pH-responsive nutrient factor liposomes is disclosed, comprising the following steps: Step S1: Dissolve phospholipids, phytosterols and nutrients in ethanol, and rotary evaporate the resulting mixture under vacuum until the ethanol is completely removed to form a uniform liposome film carrying nutrients. Hydrate the liposome film with a phosphate buffer solution containing Tween-80 to form crude liposomes. Step S2: After sonicating the crude liposome carrier carrying the nutrient factors in a low-temperature water bath, a liposome carrier for delivering the nutrient factors is further obtained. Step S3: The liposome carrier carrying the nutrient factor is mixed with a mixed solution containing cetyltrimethylammonium bromide (CTAB) and 2-methylimidazole. Then, zinc acetate dihydrate solution is rapidly injected into the mixture of 2-methylimidazole, CTAB and the liposome carrier carrying the nutrient factor. After gentle stirring and standing, the mixture is centrifuged and washed multiple times and dried to obtain the metal-organic framework carrier carrying the liposome of the nutrient factor. Step S4: The polysaccharide solution is slowly added dropwise to the metal-organic framework carrier carrying nutrient factor liposomes while stirring. Then, the mixture is centrifuged, washed, and dried to obtain a polysaccharide-modified metal-organic framework carrier carrying pH-responsive nutrient factor liposomes.

[0006] This invention designs a multi-level, multifunctional nanodelivery system. Its core innovation lies in the ingenious combination of the encapsulation and sustained-release capabilities of liposomes, the high loading and protection capabilities of metal-organic frameworks, and the biocompatibility and targeted modification capabilities of polysaccharides. This "three-in-one" strategy aims to synergistically solve the key challenges faced in nutrient delivery in the food industry, addressing the problems of low bioavailability caused by excessive cholesterol intake and premature release of nutrient factors in existing technologies.

[0007] Oral, transdermal, and injection drug delivery systems each have their unique advantages and application scenarios. However, oral drug delivery shows significant advantages in terms of patient acceptance, ease of use, system integration, and production feasibility. While transdermal and injection drug delivery have high bioavailability, they still have many drawbacks. Injection drug delivery is limited by drug properties and skin barrier due to pain, the need for professional operation, and poor drug compliance in some cases. Transdermal drug delivery increases the complexity and irritation of the drug delivery system and has a limited drug loading capacity. Oral delivery is the most natural method of drug delivery. pH-responsive systems cleverly utilize the natural physiological signal of pH gradient in different sections of the gastrointestinal tract to achieve programmed release, which is similar to the intestinal absorption mechanism of nutrients. Oral drug delivery research is developing from simple dosage forms to intelligent and precise methods, overcoming its traditional limitations while maintaining the convenience of oral drug delivery, and providing patients with more optimized treatment options.

[0008] Further, the phospholipid mentioned in step S1 is soybean lecithin SL; The nutritional factors mentioned are lutein, anthocyanins, lycopene, curcumin, astaxanthin, or resveratrol. The phytosterols mentioned are stigmasterol, β-sitosterol, rapeseed sterol, or campesterol.

[0009] Furthermore, in step S1, the concentration ratio of phospholipids, phytosterols, and nutritional factors is 9:1:1; and the vacuum degree is 0.01 MPa. The phosphate buffer solution containing Tween-80 contains 0.2 wt% Tween-80. After adding the phosphate buffer solution containing Tween-80, the concentration of the nutrient factor in the liposome suspension is 1 mg / mL.

[0010] Furthermore, the power of the low-temperature water bath ultrasound in step S2 is 300W. It is turned on for 1 second and then turned off for 2 seconds. Then it is turned on again for 1 second and then turned off for 2 seconds. This cycle is repeated for 5 minutes. The temperature of the low-temperature water bath ultrasound is 4℃.

[0011] Further, the specific method for mixing the liposome carrier carrying the nutrient factor with a mixed solution containing hexadecyltrimethylammonium bromide (CTAB) and 2-methylimidazole in step S3, followed by rapidly injecting a zinc acetate dihydrate solution into the mixture of 2-methylimidazole, CTAB, and the liposome carrying the nutrient factor, gently stirring, allowing it to stand, centrifuging and washing multiple times, and drying to obtain the metal-organic framework carrier carrying the liposome carrying the nutrient factor is as follows: S3-1: First, dissolve 1-3 g of 2-methylimidazole and 0.5-1.5 mg of CTAB in 5-20 mL of deionized water and stir slowly for a period of time. Then, add 0.5-3 mL of liposomes carrying nutritional factors to the above mixed solution. S3-2: Dissolve 0.5-1.5 g of zinc acetate dihydrate in 5-20 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB, and liposomes carrying nutrient factors. Stir gently and let stand for 20-50 seconds. Let stand for 1-3 hours. After 2-5 centrifugations at 10000-15000 g for 10-15 minutes, dry the mixture to obtain a metal-organic framework carrier carrying liposomes carrying nutrient factors.

[0012] Further, the polysaccharide mentioned in step S4 is soybean seed coat polysaccharide (SHP), low-ester pectin (PC), xanthan gum (XG), gum arabic (GA), or hyaluronic acid (HA).

[0013] Further, the specific method for slowly adding the polysaccharide solution dropwise to the metal-organic framework carrier carrying nutrient-carrying liposomes in step S4, while stirring, and then centrifuging, washing, and drying to obtain the pH-responsive nutrient-carrying liposome polysaccharide-modified metal-organic framework carrier is as follows: S4-1: Take a polysaccharide solution with a concentration of 2.0-5.0 mg / mL, and adjust the pH of the polysaccharide solution to 4.0-11.0 with 1.0 M NaOH; S4-2: Slowly add the adjusted polysaccharide solution dropwise to the metal-organic framework carrier carrying liposomes while stirring until the volume ratio of the polysaccharide solution to the metal-organic framework carrier carrying liposomes reaches 1:1. Stop adding the solution and stir for another 1.5-3 hours. Then, centrifuge and wash 2-3 times at a centrifugation force of 10,000-15,000 g for 10-15 minutes. After drying, obtain the pH-responsive polysaccharide-modified metal-organic framework carrier carrying liposomes.

[0014] Secondly, the present invention provides a polysaccharide-modified metal-organic framework carrier for pH-responsive nutrient-carrying liposomes, wherein the carrier has a core-shell structure, the core being a liposome carrying nutrient factors; the middle layer is a metal-organic framework covering the liposomes; and the outer layer is a pH-responsive polysaccharide coating covering the metal-organic framework. The carrier is structurally stable in the acidic environment of the stomach and achieves targeted release of nutrient factors in the neutral or weakly alkaline environment of the intestine.

[0015] Compared with the prior art, the present invention has the following advantages: This invention provides a polysaccharide-modified metal-organic framework (MOF) carrier based on pH-responsive nutrient-carrying liposomes. The liposomes form the inner "compartment," encapsulating and protecting the nutrient factors; the MOF acts as the middle "armor," providing mechanical strength and controlled release capability; and the polysaccharide forms the outer "smart shield," endowing it with gastrointestinal targeting capabilities. In other words, the efficient encapsulation and protection of nutrient factors by the liposomes, the "armor" function of the MOF, and the "buffering" and "barrier" functions of the polysaccharide layer construct a multi-layered, multi-functional protective barrier capable of withstanding the complex and harsh environments of food processing and the human gastrointestinal tract, ultimately achieving efficient, stable, precise, and safe delivery of nutrient factors. The polysaccharide-modified MOF carrier based on pH-responsive nutrient-carrying liposomes provided by this invention can be used for the stable delivery of various nutrient factors. Attached Figure Description

[0016] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 This is a simplified schematic diagram of the polysaccharide-modified metal-organic framework carrier of pH-responsive nutrient factor liposomes in this invention. Figure 2 Zeta potential of different polysaccharides (A); Zeta potential of different carriers (B); Encapsulation efficiency (EE) of lutein by different carriers (%) (C); Figure 3 The DPPH scavenging rates (%) of lutein, different polysaccharides, and different carriers are shown in Figures A and B. Figure 4 The Fourier transform infrared spectrum of the material; Figure 5 The images show the scanning electron microscope (AD) image and energy-dispersive X-ray (EH) spectrum of the material. Figure 6The X-ray diffraction pattern of the material; Figure 7 The Fourier transform infrared spectrum of the material; Figure 8 The lutein release curves of different carriers under different pH conditions are shown. Detailed Implementation

[0018] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art.

[0019] This invention provides a method for preparing a polysaccharide-modified metal-organic framework (MOF) carrier carrying pH-responsive nutrient factor liposomes, comprising the following steps: preparing a liposome carrier carrying nutrient factors and combining it with a MOF to obtain a MOF carrying nutrient factor liposomes; dispersing the MOF carrying nutrient factor liposomes into a pH-responsive polysaccharide composite solution, slowly stirring, centrifuging, washing, and drying to obtain the pH-responsive polysaccharide-modified MOF carrier carrying pH-responsive nutrient factor liposomes. The pH-responsive polysaccharide-modified MOF carrier carrying pH-responsive nutrient factor liposomes provided by this invention has a simple procedure and exhibits good stability and uniform particle size distribution. It avoids the adverse effects of excessive cholesterol intake on the human body and combines the advantages of polysaccharides, liposomes, and MOFs, overcoming the limitations of single delivery systems. While loading nutrient factors, it also improves the stability of nutrient factors in the gastrointestinal environment, controls their release rate to achieve targeted release, and improves the bioavailability of nutrient factors.

[0020] Liposomes are an important and widely studied food delivery system, typically composed of one or more phospholipid bilayers. Their bilayer structure, assembled like a cell membrane, reduces the side effects of the loaded substances and improves their environmental stability, exhibiting high biodegradability and biocompatibility in vivo. However, their inherent drawbacks limit their widespread application. Phospholipid bilayers are prone to aggregation and fusion during storage, processing, or the gastrointestinal environment, leading to structural damage. In the highly acidic environment of the stomach, and under the influence of bile salts and lipases, encapsulated nutrients are often released in large quantities before reaching the small intestine absorption site, limiting bioavailability. Furthermore, the current development of food-grade liposomes is constrained by the potential health risks of cholesterol. Phytosterols, as ideal alternatives, not only possess similar membrane stabilizing functions but also effectively lower serum cholesterol levels by inhibiting cholesterol synthesis, better meeting the development needs of health foods. Metal-organic frameworks (MOFs) carrying nutrients are emerging and promising materials, but their application in food requires extreme caution. Some MOFs decompose rapidly in acidic environments, causing premature release of nutrients in the stomach. The composite system consists of a metal-organic framework (MOF) for polysaccharide-modified liposomes loaded with nutrients. The liposomes act as primary protection, encapsulating hydrophilic or hydrophobic nutrients within them. The MOF provides sufficient rigidity to prevent premature leakage of the nutrients loaded within the liposomes. The polysaccharide coating acts as a stabilizer to ensure system stability. This system can be used as a drug delivery system that adheres to mucous membranes, while also imparting pH responsiveness to the carrier to increase its residence time in the gastrointestinal tract, thereby enhancing absorption after oral administration and improving the bioavailability of nutrients.

[0021] In this invention, because the pH-responsive nutrient-carrying liposome polysaccharide-modified metal-organic framework (MOF) carrier suspension passes through the oral cavity in a very short time, oral digestion is not considered. Upon entering the stomach, the nutrient-carrying liposomes are protected from gastric acid and pepsin attacks by the MOF. Simultaneously, the protonation effect of the polysaccharide reduces electrostatic repulsion between carrier particles at low pH levels, preventing premature leakage of the nutrient and inhibiting its release. Subsequently, in the neutral / weakly alkaline environment of the intestine, the deprotonation of the polysaccharide induces stronger electrostatic repulsion between carrier particles, causing the carrier particles to gradually dissociate. Under the combined action of bile salts and intestinal enzymes, bile salts permeate into the polysaccharide network, while the MOF framework begins to disintegrate. Pancreatic enzymes (such as esterases and lipases) may accelerate the degradation of organic ligands in the MOF and the digestion of the liposome membrane, permeating into the liposome membrane to form mixed micelles, leading to the gradual dissociation of the liposome structure. The micelles are further absorbed by intestinal cells, achieving targeted release of the nutrient and improving its bioavailability.

[0022] This invention provides a method for preparing a polysaccharide-modified metal-organic framework carrier for pH-responsive nutrient factor liposomes, the method comprising the following steps: Step S1: Dissolve phospholipids, phytosterols and nutrients in ethanol, and rotary evaporate the resulting mixture under vacuum until the ethanol is completely removed to form a uniform liposome film carrying nutrients. Hydrate the liposome film with a phosphate buffer solution containing Tween-80 to form crude liposomes. Step S2: After sonicating the crude liposome carrier loaded with nutrient factors in a low-temperature water bath, the liposome carrier loaded with nutrient factors is further homogenized to obtain a liposome carrier loaded with nutrient factors. Step S3: The liposome carrier carrying the nutrient factor is mixed with a mixed solution containing cetyltrimethylammonium bromide (CTAB) and 2-methylimidazole. Then, zinc acetate dihydrate solution is rapidly injected into the mixture of 2-methylimidazole, CTAB and the liposome carrier carrying the nutrient factor. After gentle stirring and standing, the mixture is centrifuged and washed multiple times and dried to obtain the metal-organic framework carrier carrying the liposome of the nutrient factor. Step S4: The polysaccharide solution is slowly added dropwise to the metal-organic framework carrier carrying nutrient factor liposomes while stirring. Then, the mixture is centrifuged, washed, and dried to obtain a polysaccharide-modified metal-organic framework carrier carrying pH-responsive nutrient factor liposomes.

[0023] Alternatively, crude liposome carriers for delivering nutrient factors from phytosterols can be prepared by thin-film hydration.

[0024] Optionally, the phospholipid mentioned in step S1 is soybean lecithin SL.

[0025] Optionally, the nutrient factor mentioned in step S1 is lutein, anthocyanin, lycopene, curcumin, astaxanthin, or resveratrol.

[0026] Optionally, the phytosterols mentioned in step S1 are stigmasterol, β-sitosterol, rapeseed sterol, or campesterol.

[0027] Optionally, the concentration ratio of phospholipids, phytosterols and nutritional factors in step S1 is 9:1:1; Optionally, the vacuum level in step S1 is 0.01 MPa.

[0028] Optionally, the phosphate buffer solution containing Tween-80 in step S1 contains 0.2 wt% Tween-80, and after adding the phosphate buffer solution containing Tween-80, the concentration of the nutrient factor in the liposome suspension is 1 mg / mL.

[0029] Optionally, the power of the low-temperature water bath ultrasound in step S2 is 300W. It is turned on for 1 second and then turned off for 2 seconds. Then it is turned on again for 1 second and then turned off for 2 seconds. This cycle is repeated for 5 minutes.

[0030] Optionally, the temperature of the low-temperature water bath ultrasound in the step is 4°C.

[0031] Optionally, the specific method for mixing the liposome carrier carrying the nutrient factor with a mixed solution containing CTAB and 2-methylimidazole in step S3, followed by rapidly injecting a zinc acetate dihydrate solution into the mixture of 2-methylimidazole, CTAB, and the liposome carrying the nutrient factor, gently stirring, allowing it to stand, centrifuging and washing multiple times, and drying to obtain the metal-organic framework carrier carrying the liposome carrying the nutrient factor is as follows: S3-1: First, dissolve 1-3 g of 2-methylimidazole and 0.5-1.5 mg of CTAB in 5-20 mL of deionized water and stir slowly for a period of time. Then, add 0.5-3 mL of liposomes loaded with nutrient factors to the above mixed solution.

[0032] S3-2: Dissolve 0.5-1.5 g of zinc acetate dihydrate in 5-20 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB, and liposomes carrying nutrient factors. Stir gently and let stand for 20-50 seconds. Let stand for 1-3 hours. After 2-5 centrifugations at 10000-15000 g for 10-15 minutes, dry the mixture to obtain a metal-organic framework carrier carrying liposomes carrying nutrient factors.

[0033] Preferably, as verified by experiments, 1.86 g of 2-methylimidazole and 0.92 mg of CTAB are dissolved in 8 mL of deionized water and stirred slowly, and then 1 mL of liposomes containing the nutritional factor is added.

[0034] Preferably, as verified by experiments, 0.5 g of zinc acetate dihydrate is dissolved in 8 mL of deionized water and rapidly injected into a mixture of 2-methylimidazole, CTAB, and nutrient-carrying liposomes. After gentle stirring, the mixture is allowed to stand for 30 seconds and 2 hours. If zinc acetate dihydrate is mixed with the liposomes beforehand, it may disrupt the stability of the liposomes. 2+As a metal ion, it may catalyze the hydrolysis of phospholipid bonds; thorough stirring can avoid excessively high local concentrations, preventing the formation of irregular and uneven metal-organic framework crystals or causing liposomes to aggregate and be destroyed due to local high ionic strength; too short a stirring time may lead to uneven mixing, while too long a stirring time may damage the fragile crystal structure that has already formed; the settling stage is a critical period for the growth, maturation and structural reorganization of metal-organic framework crystals; if the settling time is too short, the metal-organic framework shell may be too thin and porous, unable to provide effective protection; if the settling time is too long, the metal-organic framework shell may be too thick, resulting in poor stability of the complex.

[0035] Optionally, the polysaccharide mentioned in step S4 is soybean hull polysaccharide (SHP), low-easter pectin (PC), xanthan gum (XG), gum arabic (GA), or hyaluronic acid (HA).

[0036] Optionally, the specific method for slowly adding the polysaccharide solution dropwise to the metal-organic framework carrier carrying nutrient-carrying liposomes in step S4, while stirring, and obtaining the pH-responsive nutrient-carrying liposome polysaccharide-modified metal-organic framework carrier after centrifugation, washing, and drying is as follows: S4-1: Take a polysaccharide solution with a concentration of 2.0-5.0 mg / mL and adjust the pH of the polysaccharide solution to 4.0-11.0 with 1.0 M NaOH.

[0037] S4-2: Slowly add the adjusted polysaccharide solution dropwise to the metal-organic framework carrier carrying liposomes while stirring until the volume ratio of the polysaccharide solution to the metal-organic framework carrier carrying liposomes reaches 1:1. Stop adding the solution and stir for another 1.5-3 hours. Then, centrifuge and wash 2-3 times at a centrifugation force of 10,000-15,000 g for 10-15 minutes. After drying, obtain the pH-responsive polysaccharide-modified metal-organic framework carrier carrying liposomes.

[0038] Preferably, the pH of the polysaccharide solution is adjusted to 8.0.

[0039] Preferably, when preparing the polysaccharide-modified metal-organic framework (MOF) carrier for pH-responsive nutrient factor liposomes, the polysaccharide solution concentration is preferably 2.5 mg / mL. The polysaccharide concentration determines whether the polysaccharide coating of the pH-responsive polysaccharide-modified MOF carrier for nutrient factor liposomes can be successfully constructed, and ultimately affects the stability, gastrointestinal release efficiency, and bioavailability of the nanocomposite carrier. If the polysaccharide concentration is too low, there will not be enough polysaccharide molecules to cover all the MOF surfaces of the nutrient factor liposomes. The polysaccharide molecules cannot fully form coordination bonds with the metal ions on the surface of the MOF nanoparticles through electrostatic interactions, thus modifying the nanodelivery system with polymers. This leads to decreased stability and particle aggregation. If the polysaccharide concentration is too high, too many polysaccharide chains may be adsorbed onto the surfaces of multiple particles simultaneously, causing particle aggregation. At the same time, a high polysaccharide concentration will increase the solution viscosity, affecting mixing efficiency. Excessive polysaccharide may also form a gel in the solution, further promoting particle aggregation.

[0040] Preferably, as verified by experiments, when dispersing the metal-organic framework carrier carrying nutrient factor liposomes into the polysaccharide solution, a 1:1 (V:V) mixing ratio is used, and the optimal stirring time is 2 h. If the stirring time is too short, the polysaccharide molecules cannot fully form coordination bonds with the metal ions on the surface of the metal-organic framework nanoparticles through electrostatic interactions, thus modifying the nanodelivery system with polymers, resulting in an uneven polysaccharide coating and insufficient protection of the metal-organic framework carrier carrying nutrient factor liposomes. At the same time, if the stirring time of the mixed solution of polysaccharide and metal-organic framework carrier carrying nutrient factor liposomes is too long, the adsorbed long polysaccharide chains may desorb, and a long polysaccharide chain may be adsorbed onto multiple particles at the same time, causing the particles to aggregate and destroying the stability of the system.

[0041] The present invention also provides a polysaccharide-modified metal-organic framework carrier for pH-responsive nutrient factor-carrying liposomes. The carrier has a core-shell structure, with the core being a liposome carrying nutrient factors; the middle layer is a metal-organic framework covering the liposomes; and the outer layer is a pH-responsive polysaccharide coating covering the metal-organic framework. The carrier is structurally stable in the gastric acid environment and achieves targeted release of nutrient factors in the neutral or weakly alkaline environment of the intestine.

[0042] Specifically, using the above-mentioned method for preparing liposome-loaded metal-organic framework carriers, a polysaccharide-modified metal-organic framework carrier carrying pH-responsive nutrient factor liposomes was prepared. This not only avoids the adverse effects of excessive cholesterol intake on the human body, but also improves the stability of nutrient factors in the gastrointestinal environment and enhances their bioavailability through the synergistic effect of liposomes, metal-organic frameworks, and polysaccharides.

[0043] like Figure 1As shown, taking lutein as an example, this invention proposes a method for preparing a polysaccharide-modified metal-organic framework carrier for pH-responsive nutrient factor liposomes, comprising the following steps: (1) Steroidal stigmasterol-stabilized lutein liposomes (Lu-lip) were prepared by thin-film evaporation; (2) Lu-lip was combined with a zeolitic imidazolate framework-8 (ZIF-8) to obtain (ZIF-8-encapsulated lutein liposomes, ZIF-8@Lu-lip); (3) ZIF-8@Lu-lip was dispersed in a polysaccharide solution, stirred, centrifuged, washed, and dried to obtain a pH-responsive polysaccharide-modified metal-organic framework carrier carrying lutein liposomes (ZIF-8@Lu-lip@polysaccharides, ZIF-8@Lu-lip@PC, ZIF-8@Lu-lip@SHP, ZIF-8@Lu-lip@XG). This renewable composite material shows potential advantages in the fields of food, environmental protection, and pharmaceutical formulation. In addition, due to the safety, biodegradability, and availability of the raw materials, it is inexpensive and easy to commercialize.

[0044] It should be noted that the delivery system described in this invention has universality, and its core multi-layer structure design is suitable for various hydrophobic nutrient factors; except Figure 1 In addition to lutein, lycopene, anthocyanins, curcumin, astaxanthin, or resveratrol can also be used. All of these can be effectively encapsulated and targeted for release using the same or similar methods. For specific implementation procedures, please refer to the treatment methods for different nutrient factors in Examples 5 to 7.

[0045] The specific embodiments of the present invention will be described in detail below: Example 1 Control group: Preparation of metal-organic framework carrier (ZIF-8@Lu-lip) carrying lutein liposomes.

[0046] (1) Soybean lecithin (SL), stigmasterol and lutein were dissolved in 50 mL of ethanol in a ratio of 9:1:1. The resulting mixture was rotary evaporated under a vacuum of 0.01 MPa until the ethanol was completely removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the concentration of lutein was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W. The ultrasonication was turned on for 1 s and off for 2 s for 5 min. After further homogenization, Lu-lip was obtained.

[0047] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0048] (3) Dissolve 0.5 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. Let stand for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip.

[0049] Example 2 Preparation of SHP-modified metal-organic framework carriers (ZIF-8@Lu-lip@SHP) carrying lutein liposomes.

[0050] (1) Soybean lecithin (SL), stigmasterol and lutein were dissolved in 50 mL of ethanol in a ratio of 9:1:1. The resulting mixture was rotary evaporated under a vacuum of 0.01 MPa until the ethanol was completely removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the concentration of lutein was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, and the ultrasonication was turned on for 1 s and off for 2 s for 5 min. After further homogenization, Lu-lip was obtained.

[0051] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0052] (3) Dissolve 0.5 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0053] (4) Slowly add ZIF-8@Lu-lip and 2.5 mg / mL SHP solution with pH 8.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@SHP.

[0054] Example 3 Preparation of PC-modified metal-organic framework carrier (ZIF-8@Lu-lip@PC) carrying lutein liposomes.

[0055] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0056] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0057] (3) Dissolve 0.5 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0058] (4) Slowly add 2.5 mg / mL PC solution with pH 8.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@PC.

[0059] Example 4 Preparation of XG-modified metal-organic framework carriers (ZIF-8@Lu-lip@XG) carrying lutein liposomes.

[0060] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0061] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0062] (3) Dissolve 0.5 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0063] (4) Slowly add 2.5 mg / mL XG solution with pH 8.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@XG.

[0064] Example 5 Preparation of SHP-modified metal-organic framework carriers carrying lycopene liposomes.

[0065] (1) Soybean lecithin (SL), stigmasterol, and lycopene were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the concentration of lycopene was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier loaded with lycopene was sonicated in a water bath at 4 °C with a power of 300 W, sonication was on for 1 s and off for 2 s for 5 min, and Ly-lip was obtained after further homogenization.

[0066] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Ly-lip to the above mixed solution.

[0067] (3) Dissolve 0.5 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Ly-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Ly-lip.

[0068] (4) Slowly add 2.5 mg / mL SHP solution with pH 8.0 to ZIF-8@ Ly-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@ Ly-lip@SHP.

[0069] Example 6 Preparation of SHP-modified metal-organic framework carriers carrying curcumin liposomes.

[0070] (1) Soybean lecithin (SL), stigmasterol, and curcumin were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform curcumin liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the curcumin concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier loaded with curcumin was sonicated in a water bath at 4 °C with a power of 300 W, with sonication on for 1 s and off for 2 s for 5 min, to further homogenize and obtain Cur-lip.

[0071] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Cur-lip to the above mixed solution.

[0072] (3) Dissolve 0.5 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Cur-lip. Stir gently and let stand for 30 s. Let stand for 2 h, centrifuge at 12000 g for 10 min, and wash three times to obtain ZIF-8@Cur-lip.

[0073] (4) Slowly add 2.5 mg / mL SHP solution with pH 8.0 to ZIF-8@Cur-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Cur-lip@SHP.

[0074] Example 7 Preparation of SHP-modified metal-organic framework carriers carrying resveratrol liposomes.

[0075] (1) Soybean lecithin (SL), stigmasterol, and resveratrol were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform resveratrol liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the resveratrol concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier loaded with resveratrol was sonicated in a water bath at 4 °C with a power of 300 W, sonication was on for 1 s and off for 2 s for 5 min, and then further homogenized to obtain Res-lip.

[0076] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Res-lip to the above mixed solution.

[0077] (3) Dissolve 0.5 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and resveratrol liposomes. After stirring gently, let stand for 30 s and stand for 2 h. Centrifuge at 12000 g for 10 min and wash three times to obtain ZIF-8@Res-lip.

[0078] (4) Slowly add 2.5 mg / mL SHP solution with pH 8.0 to ZIF-8@Res-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Res-lip@SHP.

[0079] Example 8 Preparation of SHP-modified metal-organic framework carriers carrying lutein liposomes.

[0080] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0081] (2) Dissolve 3 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0082] (3) Dissolve 0.50 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0083] (4) Slowly add 2.5 mg / mL SHP solution with pH 8.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@SHP.

[0084] Example 9 Preparation of SHP-modified metal-organic framework carriers carrying lutein liposomes.

[0085] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0086] (2) Dissolve 1 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0087] (3) Dissolve 0.50 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0088] (4) Slowly add 2.5 mg / mL SHP solution with pH 8.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@SHP.

[0089] Example 10 Preparation of SHP-modified metal-organic framework carriers carrying lutein liposomes.

[0090] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0091] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 3 mL of Lu-lip to the above mixed solution.

[0092] (3) Dissolve 0.50 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0093] (4) Slowly add 2.5 mg / mL SHP solution with pH 8.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@SHP.

[0094] Example 11 Preparation of SHP-modified metal-organic framework carriers carrying lutein liposomes.

[0095] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0096] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 0.5 mL of Lu-lip to the above mixed solution.

[0097] (3) Dissolve 0.50 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0098] (4) Slowly add 2.5 mg / mL SHP solution with pH 8.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@SHP.

[0099] Example 12 Preparation of SHP-modified metal-organic framework carriers carrying lutein liposomes.

[0100] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0101] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 20 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0102] (3) Dissolve 0.50 g of zinc acetate dihydrate in 20 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, ZIF-8@Lu-lip is obtained.

[0103] (4) Slowly add 2.5 mg / mL SHP solution with pH 8.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@SHP.

[0104] Example 13 Preparation of SHP-modified metal-organic framework carriers carrying lutein liposomes.

[0105] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0106] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0107] (3) Dissolve 0.50 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0108] (4) Slowly add 4.0 mg / mL SHP solution with pH 8.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@SHP.

[0109] Example 14 Preparation of SHP-modified metal-organic framework carriers carrying lutein liposomes.

[0110] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0111] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0112] (3) Dissolve 0.50 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0113] (4) Slowly add 1 mg / mL SHP solution with pH 8.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@SHP.

[0114] Example 15 Preparation of SHP-modified metal-organic framework carriers carrying lutein liposomes.

[0115] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0116] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0117] (3) Dissolve 0.50 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0118] (4) Slowly add 2.5 mg / mL SHP solution with pH 8.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 3 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@SHP.

[0119] Example 16 Preparation of SHP-modified metal-organic framework carriers carrying lutein liposomes.

[0120] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0121] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0122] (3) Dissolve 0.50 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0123] (4) Slowly add 2.5 mg / mL SHP solution with pH 8.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 15000 g for 15 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@SHP.

[0124] Example 17 Preparation of SHP-modified metal-organic framework carriers carrying lutein liposomes.

[0125] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0126] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0127] (3) Dissolve 0.5 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0128] (4) Slowly add ZIF-8@Lu-lip and 2.5 mg / mL SHP solution with pH 4.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@SHP.

[0129] Example 18 Preparation of SHP-modified metal-organic framework carriers carrying lutein liposomes.

[0130] (1) Soybean lecithin (SL), stigmasterol, and lutein were dissolved in 50 mL of ethanol at a ratio of 9:1:1. The resulting mixture was then rotary evaporated under a vacuum of 0.01 MPa until all ethanol was removed to form a uniform lutein liposome film. Then, 0.2 wt% Tween-80 phosphate buffer solution was added until the lutein concentration was 1 mg / mL, and the liposome film was hydrated at 50 °C to form crude liposomes. The crude liposome carrier carrying lutein was ultrasonicated in a water bath at 4 °C with a power of 300 W, with the ultrasonic cycle on for 1 s and off for 2 s, for 5 min, to further homogenize the mixture and obtain Lu-lip.

[0131] (2) Dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly. Add 1 mL of Lu-lip to the above mixed solution.

[0132] (3) Dissolve 0.5 g of zinc acetate dihydrate in 8 mL of deionized water and quickly inject it into a mixture of 2-methylimidazole, CTAB and Lu-lip. Stir gently and let stand for 30 s. After standing for 2 h, centrifuge at 12000 g for 10 min. After centrifugation and washing 3 times, obtain ZIF-8@Lu-lip.

[0133] (4) Slowly add ZIF-8@Lu-lip and 2.5 mg / mL SHP solution with pH 10.0 to ZIF-8@Lu-lip while stirring until the volume ratio is 1:1. After stirring for 2 h, centrifuge at 12000 g for 10 min, wash, repeat centrifugation and washing 3 times, and dry to obtain ZIF-8@Lu-lip@SHP.

[0134] Comparing Examples 1 and 2, ZIF-8@Lu-lip and ZIF-8@Lu-lip@SHP were obtained, with ZIF-8@Lu-lip@SHP showing better protection of lutein than ZIF-8@Lu-lip.

[0135] Comparing Examples 2, 3, and 4, we obtained ZIF-8@Lu-lip@SHP, ZIF-8@Lu-lip@PC, and ZIF-8@Lu-lip@XG, among which ZIF-8@Lu-lip@SHP showed better protective effects on lutein.

[0136] Comparing Examples 2, 10, and 11, it was found that the optimal solution was to dissolve 1.86 g of 2-methylimidazole and 0.92 mg of CTAB in 8 mL of deionized water and stir slowly, then add 1 mL of Lu-lip to the mixture.

[0137] Comparing Examples 2, 13, and 14, it was found that ZIF-8@Lu-lip mixed with a 2.5 mg / mL SHP solution at pH 8.0 at a volume ratio of 1:1 resulted in ZIF-8@Lu-lip@SHP exhibiting the best stability.

[0138] Examples 2, 5, 6, and 7 demonstrate that the polysaccharide-modified metal-organic framework carrier for carrying nutrient factor liposomes of the present invention is applicable to other nutrient factors, which will not be listed individually here.

[0139] Figure 2A represents a comparison of the absolute values ​​of the Zeta potential for different polysaccharides (SHP, PC, XG). Figure 2 B compares the absolute values ​​of the zeta potential of ZIF-8@Lu-lip, ZIF-8@Lu-lip@SHP, ZIF-8@Lu-lip@PC and ZIF-8@Lu-lip@XG. SHP, PC and XG are all anionic polysaccharides. The coating of anionic polysaccharides further increases the number of negative charges in the system. Figure 2 C represents a comparison of the encapsulation efficiency of lutein by ZIF-8@Lu-lip, ZIF-8@Lu-lip@SHP, ZIF-8@Lu-lip@PC, and ZIF-8@Lu-lip@XG. The electrostatic interaction between the anionic polysaccharides SHP, PC, and XG and the zinc ions on the surface of ZIF-8@Lu-lip nanoparticles further modifies the nanodelivery system, thereby protecting Lu-lip.

[0140] Depend on Figure 3 A and B compare the antioxidant capacities of different polysaccharides, lutein, ZIF-8, ZIF-8@lip, ZIF-8@Lu-lip, ZIF-8@Lu-lip@SHP, ZIF-8@Lu-lip@PC, and ZIF-8@Lu-lip@XG. The free radical scavenging ability of polysaccharides is due to the fact that certain amino acids and their specific sequences are believed to scavenge free radicals. Compared to free lutein, ZIF-8@Lu-lip and the three different polysaccharide-coated ZIF-8@Lu-lip exhibit superior antioxidant activity. Furthermore, the antioxidant activities of ZIF-8@Lu-lip@SHP (54.82%), ZIF-8@Lu-lip@PC (49.21%), and ZIF-8@Lu-lip@XG (52.86%) are all higher than those of ZIF-8@Lu-lip (47.64%), indicating that polysaccharide coating can indeed protect and enhance the functional properties and antioxidant activity of lutein.

[0141] Depend on Figure 4 The thermal stability of different polysaccharides, lutein, ZIF-8, ZIF-8@lip, ZIF-8@Lu-lip, ZIF-8@Lu-lip@SHP, ZIF-8@Lu-lip@PC and ZIF-8@Lu-lip@XG is compared.

[0142] like Figure 5As shown in Figures A and B, scanning electron microscopy (SEM) images and energy-dispersive X-ray spectroscopy (EDX) analyses of ZIF-8@Lu-lip, ZIF-8@Lu-lip@SHP, ZIF-8@Lu-lip@PC, and ZIF-8@Lu-lip@XG are presented. The morphologies of ZIF-8@Lu-lip, ZIF-8@Lu-lip@PC, ZIF-8@Lu-lip@SHP, and ZIF-8@Lu-lip@XG are spherical. The EDX data further confirm that C, O, N, and Zn are the main components of the synthesized nano-delivery carrier. After polysaccharide modification, the amounts of C and O elements increased, indicating that ZIF-8@Lu-lip was successfully modified with polysaccharides.

[0143] like Figure 6 As shown, powder XRD revealed that lutein was successfully encapsulated in ZIF-8@Lu-lip, ZIF-8@Lu-lip@PC, ZIF-8@Lu-lip@SHP, and ZIF-8@Lu-lip@XG. The sharp characteristic peak of lutein disappeared, and it was in an amorphous state.

[0144] like Figure 7 As shown, the Fourier transform infrared spectrum indicates that at 1568 cm⁻¹... -1 With 995cm -1 The absorption peaks were related to the CN bending and stretching vibrations of the imidazole ring in the ZIF-8 structure, respectively. The same characteristic absorption peaks were observed in both ZIF-8@lip and ZIF-8@Lu-lip, indicating the successful synthesis of ZIF-8 and the successful encapsulation of Lu-lip within ZIF-8. (Lutein, 966 cm⁻¹) -1 The characteristic absorption peaks of lutein liposomes, which are absent in ZIF-8@Lu-lip, ZIF-8@Lu-lip@PC, ZIF-8@Lu-lip@SHP, and ZIF-8@Lu-lip@XG, are mainly because the lutein liposomes are successfully encapsulated within a metal-organic framework and a polysaccharide-coated metal-organic framework, rather than located on the surface; ZIF-8@Lu-lip exhibits a peak at 1570 cm⁻¹. -1 The characteristic absorption bands at 1617, 1632, and 1603 cm⁻¹ are represented by PC, SHP, and XG. -1 The characteristic absorption peaks at 1420 cm⁻¹ are replaced by those at 1420 cm⁻¹, which are attributed to the stretching of CN in the imidazole ring and the asymmetric contraction of COO in the carboxylate group, respectively. (ZIF-8@Lu-lip@PC, ZIF-8@Lu-lip@SHP, and ZIF-8@Lu-lip@XG spectra) -1 The peak at 421 cm⁻¹ is a characteristic peak of the CN bond in the amide group. -1The characteristic absorption peaks represent the stretching vibrations of Zn-N, ZIF-8@Lu-lip@PC, ZIF-8@Lu-lip@SHP, and ZIF-8@Lu-lip@XG at 421 cm⁻¹. -1 The decrease in Zn-N bond strength further demonstrates the successful coating of SHP, PC, and XG.

[0145] Figure 8 Simulated cumulative lutein release curves for ZIF-8@Lu-lip, ZIF-8@Lu-lip@PC, ZIF-8@Lu-lip@SHP, and ZIF-8@Lu-lip@XG in PBS at pH levels of 2.0, 4.0, 6.8, and 7.4 are presented. Due to the acid-responsive release properties of ZIF-8 nanoparticles, ZIF-8@Lu-lip exhibits a higher release rate of lutein at pH 2.0 and pH 4.0 than at pH 6.8 and pH 7.4. This may be because its pH sensitivity causes the weak coordination bonds to break in an acidic environment, leading to the initial leakage of lutein from the collapsed ZIF-8 shell. Conversely, in ZIF-8@Lu-lip@PC, ZIF-8@Lu-lip@SHP, and ZIF-8@Lu-lip@XG, the surface polysaccharide coating allows for premature lutein release, exhibiting a delayed release behavior compared to ZIF-8@Lu-lip under low pH stimulation. It protects its structure from acidic conditions and also exhibits advantages in the intestinal environment at pH 6.8 and 7.4. The polysaccharide coating acts as a barrier to the acidic environment of the stomach and is degradable under alkaline conditions in the intestine, thus ensuring targeted delivery and complete protection of the nanohybrid.

[0146] In related technologies, there have been studies on encapsulating bioactive substances using liposomes, but these single carriers suffer from problems such as drug burst release and short half-life. Metal-organic frameworks (MOFs) are nanomaterials with high specific surface area and tunable pore structures, capable of efficiently loading drugs and achieving stimulus-response release, but when used alone, they have drawbacks such as insufficient targeting and uncontrollable degradation. This invention prepares a novel nanocomposite carrier by embedding liposomes carrying nutrient factors within a MOF, and further coating the outermost layer with polysaccharides. This carrier can prevent the MOFs carrying nutrient factor liposomes from being degraded in the gastrointestinal tract, while maximizing the release of nutrient factors within the intestine.

[0147] In related technologies, liposome-metal-organic framework composite carriers already exist. For example, patent application CN120514689A discloses a transdermal drug delivery formulation of traditional Chinese medicine based on nano-encapsulation technology and its preparation method, which is used to load active ingredients of traditional Chinese medicine to achieve efficient encapsulation and transdermal absorption of these active ingredients. However, oral administration is the most natural and traditional method of drug delivery, requiring no skin puncture, causing no pain, and avoiding the local irritation problems such as itching, allergies, and redness that may be caused by transdermal patches. Furthermore, the drug loading capacity of oral administration is much higher than that of transdermal patches, and the dosage of transdermal patches is limited by patch size and skin permeability. In addition, a wide variety of food-grade / pharmaceutical-grade excipients are available at low cost, greatly facilitating the development of novel oral carriers. Patent application CN120285219A discloses a nanomedicine carrier and drug delivery system. The drug-loaded core is made of liposomes, polymer nanoparticles, or metal-organic frameworks (MOFs). It includes a drug-loaded core and a responsive shell disposed outside the core. Drug delivery includes implantation (surgery) and non-implantation (skin patch) delivery. Similarly, pH-responsive oral drug delivery systems simplify manufacturing processes and offer better physical and chemical stability. Oral drug delivery systems are more efficient for delivering nutritional factors, protein / peptide drugs, etc. Polysaccharide-coated liposome-loaded metal-organic framework carriers broaden the prospects for oral drug delivery systems, successfully integrating the high drug loading and controlled release of MOFs, the biocompatibility and barrier function of liposomes, and the mucolytic interaction and pH-responsive release of polysaccharides. With continuous advancements in materials science, formulation technology, and evaluation methods, innovative solutions can be provided for the efficient delivery of oral drugs, especially biopharmaceuticals and natural active ingredients.

[0148] None of the aforementioned related technologies disclose the preparation method of the metal-organic framework for the nutrient-carrying liposomes of the present invention, nor the polysaccharide-modified metal-organic framework carrier for the nutrient-carrying liposomes prepared by the present invention.

[0149] The beneficial technical effects of this invention are as follows: This invention provides a metal-organic framework (MOF) carrier for nutrient-carrying liposomes with multiple response and targeting mechanisms, and a polysaccharide-modified MOF carrier for nutrient-carrying liposomes prepared therefrom. The MOF acts as a "smart gatekeeper," providing physical and chemical barriers; the liposomes act as a "primary protective chamber," enhancing the stability of lutein; and the polysaccharide coating acts as a "navigation and shield," providing mucosal adhesion and prolonging the retention time of the delivery system in the intestinal mucosa, thus promoting the absorption of nutrients. This multi-stage release mechanism effectively avoids burst release in the stomach, ensuring the effective and sustained release of nutrients at the main sites of absorption, thus providing greater benefits to human health.

[0150] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for preparing a pH-responsive nutrient factor-loaded liposome- modified metal-organic framework carrier, characterized in that, The method comprises the following steps: Step S1: Dissolve phospholipid, phytosterol and nutrient factor in ethanol, and rotate evaporate the obtained mixture under vacuum condition until ethanol is completely removed to form a uniform nutrient factor-loaded liposome film, and hydrate the liposome film with a phosphate buffer solution containing Tween-80 to form a crude liposome; Step S2: After low-temperature water bath ultrasonic treatment of the crude nutrient factor-loaded liposome carrier, further obtain a nutrient factor delivery liposome carrier; Step S3: Mix the nutrient factor-loaded liposome carrier with a mixed solution containing cetyltrimethylammonium bromide CTAB and 2-methylimidazole, then quickly inject a zinc acetate dihydrate solution into the mixture of 2-methylimidazole, CTAB and the nutrient factor-loaded liposome carrier, and after gentle stirring, stand still, and after multiple centrifugal washing and drying, obtain a nutrient factor-loaded liposome metal organic framework carrier; Step S4: Slowly drop a polysaccharide solution into the nutrient factor-loaded liposome metal organic framework carrier, stir while dropping, then perform centrifugal washing, and after drying, obtain a pH-responsive polysaccharide-modified nutrient factor-loaded liposome metal organic framework carrier.

2. The preparation method of the pH-responsive polysaccharide-modified nutrient factor-loaded liposome metal organic framework carrier according to claim 1, characterized in that: the phospholipid in step S1 is soybean lecithin SL; the nutrient factor is lutein, anthocyanin, lycopene, curcumin, astaxanthin or resveratrol; the phytosterol is stigmasterol, β-sitosterol, brassicasterol or campesterol.

3. The preparation method of the pH-responsive polysaccharide-modified nutrient factor-loaded liposome metal organic framework carrier according to claim 1, characterized in that: the concentration ratio of the phospholipid, phytosterol and nutrient factor in step S1 is 9:1:1; the vacuum degree is 0.01 MPa; the phosphate buffer solution containing Tween-80 contains 0.2 wt% Tween-80; after the phosphate buffer solution containing Tween-80 is added, the concentration of the nutrient factor in the liposome suspension is 1 mg / mL.

4. The preparation method of the pH-responsive polysaccharide-modified nutrient factor-loaded liposome metal organic framework carrier according to claim 1, characterized in that: in step S2, the power of the low-temperature water bath ultrasonic treatment is 300 W, and each time the power is turned on for 1 s, then turned off for 2 s; then the power is turned on again for 1 s, and then turned off for 2 s, and the cycle is repeated for 5 min; the temperature of the low-temperature water bath ultrasonic treatment is 4℃.

5. The method for preparing a pH-responsive nutrient factor-loaded metal-organic framework support with polysaccharide modification according to claim 1, characterized in that, in step S3, the specific method for mixing the nutrient factor-loaded liposome carrier with a mixed solution containing cetyltrimethylammonium bromide CTAB and 2-methylimidazole, then quickly injecting a zinc acetate dihydrate solution into the mixture of 2-methylimidazole, CTAB and the nutrient factor-loaded liposome, and after gentle stirring, standing still, multiple centrifugal washing and drying, to obtain the nutrient factor-loaded liposome metal organic framework carrier is as follows: S3-1: 1-3 g of 2-methylimidazole and 0.5-1.5 mg of CTAB are dissolved in 5-20 mL of deionized water and slowly stirred for a period of time, then 0.5-3 mL of nutrient factor-loaded liposomes are added to the above mixed solution; S3-2: 0.5-1.5 g of zinc acetate dihydrate is dissolved in 5-20 mL of deionized water, and is quickly injected into the mixture of 2-methylimidazole, CTAB and nutrient factor-loaded liposomes, and after gentle stirring, it is left to stand, the stirring time is 20-50 s, the standing time is 1-3 h, after 2-5 times of centrifugal washing, the centrifugal force is 10000-15000 g, the time is 10-15 min, after drying, the nutrient factor-loaded liposome metal organic framework carrier is obtained.

6. The method for preparing a pH-responsive nutrient factor-loaded metal-organic framework support with polysaccharide modification according to claim 1, characterized in that, The polysaccharide in step S4 is soybean seed coat polysaccharide SHP, low-ester pectin PC, xanthan gum XG, gum arabic GA or hyaluronic acid HA.

7. The method for preparing a pH-responsive nutrient factor-loaded metal-organic framework support with polysaccharide modification according to claim 1, characterized in that, The specific method for slowly adding the polysaccharide solution to the nutrient factor-loaded liposome metal organic framework carrier in step S4, stirring while adding, washing, drying to obtain the pH-responsive nutrient factor-loaded liposome polysaccharide-modified metal organic framework carrier is: S4-1: Take a polysaccharide solution with a concentration of 2.0-5.0 mg / mL, and adjust the pH value of the polysaccharide solution to 4.0-11.0 with 1.0 mol / L NaOH; S4-2: Slowly add the adjusted polysaccharide solution to the nutrient factor-loaded liposome metal organic framework carrier, stir while adding, until the volume ratio of the polysaccharide solution to the nutrient factor-loaded liposome metal organic framework carrier reaches 1:1, then stop adding, stir for 1.5-3 h, centrifugal wash 2-3 times, centrifugal force is 10000-15000 g, time is 10-15 min, dry to obtain the pH-responsive nutrient factor-loaded liposome polysaccharide-modified metal organic framework carrier.

8. A polysaccharide-modified metal-organic framework carrier of the pH-responsive nutrient factor-loaded liposome prepared by the method of claims 1-7, characterized in that, The carrier is a core-shell structure, the inner core is a nutrient factor-loaded liposome; the middle layer is a metal organic framework, which coats the liposome; the outer layer is a pH-responsive polysaccharide coating, which coats the metal organic framework; The carrier is structurally stable in a gastric acid environment, and realizes targeted release of the nutrient factor in an intestinal neutral or weak alkaline environment.

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