CN-121987591-A - Nucleic acid-loaded metal polyphenol nano-drug targeting macrophages and preparation method and application thereof

CN121987591ACN 121987591 ACN121987591 ACN 121987591ACN-121987591-A

Abstract

The invention discloses a nucleic acid-loaded metal polyphenol nano-drug targeting macrophages, a preparation method and application thereof, the nano-drug takes a metal polyphenol network formed by self-assembly of cerium ions and kaempferol through coordination bonds as a core carrier, therapeutic nucleic acid is loaded in the nano-drug, and a hyaluronic acid targeting layer is coated on the outer layer. The invention adopts the steps of mixing Ce, kae and DNA to self-assemble to form a Ce-Kae-DNA core, and coating HA by electrostatic action. The nano-drug can target and deliver nucleic acid to macrophages, remarkably promote cholesterol excretion, simultaneously remove Reactive Oxygen Species (ROS), regulate inflammation microenvironment and have important application prospects in preparing drugs for treating inflammation-related diseases such as atherosclerosis and the like.

Inventors

PAN QINGSHAN
SUN YI
ZHANG JIANYE
XU CHONGHUI
ZHOU YUTONG
ZHAO YUERAN
XIN TONGXUAN
Nie Cunpeng
Zhu Sichong
MA MEIGUI
XU SHAN
Zhu wufu
ZHENG PENGWU
Xiang Dongliu

Assignees

江西科技师范大学

Dates

Publication Date: 20260508
Application Date: 20260312

Claims (10)

1. A nucleic acid-loaded metal polyphenol nano-drug targeting macrophages, which is characterized by comprising, from inside to outside, in order: the core carrier is a metal polyphenol network formed by self-assembling cerium ions and kaempferol through coordination bonds; A therapeutic nucleic acid loaded inside the core vector, forming a nucleic acid-containing core vector; And the targeting shell is a hyaluronic acid coating coated on the surface of the core carrier containing the nucleic acid, so that the final nano-drug is formed.
2. The macrophage-targeted nucleic acid-loaded metal polyphenol nano-drug according to claim 1, wherein the therapeutic nucleic acid is physically embedded inside the core carrier by electrostatic adsorption.
3. The nucleic acid-loaded metal polyphenol nano-drug targeting macrophages, according to claim 2, wherein the molecular weight of the hyaluronic acid is 30kDa.
4. The macrophage-targeted nucleic acid-loaded metal polyphenol nano-drug according to claim 3, wherein the nano-drug has the characteristics of hierarchical assembly of particle size and Zeta potential, the average particle size of the naked core carrier is 80nm, zeta potential is +18.2mV, the average particle size of the core carrier containing nucleic acid is 110nm, zeta potential is +4mV, and after the targeting shell is coated, the average particle size of the nano-drug is 140nm, zeta potential is-24.5mV.
5. A method of preparing a macrophage-targeted nucleic acid-loaded metal polyphenol nano-drug according to any of claims 1-4, comprising the steps of: S1, mixing cerium salt solution, kaempferol solution and therapeutic nucleic acid solution, and reacting to obtain a core carrier containing nucleic acid; s2, mixing the core carrier containing the nucleic acid obtained in the step S1 with a hyaluronic acid solution, and reacting to obtain the nano-drug.
6. The method according to claim 5, wherein in step S1, the molar ratio of cerium ions, kaempferol to therapeutic nucleic acid is 10:4:1.
7. The method of claim 6, wherein in step S1, the reaction is carried out at room temperature with a stirring speed of 500rpm for 30 minutes.
8. The method according to claim 7, wherein in the step S2, the reaction is carried out at room temperature with a stirring speed of 500rpm and a reaction time of 120 minutes.
9. The method according to claim 5, wherein the method further comprises a step of centrifugal washing and/or freeze-drying after step S2.
10. Use of a nucleic acid-loaded metal polyphenol nano-drug targeting macrophages according to any of claims 1-4 in the manufacture of a medicament for the prevention or treatment of cardiovascular disease.

Description

Nucleic acid-loaded metal polyphenol nano-drug targeting macrophages and preparation method and application thereof Technical Field The invention belongs to the technical field of biological medicine and nano delivery, and in particular relates to a nucleic acid-loaded metal polyphenol nano-drug targeting macrophages, a preparation method thereof and application thereof in preparing medicines for preventing or treating cardiovascular inflammatory diseases such as atherosclerosis. Background Atherosclerosis (AS) is the main pathological basis for inducing serious cardiovascular diseases such AS myocardial infarction, cerebral apoplexy and the like, and has extremely high mortality and disability rate. Macrophages play a central role in the development and progression of atherosclerosis. Macrophages at the focal site can phagocytose oxidized low density lipoproteins (ox-LDL) in large amounts, and due to the blockage of intracellular cholesterol efflux mechanisms, lipid is excessively accumulated, eventually transforming into foam cells and forming plaque lipid cores. Meanwhile, macrophages produce large amounts of Reactive Oxygen Species (ROS) during phagocytosis, initiate severe oxidative stress, and secrete large amounts of pro-inflammatory factors (e.g., IL-6, TNF- α) to form a sustained chronic inflammatory microenvironment. Thus, promoting cholesterol efflux in macrophages, scavenging excess ROS, and alleviating local inflammation are key strategies for treating atherosclerosis. In recent years, gene therapy has shown great potential in the field of cardiovascular diseases. For example, it has been found that inhibitors of specific micrornas (such as miR-33) (Anti-miR-33) can significantly up-regulate protein expression associated with cholesterol efflux, thereby promoting lipid efflux and reversing foam cell formation. However, free therapeutic nucleic acids are subject to difficult physiological barriers to overcome when used in vivo, on the one hand, naked nucleic acids are very easily degraded by nucleases in blood, have short half-lives and poor physiological stability, and on the other hand, free nucleic acids lack targeting and are difficult to concentrate in macrophages in focal areas across cell membrane barriers, so that the drug efficacy is low and off-target side effects can occur. To overcome the barrier to nucleic acid delivery, researchers have developed a variety of nanocarriers (e.g., cationic liposomes, high molecular polymers, etc.). However, there are still a number of significant drawbacks to existing conventional nano-delivery systems: first, most of traditional nano-carriers are "inert" carriers, only have a single delivery function, and cannot actively regulate complex "high ROS, high inflammation" microenvironments at atherosclerotic lesions. Second, some inorganic or cationic polymer drug-carrying systems have the problems of complex preparation process, low nucleic acid loading rate, easy leakage, potential cytotoxicity and the like. Third, the lack of specific recognition of focal zone macrophages results in a need for improved targeted delivery efficiency. The nano-materials based on the Metal Polyphenol Network (MPNs) have been paid attention to in recent years, but how to screen out the metal-polyphenol combination with the optimal antioxidant enzyme activity and simultaneously realize the efficient, stable load and accurate targeted delivery of nucleic acid, and no mature and excellent technical scheme exists at present. In summary, existing single nucleic acid drugs or conventional delivery vehicles cannot meet the therapeutic needs in complex inflammatory microenvironments. Therefore, there is a need in the art to develop a novel multifunctional nano-drug system which can precisely target macrophages, efficiently and stably load protective nucleic acid, and can remove ROS and reverse inflammatory microenvironment by means of the characteristics of a vector while delivering genes, so as to realize the multidimensional synergistic therapeutic effect of gene-antioxidation-anti-inflammatory. Disclosure of Invention The invention aims to solve the technical problems that in the prior art, therapeutic nucleic acid is easy to degrade in vivo and lacks targeting, and the traditional nano-carrier has single function and cannot effectively improve the complex inflammatory microenvironment of atherosclerosis. In order to achieve the above purpose, the present invention provides the following technical solutions: A nucleic acid-loaded metal polyphenol nano-drug targeting macrophages, which comprises the following components from inside to outside in sequence: The core carrier is a metal polyphenol network formed by self-assembling cerium ions and kaempferol through coordination bonds; a therapeutic nucleic acid loaded inside the core vector to form a nucleic acid-containing core vector; And the targeting shell is a hyaluronic acid coating coated on the surface of the core carrier co