DNA纳米花生物医学研究进展概述

doi:10.6023/A24030075

摘要/Abstract

DNA纳米结构因其可编程性、自主设计性和良好的生物相容性, 在生物医学领域显示出巨大的应用潜力. DNA纳米花(DNA nanoflower, DNF)作为一种独特的DNA-有机无机杂化纳米结构, 在近几年内引起了相当多的关注. 其矿化的无机内核不仅有助于维持DNA的稳定性, 还提供了金属离子的辅助矿化功能. 其中DNF凭借其高密度的核酸序列和良好的载荷能力, 可高效装载药物、荧光探针、酶及核酸适配体等功能性分子. 此外, 还可通过控制反应条件调节纳米颗粒的尺寸, 实现在不同生理环境下的高渗透、长滞留效应, 进而应用于生物医学的多个领域. 综述了DNF的合成及其生物医学应用. 首先简要介绍了DNF的合成方法以及合成条件的控制; 其次总结了工程化的DNF在生物检测、生物成像和药物治疗方面的应用; 最后, 讨论了DNF在生物医学应用中的挑战并对其在实际临床的应用进行展望. 未来基于DNF更广泛的生物医学发展有待研究人员们的探索.

关键词: DNA纳米花, 生物检测, 生物成像, 药物治疗

DNA nanostructures show great potential for biomedical applications due to their programmability, autonomous design and good biocompatibility. DNA nanoflower (DNF), as a unique DNA-organic inorganic hybrid nanostructure, has attracted considerable attention within recent years. Its mineralized inorganic core not only helps to maintain the stability of DNA, but also provides an auxiliary mineralization function of metal ions. Among them, DNFs can efficiently load functional molecules such as drugs, fluorescent probes, enzymes, nucleic acid aptamers, and so on, by virtue of their high-density nucleic acid sequences and good loading capacity. In addition, the size of the nanoparticles can be adjusted by controlling the reaction conditions, which is suitable for high permeability and long retention effects in different physiological environments, and thus applied in many fields of biomedicine. In this paper, the synthesis and biomedical applications of DNF are reviewed. Firstly, the main synthesis methods of DNF, rolling circle amplification (RCA) as well as salt aging method, are firstly introduced in detail, and different reaction conditions including enzymes, reaction time, temperature, pH, etc., the synthesis of DNF with different cationic metal cores or modification of DNF by different substances are highlighted for the functional as well as structural alteration of DNF, which can adapt the DNF to the applications in various scenarios. Secondly, the biomedical applications of DNF, including the latest research progress in bio-detection, bio-imaging and drug therapy, are demonstrated. Due to the unique physicochemical properties of DNF, including good biocompatibility, biodegradability, and structural and functional diversities, DNF has become a kind of nucleic acid nanomaterials with great potentials for applications. Finally, the prospects for the application of DNF and the current challenges are summarized, and great hopes are placed on researchers to explore the understanding of the formation mechanism and function of DNF as well as the applied research of metal salt cores to effectively promote the development of DNF-based biomedicine.

Key words: DNA nanoflower, bio-detection, bio-imaging, drug therapy

引用此文

王丹钰, 郭子涵, 郭梦珂, 易桦, 黄梦雨, 段捷, 张开翔. DNA纳米花生物医学研究进展概述[J]. 化学学报, 2024, 82(6): 677-689.

Danyu Wang, Zihan Guo, Mengke Guo, Hua Yi, Mengyu Huang, Jie Duan, Kaixiang Zhang. Overview of Advances in DNA Nanoflower Biomedical Research[J]. Acta Chimica Sinica, 2024, 82(6): 677-689.

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图/表 7

图1. 通过RCA方法合成DNF (A)通过RCA反应形成DNF的机制, 在Φ-29和Mg2+的共同作用下利用DNA环形模板来合成DNA长链与反应中生成的焦磷酸镁共结晶形成DNF[3]. (B)利用被修饰的dNTP来生成具有叠氮化物、炔烃和/或胺的长ssDNA, 生成具有胺、炔烃和叠氮化物的化学手柄的功能化的DNF[4]

Figure 1. Synthesis of DNF by the RCA method (A) Mechanism of the formation of DNF by RCA reaction, in which the DNA circular template is used to synthesize the long DNA strand under the combined action of Φ-29 and Mg2+ to co-crystallize with the magnesium pyrophosphate generated in the reaction to form DNF[3]. Copyright 2018, Nucleic Acids Research. (B) The modified dNTP is used to generate long ssDNA with azide, alkyne and/or amine to generate a functionalized DNF with a chemical handle of amine, alkyne and azide[4]. Copyright 2021, Nucleic Acids Research.

图2. DNF在生物医学方面的应用(由BioRender.com创建)

Figure 2. Applications of DNF in biomedicine (Created with BioRender.com)

图3. DNF在生物标志物检测方面的应用 (A)采用靶标和模拟靶标的同步循环扩增策略, 以进一步触发RCA过程, 在传感界面上原位生成ECL DNA NFs的信号标签, 超灵敏地检测粘蛋白1 (MUC1)[18]. (B)利用氧化石墨烯包被的铜掺杂氧化锌量子点作为光活性材料和葡萄糖氧化酶包封的DNA纳米花(GOx-DFs)进行信号放大, 用于灵敏地检测凝血酶[19]. (C)利用DNA-Cu3(PO4)2 HNFs作为捕获元件, 构建了一个简单的微RNA (miRNA)检测的线程平台, 其信号可被个人血糖仪读取[21]. (D) RCA合成包封葡萄糖氧化酶和辣根过氧化物酶(GHDFs), 将GHDFs作为DNA水凝胶的载物, 应用于HPV DNA检测. 当存在靶DNA时, DNA水凝胶交联结构被破坏, 释放GHDF, 然后催化葡萄糖和四甲基联苯胺的级联氧化, 产生显著的电信号[23]. (E)利用DNFs包封纳米酶作为RCA自组装探针, 来实现对MCF-7细胞来源外泌体的比色/光热双模式检测[26]. (F) CNDNF适配传感器与细胞膜中的靶受体PSMA结合, 经历受体介导的内化为靶细胞, 进入胞质溶胶后, 与细胞内靶标(ATP)识别触发CNDNF适配传感器释放AE实现基于FRET的比率ATP水平监测[30]

Figure 3. Application of DNF in biomarker detection (A) A synchronous cyclic amplification strategy of target and mock targets was employed to further trigger the RCA process to generate in situ a signal label of ECL DNA NFs at the sensing interface for ultra sensitively detecting mucin 1 (MUC1)[18]. Copyright 2017, Chemical Communications. (B) Signal amplification using graphene oxide-coated copper doped zinc oxide quantum dots as photoactive materials and glucose oxidase-coated DNA nanoflowers (GOx-DFs) for sensitive detection of thrombin[19]. Copyright 2017, Chemical Communications. (C) DNA-Cu3(PO4)2 HNFs as capture elements, A simple threading platform for microrna (miRNA) detection was constructed, and its signal could be read by a personal glucose meter[21]. Copyright 2018, Applied Materials. (D) RCA synthesized encapsulated glucose oxidase and horseradish peroxidase (GHDFs), and used GHDFs as the carrier of DNA hydrogel for HPV DNA detection. In the presence of target DNA, the DNA hydrogel cross-linked structure is disrupted, releasing GHDF, which then catalyzes the cascade oxidation of glucose and tetramethylbenzidine, producing a significant electrical signal[23]. Copyright 2022, Sensors and Actuators B: Chemical. (E) using DNFs-encapsulated nanozymes as RCA self-assembly probes to achieve the colorimetric/photothermal dual-mode detection of MCF-7 cell-derived exosomes[26]. Copyright 2023, Talanta. (F) The CNDNF-aptamer binds to the target receptor PSMA in the cell membrane, undergoes receptor-mediated internalization into the target cells, and upon entry into the cytosol, it recognizes the intracellular target (ATP) and triggers the release of AE from the CNDNF-aptamer for FRET-based monitoring of the ratio ATP level[30]. Copyright 2021, Applied Materials.

图4. DNF在生物成像方面应用的示意图(由BioRender.com创建)

Figure 4. Schematic diagram of the application of DNF in biological imaging (Created with BioRender.com)

图5. DNFs在生物成像方面的应用 (A)通过滚动循环复制来制造适配体偶联的FRET纳米花, 用于多重细胞成像和可追溯的靶向药物递送[33]. (B) RCA形成的DNF结构的序列编码扩增子(SeqEA)可以通过与荧光团标记的检测探针(P1和P2)杂交来可视化, 将具有离散荧光强度的扩增子精确编码为荧光条形码, 用于通过调整B1序列来标记不同的靶RNA. 通过原位扩增和序列编码方法, 可以以单分子分辨率可视化多种RNA[34]. (C)由DNA/Mg2+混合DNFCas12a/crRNA和圆形报告基因组成集成的纳米Cas12a传感器(InCasor), 用于活细胞的mtDNA成像[35]. (D) DMFN在酸的作用释放Mn2+, 并利用AS1411适配体的主动靶向, 增强MR信号进行荷瘤小鼠体内磁共振成像[37]

Figure 5. Application of DNFs in biological imaging (A) Fabrication of aptamer-conjugated FRET nanoflowers by rolling cycle replication for multiplex cell imaging and traceable targeted drug delivery[33]. Copyright 2014, Angewandte Chemie International Edition. (B) Sequence-encoded amplicons (SeqEA) of RCA-formed DNF structures can be visualized by hybridization with fluorophore labeled detection probes (P1 and P2), allowing amplicons with discrete fluorescence intensities to be precisely encoded as fluorescent barcodes for labeling different target RNAs by tuning the B1 sequence. A variety of RNAs can be visualized at single-molecule resolution by in situ amplification and sequence coding methods[34]. Copyright 2018, Chem. (C) Consists of DNA/Mg2+ hybrid DNFCas12a/crRNA and circular reporter to form an integrated nano-cas12a sensor (InCasor) for mtDNA imaging in living cells[35]. Copyright 2023, Nature Communications. (D) DMFN released Mn2+ in the presence of acid and utilized active targeting of AS1411 aptamer to enhance MR signal for in vivo MR Imaging in tumor-bearing mice[37]. Copyright 2021, Biomaterials

图6. DNF在生物治疗方面应用的示意图(由BioRender.com创建)

Figure 6. Schematic diagram of the application of DNF in biotherapy (Created with BioRender.com)

图7. DNF在生物治疗方面的应用 (A)通过序列杂交将Cas9/sgRNA加载到DNF上, 通过MUC1介导的内吞作用、溶酶体逃逸以及miRNA-21介导的Cas9/sgRNA释放进行基因组编辑[43]. (B) CpG互补链和FITC标记的引物形成环状模板. 使用Φ29 DNA聚合酶进行RCA通过液晶自组装DNFs. DNFs被巨噬细胞吸收后, 可被TLR9识别, 随后分泌细胞因子, 起到免疫治疗的作用[47]. (C)掺入人工三明治基质, 设计了生物启发、大小可控且可自降解的癌症靶向DNA纳米花(Sgc8-NFs-Fc). 通过芬顿的反应, Sgc8-NFs-Fc在H2O2存在下具有自降解性, 并可以携带DOX显著提高肿瘤的治疗效果[51]. (D)由肿瘤靶向适配体和DNA酶组成多功能的DNFs, 并表面修饰低剂量光敏剂Ce6, 用于沉默自噬相关基因, 增敏低剂量光动力学治疗[61]

Figure 7. Applications of DNF in biotherapy (A) Loading Cas9/sgRNA onto DNF by sequence hybridization for genome editing via MUC1-mediated endocytosis, lysosomal escape, and miRNA-21-mediated Cas9/sgRNA release[43]. Copyright 2021, Biomaterials. (B) CpG complementary strand and FITC-labeled primer form a circular template. RCA through liquid crystal self-assembly of DNFs was performed using Φ29 DNA polymerase. After being absorbed by macrophages, DNFs can be recognized by TLR9 and then secrete cytokines to play a role in immunotherapy[47]. Copyright 2015, ACS Applied Materials & Interfaces. (C) By incorporating an artificial sandwich matrix, bioinspired, size-controllable, self-degradable cancer-targeting DNA nanoflowers (Sgc8-NFs-Fc) were designed. Through Fenton's reaction, Sgc8-NFs-Fc is self-degradable in the presence of H2O2 and can carry DOX to significantly improve the therapeutic effect of tumors[51]. Copyright 2019, Journal of the American Chemical Society. (D) DNFs are composed of tumor targeting aptamer and DNase, and the surface is modified with low-dose photosensitizer Ce6 to silence autophagy-related genes and enhance the sensitivity of low-dose photodynamic therapy[61]. Copyright 2021, Small

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