Overview of Advances in DNA Nanoflower Biomedical Research

doi:10.6023/A24030075

Acta Chimica Sinica ›› 2024, Vol. 82 ›› Issue (6): 677-689.DOI: 10.6023/A24030075 Previous Articles Next Articles

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DNA纳米花生物医学研究进展概述

王丹钰^a, 郭子涵^a, 郭梦珂^a, 易桦^a, 黄梦雨^a, 段捷^a, 张开翔^a^,^b^,^*()

a 郑州大学药学院郑州 450001
b 河南省肿瘤重大疾病靶向治疗与诊断重点实验室郑州 450001

投稿日期:2024-03-08 发布日期:2024-04-28

作者简介:

王丹钰, 郑州大学药学院2021级药学专业博士研究生. 以第一作者在Nat. Commun., ACS Nano, Small, Adv. Healthcare Mater.及ACS Appl. Mater. Interfaces期刊发表研究论文5篇, 累计发表SCI收录论文10篇, 被引180余次, 参与多项国家自然科学基金项目.

张开翔, 郑州大学药学院教授, 博士生导师. 以第一作者或通讯作者在Nat. Commun., Sci. Adv., J. Am. Chem. Soc., Angew. Chem., Int. Ed., Adv. Mater.及Chem. Soc. Rev.等期刊发表研究论文50余篇, 累计发表SCI收录论文100余篇, 被引5000余次, 作为项目负责人承担国家自然科学基金项目4项.

基金资助:
国家自然科学基金(22122409); 国家自然科学基金(22377110); 河南省优势学科培育基金(222301420019)

Overview of Advances in DNA Nanoflower Biomedical Research

Danyu Wang^a, Zihan Guo^a, Mengke Guo^a, Hua Yi^a, Mengyu Huang^a, Jie Duan^a, Kaixiang Zhang^a^,^b,*()

a School of Pharmacy, Zhengzhou University, Zhengzhou 450001
b Henan Provincial Key Laboratory of Targeted Therapy and Diagnosis of Major Tumor Diseases, Zhengzhou 450001

Received:2024-03-08 Published:2024-04-28
Contact: * E-mail: zhangkx@zzu.edu.cn
Supported by:
National Natural Science Foundation of China(22122409); National Natural Science Foundation of China(22377110); Henan Province Advantage Discipline Cultivation Fund(222301420019)

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

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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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Fig. & Tab. 7

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.

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

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.

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

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

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

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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DNA纳米花生物医学研究进展概述

Overview of Advances in DNA Nanoflower Biomedical Research

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