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CN-121971408-A - Membrane bionic modified siRNA delivery system and preparation method and application thereof

CN121971408ACN 121971408 ACN121971408 ACN 121971408ACN-121971408-A

Abstract

The invention provides a membrane bionic modified siRNA delivery system and a preparation method and application thereof, wherein the preparation method comprises the steps of (1) dispersing MnO 2 nano particles in water, adding siANGPTL3 and a calcification agent for reaction to obtain siANGPTL3@MnO 2 nano particles after reaction, wherein siANGPTL3 is lipid-lowering siRNA for targeted inhibition of ANGPTL3 expression, (2) dispersing siANGPTL3@MnO 2 nano particles in water, adding platelet membrane for reaction to obtain siANGPTL3@P-MnO 2 nano particles after reaction. Compared with free siANGPTL3 molecules, the synthesized sialGPTL3@P-MnO 2 shows better oxygen production performance and biocompatibility, and shows better anti-atherosclerosis therapeutic effect.

Inventors

  • DONG JUNLIANG
  • ZHANG WENBIN
  • JIAO XIAOLU
  • LIN YUTONG

Assignees

  • 浙江大学

Dates

Publication Date
20260505
Application Date
20260409

Claims (10)

  1. 1. A method for preparing a membrane biomimetic modified siRNA delivery system, comprising the steps of: (1) Dispersing MnO 2 nano particles in water to obtain aqueous dispersion of MnO 2 nano particles, adding siANGPTL3 and calcification agent to react to obtain siANGPTL3@MnO 2 nano particles, wherein siANGPTL3 is lipid-lowering siRNA for targeted inhibition of ANGPTL3 expression; (2) Dispersing the siANGPTL3@MnO 2 nano particles in water to obtain an aqueous dispersion of the siANGPTL3@MnO 2 nano particles, adding a platelet membrane for reaction to obtain the siANGPTL3@P-MnO 2 nano particles after reaction, namely the membrane bionic modified siRNA delivery system.
  2. 2. The method according to claim 1, wherein in the step (1), the particle size of the MnO 2 nanoparticles is 200-250 nm, the pore volume of the MnO 2 nanoparticles is 0.15-0.30 cm 3 /g, and the specific surface area of the MnO 2 nanoparticles is 120-160 m 2 /g.
  3. 3. The preparation method of the nano-sized MnO 2 , wherein the micro-morphology of the nano-sized MnO 2 is in a nano-flower shape, and the preparation method is characterized in that KMnO 4 is dissolved in water and oleic acid is added for reduction reaction.
  4. 4. The method of claim 3, wherein the KMnO 4 , water and oleic acid are added in a ratio of (25-35) mg/15 mL/400. Mu.L, the temperature of the reduction reaction is 15-35 ℃ and the time is 3.5-5 h.
  5. 5. The method of claim 3, further comprising a purification step of washing the crude MnO 2 with a mixed solution of ethanol and water, and drying to obtain MnO 2 nanoparticles, wherein the volume ratio of ethanol to water in the mixed solution of ethanol and water is (1-2): 1.
  6. 6. The method according to claim 5, wherein in the step (1), the calcification agent is CaCl 2 , the reaction temperature is 2-5 ℃, and the concentration of the aqueous dispersion of MnO 2 nano particles is 0.1-1.5 mg/ml.
  7. 7. The preparation method of the nano-particles according to claim 1, wherein in the step (2), the reaction temperature is 2-5 ℃, the concentration of the aqueous dispersion of the siANGPTL3@MnO 2 nano-particles is 0.1-1.5 mg/ml, and the volume ratio of the platelet membrane to the aqueous dispersion of the siANGPTL3@MnO 2 nano-particles is 1 (1-2).
  8. 8. The method according to claim 1, wherein in the step (1), the feed ratio of the MnO 2 nanoparticles to siANGPTL is 200. Mu.g (1500-2000) OD.
  9. 9. A membrane biomimetic modified siRNA delivery system prepared by the method of any one of claims 1 to 8.
  10. 10. Use of the membrane-biomimetic modified siRNA delivery system of claim 9 in the manufacture of a medicament for the treatment of atherosclerosis.

Description

Membrane bionic modified siRNA delivery system and preparation method and application thereof Technical Field The invention relates to the technical field of biomedical drug molecules, in particular to a membrane bionic modified siRNA delivery system and a preparation method and application thereof. Background Atherosclerosis (As) is the most common cardiovascular disease, with long latency and chronic processes, and can remain asymptomatic for decades before serious health consequences occur. Its pathological features include lipid accumulation, chronic inflammation, plaque formation, etc. As plaque forms, they gradually reduce the space within the arterial lumen, damaging blood flow and interrupting the supply of oxygen and nutrients to organs and tissues. Currently, the treatment of atherosclerosis includes traditional drug therapies and surgical therapies. Among them, the drug therapy mainly uses various statin drugs to reduce lipid, and has relatively good curative effects, but has remarkable side effects caused by long-term drug use, drug resistance generation, drug allergy, recurrent cardiovascular events and the like. Patients undergoing surgical treatment often require lifelong treatment with anticoagulants, antiplatelet agents, and lipid-lowering agents to reduce the risk of recurrence and thrombosis. In view of these challenges, there is an increasing need for more accurate, targeted and less invasive treatments to effectively modulate the disease mechanisms of atherosclerosis. With the development of science, nano-drug delivery systems (NDDS) are a revolutionary method of treating atherosclerosis. NDDS have advantages over traditional therapies because they allow site-specific drug delivery and minimize systemic toxicity. NDDS can selectively accumulate within atherosclerotic plaques through receptor-mediated targeting or microenvironment, which designs both enhance drug efficacy and reduce off-target effects. NDDS can also facilitate the combined delivery of multiple therapeutic agents, allowing for simultaneous targeting of several pathological processes (e.g., inflammation, oxidative stress, cholesterol metabolism, and immune response), effectively solving the limitations of traditional drug therapies, enabling personalized interventions, achieving efficient therapeutic efficacy. Biomedical nanomaterials have made significant progress in fundamental research of integration of multiple modality treatment of atherosclerosis. But has been applied clinically or in clinical trials with little research effort. Disclosure of Invention In view of the above-mentioned drawbacks of the prior art, an object of the present invention is to provide a membrane biomimetic modified siRNA delivery system, and a preparation method and application thereof, for solving the problems that the existing methods for treating atherosclerosis by using traditional medicines need to be used for a long time, drug resistance, drug allergy, recurrent cardiovascular events and the like cause significant side effects, and patients receiving surgical treatment need to be treated with anticoagulants, antiplatelet medicines and lipid lowering medicines for life. To achieve the above and other related objects, the present invention provides a method for preparing a membrane biomimetic modified siRNA delivery system, comprising the steps of: (1) Dispersing MnO 2 nano particles in water to obtain aqueous dispersion of MnO 2 nano particles, adding siANGPTL3 and calcification agent to react to obtain siANGPTL3@MnO 2 nano particles, wherein siANGPTL3 is lipid-lowering siRNA for targeted inhibition of ANGPTL3 expression, and the water is preferably distilled water or deionized water. (2) Dispersing the siANGPTL3@MnO 2 nano particles in water to obtain an aqueous dispersion of the siANGPTL3@MnO 2 nano particles, adding a platelet membrane for reaction to obtain the siANGPTL3@P-MnO 2 nano particles after reaction, namely the membrane bionic modified siRNA delivery system. The platelet membrane is a biomimetic modification coating and is prepared by reaction through a normal temperature solvent method. ANGPTL3 acts as a natural inhibitor of lipoprotein esterases (lipoprotein lipase, LPL) and also inhibits the activity of endothelial lipases (endothelial lipase, EL), thus becoming a key molecule in lipid metabolism regulation studies. LPL plays a rate limiting role in the removal of triglyceride-rich lipoproteins from the circulation, while EL is localized primarily to the luminal surface of vascular endothelial cells, with higher specificity for the hydrolysis of lipoprotein phospholipids, particularly when acting on high density lipoproteins. Thus, inhibition of LPL and EL can be released by inhibiting the function of ANGPTL3, thereby enhancing the activity of both enzymes and further lowering the levels of low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), high density lipoprotein cholesterol (