Composite carrier for targeted drug delivery based on diatom shells

Abstract

The invention relates to the field of biomedical materials, in particular to a composite carrier for targeted drug delivery based on a diatom shell, and the carrier utilizes a natural diatom shell porous structure to anchor FeOmagnetic nanoparticles and graft a PNIPAM-co-AAc temperature-sensitive polymer film on the shell surface through oxygen plasma pretreatment and Schiff base reaction. The carrier realizes double-drug loading: a hydrophobic drug is loaded in a shell pore channel, and a hydrophilic drug is adsorbed on the surface of the membrane. And the anti-immune layer is grafted through a PEG silane coupling agent, so that the in-vivo circulation is prolonged to 45 hours. Heat is generated to 42-45 DEG C in an alternating magnetic field to trigger the temperature-sensitive film to shrink and release drugs, meanwhile, cancer cells are directly killed through thermal therapy, and the tumor inhibition rate reaches 78% and is remarkably improved compared with a traditional magnetic targeting carrier. Precise synergy of magnetic hyperthermia and drug release is achieved through structural innovation, and an efficient and low-toxicity solution is provided for cancer treatment.

Description

Technical Field

[0001] The present invention relates to the field of biopharmaceutical materials, and specifically to a composite carrier for targeted drug delivery based on diatom frustules and a preparation method thereof, which is suitable for precise targeted delivery of combined cancer treatments. Background Art

[0002] In recent years, research on natural nanostructures in the field of biomedical materials has flourished. Diatom frustules, in particular, have garnered widespread attention due to their unique biomineralized structure. Diatom frustules, the cell walls of single-celled algae, are composed of amorphous silica and possess a highly ordered nanoscale porous network. This natural structure endows them with exceptional surface areas exceeding 50 m² / g and pore sizes ranging from 10 nm to 1 μm, providing an ideal physical space for drug loading. Furthermore, the silica framework's chemical inertness and biocompatibility, which have been approved by the FDA, make it a highly promising drug delivery vehicle.

[0003] Extensive research has explored the functionalization of diatom frustules. Surface modification techniques, such as polyethylene glycol (PEG) grafting, can significantly reduce the immunogenicity of carriers and prolong their in vivo circulation (Patent CN110585763A). In terms of magnetic functionalization, diatom frustules loaded with Fe₃O₄ nanoparticles achieve magnetically targeted delivery, with in vitro magnetic field enrichment efficiency exceeding three times that of traditional carriers (Patent CN109806877A). Furthermore, the introduction of environmentally responsive materials has further expanded their application. For example, coating with pH-sensitive chitosan or the thermosensitive polymer PNIPAM enables precise drug release in the tumor microenvironment (Reference: Advanced Drug Delivery Reviews, 2015).

[0004] However, the current diatom frustule-based delivery system still faces multiple technical bottlenecks. First, existing modification methods mostly focus on a single function, such as only achieving magnetic targeting or only having controlled release capabilities, which makes it difficult to meet the clinical demand for multi-mechanism synergy. Secondly, the combination of the functional layer and the diatom frustule mostly relies on physical adsorption, which is prone to shedding in a physiological environment, resulting in a decrease in targeting efficiency (the antibody modification layer of patent CN112316234A has a shedding rate of more than 30%). In addition, the traditional preparation process has limited adaptability to drug types and can only load hydrophobic drugs, which cannot meet the co-delivery requirements of drugs of different properties in combination therapy.

[0005] Compared to diatom frustules, other nanocarriers, such as liposomes and polymeric nanoparticles, also have significant drawbacks. Liposomes typically have drug loadings below 5% (w / w), and their phospholipid bilayer structure is susceptible to degradation during circulation. While polymeric nanoparticles offer some controlled release capabilities, rapid clearance by the reticuloendothelial system limits their effective accumulation time to less than 24 hours (Nature Reviews Drug Discovery, 2012). These limitations collectively restrict the application of existing delivery systems in combination cancer therapy. Summary of the Invention

[0006] Based on this technical background, the present invention proposes a multifunctional integrated diatom frustule composite carrier. Through hierarchical pore design, interface engineering techniques, and multilayered construction, it achieves synergistic optimization of precise targeting, efficient drug loading, time-controlled release, and in vivo stability. This carrier not only breaks through the limitations of single functionality but also, through structural innovation, addresses core issues of traditional delivery systems, providing a novel solution for cancer treatment.

[0007] The technical solution adopted by the present invention is: A composite carrier for targeted drug delivery based on diatom frustules, comprising a diatom frustule body with a natural porous structure and convex surfaces and grooves distributed on the surface. Unlike the prior art, it also includes a functional composite layer bonded to the convex surfaces and grooves of the diatom frustule body, a drug-loading layer distributed in the pores of the diatom frustule body and on the surface of the functional composite layer, and an anti-immune clearance layer grafted to the outer surface of the functional composite layer; the functional composite layer comprises Fe3O4 magnetic nanoparticles and a thermosensitive polymer film anchored to the amino surfaces of the convex surfaces and grooves via Schiff base bonds, wherein the Fe3O4 magnetic nanoparticles have a particle size of 10-30 nm and a coverage of 40-60%, and the thermosensitive polymer film is a copolymer of poly (N-isopropylacrylamide) and acrylic acid, has a thickness of 10-30 nm, is connected to the magnetic nanoparticles via amide bonds, and has a phase transition temperature of 32-35°C.

[0008] Furthermore, the drug loading layer comprises a hydrophobic drug loaded in the pores of the diatom shell and a hydrophilic drug adsorbed on the surface of the thermosensitive polymer membrane, wherein the hydrophobic drug loading amount is 120-180 μg / mg, the hydrophilic drug loading amount is 50-80 μg / mg, and the loading ratio of the two is 1:0.5-2.

[0009] Furthermore, the anti-immune clearance layer is polyethylene glycol covalently linked to the thermosensitive polymer membrane through a silane coupling agent, with a molecular weight of 2000-5000 Da, a grafting density of 0.5-2 chains / nm², and a surface roughness Ra of 5-20 nm.

[0010] Furthermore, the inner wall of the pores of the diatom shell body is treated with oxygen plasma to form a hydroxylated surface with a hydroxyl density of 1-3nm⁻², a pore diameter of 50-200nm and uniform distribution on the shell wall, and a pore length consistent with the shell wall thickness; an air layer with a thickness of 10-50nm is provided on the inner wall of the pores to reduce heat conduction to normal tissues.

[0011] Furthermore, the magnetic nanoparticles generate heat in an alternating magnetic field (magnetic field strength 20-50kA / m, frequency 80-150kHz), causing the local temperature to rise to 42-45°C, triggering a shrinkage rate of the thermosensitive polymer film of >60% to release drugs, while killing cancer cells through thermal effects; the mass ratio of magnetic nanoparticles to thermosensitive polymer film is 1:5-1:10, and the anchoring density of magnetic nanoparticles on the convex surface and groove is 5-10 particles / μm² to ensure heat generation uniformity of ±10%.

[0012] The present invention also discloses a method for preparing the composite carrier, comprising the following steps: S1 pretreatment: Use oxygen plasma with a power of 100-200W to treat the surface of the diatom frustules for 30 seconds to introduce high-density hydroxyl groups, and then soak it in 5% (v / v) 3-aminopropyltriethoxysilane ethanol solution with a pH of 4.5-5.5 for 2 hours to form an amino surface; S2 magnetic nanoparticle anchoring: Fe3O4 nanoparticles were prepared by coprecipitation at a molar ratio of Fe²⁺ to Fe³⁺ of 1:2. After modification with dopamine at pH 8.5 for 2 hours, they were covalently linked to amino-diatom frustules via a Schiff base reaction at pH 8.5 and room temperature for 2 hours. The coverage was controlled at 40-60% by centrifugation at 5000-10000 rpm for 10-20 minutes. S3 thermosensitive membrane construction: A copolymer of poly (N-isopropylacrylamide) and acrylic acid containing carboxylic acid groups was synthesized and grafted onto the surface of magnetic particles using a 0.1-0.5 M EDC / NHS coupling agent for 4 hours. The membrane thickness was controlled to 10-30 nm by adjusting the copolymer solution concentration (5-15% w / v). The grafting density was 0.5-1.5 mg / mg of magnetic particles, and the phase transition temperature was regulated to 32-35°C by adjusting the acrylic acid content. S4 drug loading and anti-immune modification: The diatom shells were immersed in a hydrophobic drug ethanol solution with a concentration of 20-50 mg / mL and ultrasonically treated for 10-15 minutes to load the drug. After vacuum drying, they were immersed in a hydrophilic drug PBS solution with a concentration of 10-30 mg / mL and stirred at 4°C for 2 hours to load the drug and control the ratio; a polyethylene glycol silane coupling agent solution with a concentration of 1-5 mg / mL was reacted at room temperature for 4 hours to graft the anti-immune layer, and the surface roughness Ra was controlled to 5-20 nm by spin coating at a speed of 2000-3000 rpm.

[0013] Furthermore, the oxygen plasma treatment uses oxygen as a treatment gas with a pressure of 0.1-0.5 mbar.

[0014] Furthermore, the dopamine modification reaction is carried out in Tris-HCl buffer.

[0015] Furthermore, the vacuum drying temperature after loading the hydrophobic drug is 30-40° C. and the time is 12-24 hours.

[0016] Furthermore, after the grafted anti-immune clearance layer is applied, the grafted surface is washed with deionized water for 3-5 times, each time for 5-10 minutes.

[0017] Core principles and technical effects of the invention 1. Core Action Principle The present invention achieves efficient targeted drug delivery through structural innovation and functional synergy. Its core mechanism is as follows: 1. Magnetic targeting and magnetic hyperthermia synergy -Magnetic targeting: Fe3O4 magnetic nanoparticles (particle size 10-30nm) are anchored on the convex surfaces and grooves of diatom frustules. Under the action of an external alternating magnetic field (20-50kA / m, 80-150kHz), heat is generated through hysteresis loss and Néel relaxation, and the local temperature rises to 42-45°C.

[0018] -Thermal effect: Cancer cells will die if they are heated at 42-45°C for more than 30 minutes, while normal cells can tolerate temperatures up to 47°C, achieving selective killing.

[0019] 2. Controlled release of thermosensitive drugs -Phase transition trigger: The thermoresponsive polymer film (PNIPAM-co-AAc) shrinks above the critical solution temperature (LCST, 32-35°C), releasing the encapsulated drug.

[0020] -Synergistic temperature window: The magnetic hyperthermia temperature (42-45°C) is higher than the LCST, which triggers drug release and hyperthermia synchronously, enhancing the therapeutic effect.

[0021] 3. Multi-drug layered loading -Hydrophobic drugs: loaded into the pores of diatom frustules (120-180 μg / mg) and fixed by physical adsorption and hydrogen bonding.

[0022] -Hydrophilic drugs: adsorbed on the surface of the thermosensitive membrane (50-80 μg / mg), and stabilized by electrostatic interactions.

[0023] - Ratio control: The dual-drug loading ratio is 1:0.5-2, suitable for combination regimens such as chemotherapy + immunotherapy.

[0024] 4. Anti-immune clearance design -PEG layer: The polyethylene glycol layer with a grafting density of 0.5-2 chains / nm² forms steric hindrance, reducing macrophage recognition.

[0025] -Surface roughness: Ra values of 5-20 nm further reduce protein adsorption and extend the in vivo circulation time to more than 48 hours.

[0026] 2. Technical Effect Through the above innovative design, the present invention is significantly superior to the prior art in the following aspects: 1. Improved targeting efficiency -Magnetic targeted enrichment: 40-60% magnetic particle coverage and an anchoring density of 5-10 particles / μm² enable the carrier to aggregate at a rate of 85% within 10 minutes under an in vitro magnetic field, a 42% increase compared to traditional random loading.

[0027] - Hyperthermia precision: The convex / groove-anchored particle distribution, combined with the air layer (10-50nm) in the pores for thermal insulation, ensures that the hyperthermia area is concentrated on the tumor tissue, and the temperature rise of normal tissue is less than 1°C.

[0028] 2. Controllable drug release -Dual-stage controlled release: - Rapid release: The thermosensitive membrane releases 90% of the hydrophilic drug within 60 minutes at 42°C; -Sustained release: Hydrophobic drugs diffuse through the pores, with a cumulative release of 60% over 72 hours.

[0029] -Response speed: The temperature-sensitive film thickness is 10-30nm, and the thermal response time is less than 2 minutes, which is 3 times faster than the traditional thick film design (>50nm).

[0030] 3. Enhanced therapeutic effect - Synergistic treatment: The cancer cell survival rate in the magnetic hyperthermia combined with drug group was 15%, significantly lower than that in the single-drug group (magnetic hyperthermia 35%, drug 40%).

[0031] -Tumor inhibition rate: In the mouse model, the tumor volume of the synergistic treatment group was reduced by 75%, which was higher than that of the single group (magnetic hyperthermia 40%, drug 50%).

[0032] 4. Biocompatibility optimization - Anti-immune clearance: The PEG layer reduces protein adsorption by 60% within 7 days in PBS and prolongs the in vivo circulation time to 48 hours (compared to <24 hours for traditional carriers).

[0033] -Structural stability: The binding strength of Schiff base bond and amide bond is greater than 5MPa, and the retention rate of the functional layer after immersion in PBS for 7 days is greater than 90%.

[0034] 5. Preparation process advantages -High-efficiency loading: The hydrophobic drug loading capacity reaches 180μg / mg, which is 80% higher than that of traditional diatom frustule carriers (100μg / mg).

[0035] -Universality: By adjusting the AAc content, the phase transition temperature of the thermosensitive membrane can be precisely controlled (32-35°C) to adapt to different tumor microenvironments.

[0036] In summary, this invention, through the synergistic integration of magnetic hyperthermia and thermosensitive release, dual-drug layered loading, and anti-immune clearance design, breaks through the efficiency bottleneck of traditional drug delivery systems, achieving the triple goals of precise targeting, highly effective treatment, and minimal toxicity and side effects. Its technological advantages directly address clinical needs, providing an innovative solution for cancer treatment and possessing significant scientific value and industrial potential. DETAILED DESCRIPTION

[0037] The present invention will be further described below with reference to specific embodiments.

[0038] Example 1: Magnetic Hyperthermia-Thermosensitive Drug Co-carrier 1. Diatom frustule pretreatment: Oxygen plasma treatment: The instrument used was an oxygen plasma cleaning machine (Model: PDC-32G). The treatment parameters were 150W power, 0.3mbar O2 pressure, and 30 seconds. XPS analysis after treatment revealed a hydroxyl density of 2.5nm⁻².

[0039] APTES amination: Adjust the pH of 5.0 (HCl) to 5% (v / v) 3-aminopropyltriethoxysilane (APTES) in ethanol. Immerse the diatom frustules in this solution and stir at room temperature for 2 hours. Then, wash them three times with deionized water by centrifugation (5000 rpm, 5 minutes).

[0040] Preparation of magnetic nanoparticle-anchored Fe₃O₄ nanoparticles: A coprecipitation method (Fe²⁺ to Fe³⁺ molar ratio of 1:2) was used. The specific steps were: a mixed solution of FeCl₂・4H₂O (0.5M) and FeCl₃・6H₂O (1M) was added with NH₄OH to a pH of 10 and stirred at 70°C for 1 hour. The particles were collected by magnetic separation and washed with deionized water until neutral. The resulting Fe₃O₄ nanoparticles (particle size 25 nm, as determined by TEM) were then freeze-dried.

[0041] Dopamine modification: Dissolve 10 mg / mL dopamine hydrochloride in Tris-HCl buffer (pH 8.5), add Fe₃O₄ particles (100 mg), and stir at room temperature for 2 hours. Remove unbound dopamine by magnetic separation.

[0042] Schiff base reaction ligation: Amination-modified diatom frustules (100 mg) were dispersed in Tris-HCl buffer (pH 8.5), and dopamine-modified Fe₃O₄ particles (50 mg) were added. The mixture was stirred at room temperature for 2 hours. Centrifugation was performed at 8000 rpm for 15 minutes. The Fe content was determined by ICP-OES, and the coverage was controlled at 55%.

[0043] Synthesis of PNIPAM-co-AAc for Thermosensitive Membrane Construction: NIPAM (10 g) and AAc (1.5 g) were dissolved in deionized water (100 mL). Initiator AIBN (0.1 g) was added and polymerization was carried out at 60°C under nitrogen atmosphere for 4 h. The copolymer was purified by dialysis (MWCO 3.5 kDa) and lyophilized.

[0044] Grafting Reaction: Magnetic particles (50 mg) were dispersed in MES buffer (pH 6.0) and activated with EDC (0.3 M) and NHS (0.3 M) for 30 minutes. The copolymer (50 mg) was then added and stirred at room temperature for 4 hours. The mixture was washed three times with deionized water by centrifugation. AFM analysis revealed a film thickness of 20 nm.

[0045] Drug loading Hydrophobic drug (paclitaxel) loading: Diatom frustules (100 mg) were soaked in 25 mg / mL paclitaxel ethanol solution and sonicated for 10 minutes. After vacuum drying (35°C, 18 hours), the loading capacity was 160 μg / mg as determined by HPLC.

[0046] Hydrophilic drug (doxorubicin) loading: The carrier was immersed in a 20 mg / mL doxorubicin PBS solution (pH 7.4) and stirred at 4°C for 2 hours. After centrifugation and washing with deionized water, the loading capacity was determined to be 65 μg / mg by fluorescence spectrophotometry.

[0047] Anti-immune modification PEG grafting: The carrier was immersed in a 2 mg / mL PEG-silane coupling agent (MW 3000) ethanol solution and reacted at room temperature for 4 hours. The solution was washed three times with deionized water by centrifugation. XPS analysis showed a grafting density of 1.2 chains / nm².

[0048] Roughness control: Spin coating was used with a rotation speed of 2500 rpm and a time of 30 seconds. The roughness Ra measured by AFM was 12 nm.

[0049] Comparative Example 1: Traditional magnetic targeting diatom frustule carrier (compared with prior art CN109806877A) 1. Preparation Procedure: Diatom frustule pretreatment: Diatom frustules were directly immersed in a 5% (v / v) APTES solution (pH 5.0) without oxygen plasma treatment. Magnetic Particle Loading: Fe₃O₄ nanoparticles (50 nm in diameter) were physically adsorbed onto the diatom frustules at a loading of 80 μg / mg (without dopamine modification or Schiff base reaction). Drug Loading: Paclitaxel loading was 90 μg / mg, without thermosensitive membrane or dual-drug loading. Anti-immune Modification: No PEG grafting was performed.

[0050] Key parameters: This carrier has no temperature-sensitive membrane, and drug release depends on diffusion; the magnetic targeting enrichment rate is 62% (without coverage control).

[0051] Comparison of Examples and Comparative Examples project Example Comparative Example Magnetic hyperthermia temperature stability 43℃±0.5℃ (30 minutes) 42℃±1.5℃ (15 minutes) Drug release rate (paclitaxel) 15μg / (cm²·h) 10μg / (cm²·h) Total dual drug load 225 μg / mg 90 μg / mg Circulation time in the body 45 hours 22 hours Tumor inhibition rate 78% 52% The performance comparison data of the examples and comparative examples show that the present invention has made breakthrough progress in the following aspects: Magnetic Hyperthermia Stability: The Example maintained a stable temperature of 43°C ± 0.5°C for 30 minutes in an alternating magnetic field, significantly outperforming the Comparative Example (42°C ± 1.5°C for 15 minutes). This is attributed to the high coverage (55%) and uniform anchoring (5-10 particles / μm²) of the Fe₃O₄ nanoparticles (25 nm), which ensure efficient heat generation through hysteresis losses and Néel relaxation.

[0052] Drug Release Efficiency: The paclitaxel release rate in the Example reached 15 μg / (cm²・h), a 50% increase over the Comparative Example. This is due to the ultra-thin design of the thermosensitive membrane (20 nm) and the rapid response of the PNIPAM-co-AAc copolymer (LCST = 34°C), resulting in a 92% drug release rate over 60 minutes at 42°C.

[0053] Dual-drug loading capacity: The example achieved a combined dual-drug loading of 225 μg / mg, 2.5 times the single-drug loading of 90 μg / mg in the control. Layered loading technology (hydrophobic drug within the pores + hydrophilic drug on the membrane surface) prevents drug interactions through spatial separation, enhancing the efficacy of combined therapy.

[0054] In vivo circulation time: The in vivo circulation time of the example was extended to 45 hours, a 105% increase compared to the control example (22 hours). This is due to the high grafting density (1.2 chains / nm²) and controlled surface roughness (Ra = 12nm) of the PEG layer, which effectively reduces protein adsorption and macrophage recognition.

[0055] Tumor inhibition: The example achieved a 78% tumor inhibition rate, a 50% increase over the control (52%). The synergistic effect of magnetic hyperthermia (43°C) and drug release not only directly kills cancer cells but also enhances cell membrane permeability through hyperthermia, promoting drug penetration and creating a "thermo-chemotherapy" synergistic effect.

[0056] Conclusion: The present invention significantly outperforms existing technologies in key indicators such as targeting efficiency, drug loading, controlled release accuracy and therapeutic effect through the synergistic combination of magnetic hyperthermia and thermosensitive release, dual-drug layered loading and anti-immune clearance design, providing an innovative solution for cancer treatment.

Claims

1. A diatom frustule-based intelligent controlled-release drug carrier, characterized in that: include: A pretreated diatom frustule core having a specific porosity of 75% to 85%; A magnetic nanoparticle layer coated on the surface of the core, wherein the magnetic nanoparticles are Fe3O4@SiO2, and the loading amount thereof accounts for 5-15wt% of the total weight of the carrier; A targeting ligand grafted onto the surface of the magnetic layer, wherein the targeting ligand is an RGD peptide; The pH response layer, enzyme response layer and temperature-sensitive response layer are sequentially coated on the outside of the targeting ligand modification layer, wherein the pH response layer is polydopamine, the enzyme response layer is chitosan, and the temperature-sensitive response layer is poly N-isopropylacrylamide (PNIPAM).

2. The diatom frustule-based intelligent controlled-release drug carrier according to claim 1, characterized in that: The thickness of the polydopamine layer is 50-200 nm, and the thickness of the chitosan layer is 50-200 nm.

3. The diatom frustule-based intelligent controlled-release drug carrier according to claim 1, characterized in that: The carrier has a multi-drug loading capacity, hydrophobic drugs are embedded in the pores of the diatom shell, hydrophilic drugs are adsorbed on the surface of the chitosan layer, and the photothermal agent is loaded on the surface of the magnetic nanoparticles.

4. A method for preparing the diatom frustule-based intelligent controlled-release drug carrier according to claim 1, characterized in that: The following steps are involved: S1 diatomite was subjected to hydrofluoric acid etching treatment, the etching time was 2 hours, the concentration of the hydrofluoric acid solution used for etching was 5%, after etching, it was washed with deionized water to neutrality, and then calcined at a high temperature of 600 ° C for 3 hours; S2. Fe3O4@SiO2 magnetic nanoparticles were loaded by the sol-gel method, specifically by dispersing the calcined diatom shells in a 0.1 M FeCl3 solution, adjusting the pH to 10 with aqueous ammonia, and hydrolyzing with ethyl orthosilicate for 3 hours; S3. RGD peptide was grafted onto the surface of the magnetic nanoparticle-loaded carrier using the EDC / NHS method, wherein the carrier was suspended in MES buffer (pH 5.5), activated with 0.1 M EDC and 0.05 M NHS for 30 minutes, and then RGD peptide was added at a concentration of 1 mg / mL and reacted for 2 hours; S4. Prepare the polydopamine layer, chitosan layer, and grafted PNIPAM thermosensitive layer sequentially by dip coating. The polydopamine solution used in the preparation of the polydopamine layer has a concentration of 2 mg / mL, and the solvent is Tris-HCl buffer with a pH of 8.

5. The chitosan solution used in the preparation of the chitosan layer has a concentration of 1%, and the solvent is acetic acid solution. The concentration of PNIPAM grafting is 0.5%.

5. The preparation method according to claim 4, characterized in that Before the step of loading the magnetic nanoparticles, the surface of the etched and calcined diatom frustules is subjected to a hydroxylation treatment to enhance the loading effect of the magnetic nanoparticles.

6. The preparation method according to claim 4, characterized in that After grafting the RGD peptide, the carrier is subjected to a blocking treatment to block unreacted active sites and improve the stability of the carrier.

7. A method for drug delivery using the diatom frustule-based intelligent controlled-release carrier according to any one of claims 1 to 3, characterized in that: The drug-loaded carrier is introduced into the body through injection or oral administration. In the in vivo environment, the drug is intelligently released based on the pH response, enzyme response and temperature-sensitive response characteristics of the carrier.

8. The drug delivery method according to claim 7, characterized in that In tumor treatment applications, RGD peptides on the carrier surface are used to target tumor cells, and the therapeutic effect is enhanced through the combined action of photothermal agents and external light.

9. Use of the diatom frustule-based intelligent controlled-release drug carrier according to any one of claims 1 to 3 in the preparation of a pharmaceutical preparation for tumor targeted therapy, gene delivery or vaccine adjuvant.

10. The use according to claim 9, characterized in that The tumor targeted therapy includes the treatment of solid tumors such as liver cancer, lung cancer, and breast cancer.