基于核酸和蛋白质生物分子阵列传感器的构建及检测应用的研究进展

doi:10.12211/2096-8280.2022-035

合成生物学 ›› 2023, Vol. 4 ›› Issue (1): 185-203.DOI: 10.12211/2096-8280.2022-035

基于核酸和蛋白质生物分子阵列传感器的构建及检测应用的研究进展

倪伟伟, 周玲佳, 王浩, 李飞, 韩进松

中国药科大学工学院食品质量与安全系，天然药物活性组分与药效国家重点实验室，国家中药材加工研发专业中心，江苏南京 211109

收稿日期:2022-06-25 修回日期:2022-08-26 出版日期:2023-02-28 发布日期:2023-03-07
通讯作者: 李飞,韩进松
作者简介:倪伟伟（1993—），男，博士研究生。研究方向为食品/药品质量控制及疾病的快速检测。E-mail：3120080256@stu.cpu.edu.cn
周玲佳（2000—），女，硕士研究生。研究方向为食品/药品质量控制及疾病的快速检测。
周玲佳（2000—），女，硕士研究生。研究方向为食品/药品质量控制及疾病的快速检测。E-mail：3221081884@stu.cpu.edu.cn
李飞（1990—），男，博士，特聘副研究员，博士生导师。研究方向为食品/药品安全及疾病快检与手性发光分子应用研究。E-mail：fei.li@cpu.edu.cn
韩进松（1987—），男，博士，教授，博士生导师。研究方向为食品/药品质量控制及疾病的快速检测与药物化学与新药研发。E-mail：Jinsong.han@cpu.edu.cn
第一联系人：倪伟伟（1993—），男，博士研究生。研究方向为食品/药品质量控制及疾病的快速检测。
基金资助:
国家自然科学基金(82072017)

Research progress in the construction of nucleic acid and protein biomolecular sensor arrays and their applications for rapid detection

Weiwei NI, Lingjia ZHOU, Hao WANG, Fei LI, Jinsong HAN

State Key Laboratory of Natural Medicines and National R&D Center for Chinese Herbal Medicine Processing，Department of Food Quality and Safety，College of Engineering，China Pharmaceutical University，Nanjing 211109，Jiangsu，China

Received:2022-06-25 Revised:2022-08-26 Online:2023-02-28 Published:2023-03-07
Contact: Fei LI, Jinsong HAN

摘要/Abstract

摘要：

阵列传感器是组合多个传感元件，通过交叉反应机理来区分一类目标分析物的策略，不同于传统探针类传感器“锁-钥”结合模式，阵列传感器为非特异性结合，可实现一对多的识别。然而，传感元件的制备仍然存在设计困难、合成复杂、信号转换效率低等诸多挑战。核酸和蛋白具有优良的生物相容性、灵活的可编程性、易实现的功能化和优越的分子识别性质等优点。目前已经通过合理设计和可控化制备手段构建了多种基于核酸和蛋白类传感元件的阵列传感器，结合机器学习算法对所得数据进行处理，使数据可视化，构建待测物“指纹图谱”，对待测物进行区分。在此综述中，重点介绍了基于核酸和蛋白类传感元件构建的阵列传感器的多目标检测应用，并讨论了其合理的应用前景以及挑战。

关键词: 阵列传感器, 核酸, 蛋白, 功能材料, 传感元件

Abstract:

The advent of sensor arrays is inspired by the superior performance of biological olfactory and taste systems on detection, recognition, tracking, and localization. By simulating the sensing mechanism of cross-response with the olfactory and taste systems, a sensor array can be constructed. Meanwhile, a series of algorithms are used to detect and distinguish targets based on fingerprints generated by the analyte to the array. However, the fabrication of sensing elements still faces many challenges, such as difficult design, complicated synthesis, and low signal collecting efficiency. Nucleic acids and proteins have advantages in biocompatibility, flexible programmability, easy functionalization, and superior molecular recognition properties. At present, a variety of sensor arrays based on nucleic acid and protein sensing elements have been constructed through rational design and controllable preparation methods. In this review, the multi-target detection applications of these sensor arrays are highlighted, and their application prospects and challenges are addressed. {L-End}

Key words: sensor array, nucleic acid, protein, functional material, sensing element

中图分类号:

Q816

倪伟伟, 周玲佳, 王浩, 李飞, 韩进松. 基于核酸和蛋白质生物分子阵列传感器的构建及检测应用的研究进展[J]. 合成生物学, 2023, 4(1): 185-203.

Weiwei NI, Lingjia ZHOU, Hao WANG, Fei LI, Jinsong HAN. Research progress in the construction of nucleic acid and protein biomolecular sensor arrays and their applications for rapid detection[J]. Synthetic Biology Journal, 2023, 4(1): 185-203.

图/表 7

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111	LIU C, YOU X R, LU D K, et al. Gelsolin encountering Ag nanorods/triangles: an aggregation-based colorimetric sensor array for in vivo monitoring the cerebrospinal Aβ₄₂% as an indicator of Cd²⁺ exposure-related Alzheimer's disease pathogenesis[J]. ACS Applied Bio Materials, 2020, 3(11): 7965-7973.
112	MIRANDA O R, CHEN H T, YOU C C, et al. Enzyme-amplified array sensing of proteins in solution and in biofluids[J]. Journal of the American Chemical Society, 2010, 132(14): 5285-5289.
113	MIRANDA O R, LI X N, GARCIA-GONZALEZ L, et al. Colorimetric bacteria sensing using a supramolecular enzyme-nanoparticle biosensor[J]. Journal of the American Chemical Society, 2011, 133(25): 9650-9653.
114	HAN J S, CHENG H R, WANG B H, et al. A polymer/peptide complex-based sensor array that discriminates bacteria in urine[J]. Angewandte Chemie International Edition, 2017, 56(48): 15246-15251.
115	FAN X B, XU W, HAN J S, et al. Antimicrobial peptide hybrid fluorescent protein based sensor array discriminate ten most frequent clinic isolates[J]. Biochimica et Biophysica Acta (BBA)-General Subjects, 2019, 1863(6): 1158-1166.
116	FAN X B, XU W, GAO W, et al. A facile method to classify clinic isolates with a turn-off sensor array based on graphene oxide and antimicrobial peptides[J]. Sensors and Actuators B: Chemical, 2020, 307: 127607.
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118	GHANEM E, HOPFER H, NAVARRO A, et al. Predicting the composition of red wine blends using an array of multicomponent peptide-based sensors[J]. Molecules, 2015, 20(5): 9170-9182.

发表时间	传感元件	应用	参考文献
2012	适配体修饰的磁性纳米粒子结合有核酸适配体的磁性纳米粒子（ACMNP）	区分不同的细胞类型癌细胞的模式识别	[15]
2014	荧光标记的适配体异硫氰酸荧光素酯（FITC）、花菁染料3（Cy3）和花菁染料5（Cy5）标记的核酸	区分癌细胞的类型	[16]
1993	荧光团标记的单链DNA（ssDNA）	检测蛋白酶	[20]
2018	DNA-染料-金属离子复合体系	区分硫醇	[21]
2018	结合铕（Eu³⁺）的富含胞嘧啶和胸腺嘧啶的ssDNA（Eu-C₁₆和Eu-T₁₆）	金属离子的检测	[23]
2019	吸附荧光团标记的ssDNA的含有Cu、Fe、Zr离子的纳米级金属有机框架	对蛋白质和细胞的并行检测	[24]
2018	nGO、MoS₂和WS₂纳米片和多个荧光团标记的DNA	对蛋白质、癌细胞、miRNA和不同结构状态的大分子的鉴定	[25-27]
2018	5个荧光标记的ssDNA	区分具有单核苷酸差异的let-7 miRNA 家族的9个成员	[28]
2021	GO、MoS₂纳米片和一个DNA 库	细菌和蛋白质的检测	[29]
2015	三个金属氧化物纳米颗粒与DNA 的复合物	磷酸根、砷酸根和亚砷酸根等常见阴离子的检测	[30]
2020	纳米多孔阳极氧化铝 (NAA) 支架装载荧光指示剂罗丹明B，在孔入口用 DNA 适体进行覆盖	检测金黄色葡萄球菌	[31]
2013	AuNPs 和碱基形成的复合物	区分不同的蛋白质和细胞类型	[32]
2017	含有两条不同长度的ssDNA的AuNPs	识别残留的抗生素	[33]
2018	ssDNA-AuNPs复合物	识别牛奶中的抗生素	[34]
2017	两条不同摩尔比的DNA修饰的AuNPs	蛋白质测定	[35]
2019	非特异性寡核苷酸修饰的AuNPs	区分蛋白质	[36]
2018	三个非特异性DNA链与不同的蛋白质混合后，加入阳离子聚-(二烯丙基二甲基氯化铵)(PDDA)和AuNPs	区分不同的蛋白质	[37]
2013	使用DNA修饰的催化AuNPs	蛋白质识别	[38]
2014	DNA-AuNPs	区分细胞类型	[39]
2015	DNA-AuNPs-GO	区分不同亚型和等级的肿瘤细胞	[40]
2019	锆金属-有机框架（Zr-MOFs）与固定有ssDNA 的 AuNPs 复合	识别蛋白质和人类精液样本	[41]
2017	基于蛋白质和DNA 之间的相互作用	蛋白质识别	[42]
2017	基于AuNPs在H2O2 存在下可催化3,3,5,5-四甲基联苯胺（TMB）产生蓝色，使用三种DNA 修饰的AuNPs	蛋白质识别	[43]
2015	AuNPs 和非特异性染料标记的DNA	蛋白质的区分	[44]
2019	AuNPs 与三个染料标记的ssDNA 序列复合	区分正常细胞与病理性细胞	[45]
2016	AuNPs-DNA复合物	检测并区分重金属离子	[46]
2019	以DNA为模板的Cu纳米颗粒和金属介导的碱基对	区分生物硫醇	[51]
2012	GO和荧光染料标记的非特异性DNA序列	对蛋白质、细胞和细菌进行定性和定量分析	[55]
2017	纳米氧化石墨烯（nGO）和荧光团修饰的单链DNA共轭	确定抗体降解途径	[56]
2017	nGO和三个表现出不同序列和荧光团的（ssDNA）共轭	识别蛋白质	[57]
2015	表面固定有核酸适配体的磁性纳米粒子	检测氯霉素	[58]
2019	核酸适配体共轭磁性纳米粒子	检测广泛存在的食源性病原体副溶血弧菌	[59]
2020	适配体和抗体结合的双重识别单元	检测单核细胞增生李斯特菌	[60]
2021	吸附三种靶向外泌体蛋白的核酸的C₃N₄纳米片	检测和诊断癌症	[62]
2009	使用阳离子共轭低聚电解质（COE）与6-羧基荧光素（6-FAM）标记的ssDNA聚集体	蛋白质识别	[63]
2021	ssDNA 苝复合物	进行蛋白质的区分	[64]
2010	共轭聚电解质和荧光素（FAM）标记的 ssDNA 的复合物	检测细菌	[65]
2017	DNA和两种染料的复合物	区分金属离子	[66]
2017	苯并呋喃尿苷荧光团标记的RNA	RNA 结构模式识别分析	[68]
2019	市售染料	DNA 的高通量二级结构分析	[72]
2020	核酸的自身荧光	探索 DNA 的二级结构	[73]
2018	包含各种化学支架的30个已知核酸黏合剂库	筛选特定核酸结构的选择性配体	[74]
2018	三种荧光蛋白（H-mTagBFP-H、H-EGFP-H、H-sfCherry-H）	在水溶液中实现了对9种金属离子的区分	[101]
2009	绿色荧光蛋白（GFP）和五种纳米颗粒形成的复合物	检测缓冲液和人血清中生物相关浓度的蛋白质	[102]
2010	纳米粒子与GFP	有效识别多种哺乳动物癌细胞	[103]
2020	由金纳米粒子（AuNPs）和高效绿色荧光蛋白（EGFP）组成	低剂量条件下快速检测细胞异常的早期迹象	[104]
2018	由功能化金纳米粒子（BenzNP）和三个荧光蛋白（EGFP, EBFP, tdTomato）组成	快速区分乳腺癌干细胞和非肿瘤干细胞	[105]
2017	功能化的金纳米粒子（BenzNP）作为识别元件，GFP作为荧光报告传感器	在超低浓度下（兆分之一和千万亿分之一摩尔水平）检测细胞的雌激素EDC反应	[106]
2018	聚亚苯基乙炔（PPE）和改性GFP（GFP-K72）的复合物	在25 mmol浓度下以100%的准确度识别20种天然氨基酸	[107]
2016	由一系列共轭聚合物（CPs）和GFP构成的静电复合物	识别16种不同的细胞类型，并区分健康细胞、癌细胞和转移细胞	[108]
2017	共轭荧光聚电解质与三种荧光蛋白（GFP、GFP-K36、GFP-E36）构建成传感元件	识别威士忌的关键品质信息，如麦芽状态、酒龄、原产地甚至口味等	[109]
2021	胶溶蛋白（Gelsolin）修饰的Ag-NTs和Ag-NRs	同时识别和检测复杂脑样本中的Aβ₄₀和Aβ₄₂	[110]
2020	带负电的PPE与四种带正电的抗菌肽（AMPs）形成的静电复合物	准确识别和区分14种细菌	[111]
2010	抗菌肽Ib-AMP4融合GFP形成的重组IGP蛋白	识别10种最常见的临床分离菌	[112]
2011	基于GO猝灭的聚组氨酸适配器与AMPs融合体	细菌识别	[113]
2017	基于肽单元和荧光团	识别溶解在水中的合成聚合物	[114]
2019	由荧光肽和氧化石墨烯（GO）复合组成	可以靶向病毒半胱氨酸上的糖蛋白，利用主成分分析促进埃博拉病毒、马尔堡病毒和水泡性口炎病毒的鉴别	[115]
2020	由1个含组氨酸的短肽、1个二价金属离子和1个pH比色指示剂组成	区分和预测红酒混合物成分	[116]
2020	结合有β-半乳糖苷酶的AuNPs	蛋白质的识别	[117]
2015	结合有β-半乳糖苷酶的端基为季铵盐的AuNPs	检测微生物污染	[118]

发表时间	传感元件	应用	参考文献
2012	适配体修饰的磁性纳米粒子结合有核酸适配体的磁性纳米粒子（ACMNP）	区分不同的细胞类型癌细胞的模式识别	[15]
2014	荧光标记的适配体异硫氰酸荧光素酯（FITC）、花菁染料3（Cy3）和花菁染料5（Cy5）标记的核酸	区分癌细胞的类型	[16]
1993	荧光团标记的单链DNA（ssDNA）	检测蛋白酶	[20]
2018	DNA-染料-金属离子复合体系	区分硫醇	[21]
2018	结合铕（Eu³⁺）的富含胞嘧啶和胸腺嘧啶的ssDNA（Eu-C₁₆和Eu-T₁₆）	金属离子的检测	[23]
2019	吸附荧光团标记的ssDNA的含有Cu、Fe、Zr离子的纳米级金属有机框架	对蛋白质和细胞的并行检测	[24]
2018	nGO、MoS₂和WS₂纳米片和多个荧光团标记的DNA	对蛋白质、癌细胞、miRNA和不同结构状态的大分子的鉴定	[25-27]
2018	5个荧光标记的ssDNA	区分具有单核苷酸差异的let-7 miRNA 家族的9个成员	[28]
2021	GO、MoS₂纳米片和一个DNA 库	细菌和蛋白质的检测	[29]
2015	三个金属氧化物纳米颗粒与DNA 的复合物	磷酸根、砷酸根和亚砷酸根等常见阴离子的检测	[30]
2020	纳米多孔阳极氧化铝 (NAA) 支架装载荧光指示剂罗丹明B，在孔入口用 DNA 适体进行覆盖	检测金黄色葡萄球菌	[31]
2013	AuNPs 和碱基形成的复合物	区分不同的蛋白质和细胞类型	[32]
2017	含有两条不同长度的ssDNA的AuNPs	识别残留的抗生素	[33]
2018	ssDNA-AuNPs复合物	识别牛奶中的抗生素	[34]
2017	两条不同摩尔比的DNA修饰的AuNPs	蛋白质测定	[35]
2019	非特异性寡核苷酸修饰的AuNPs	区分蛋白质	[36]
2018	三个非特异性DNA链与不同的蛋白质混合后，加入阳离子聚-(二烯丙基二甲基氯化铵)(PDDA)和AuNPs	区分不同的蛋白质	[37]
2013	使用DNA修饰的催化AuNPs	蛋白质识别	[38]
2014	DNA-AuNPs	区分细胞类型	[39]
2015	DNA-AuNPs-GO	区分不同亚型和等级的肿瘤细胞	[40]
2019	锆金属-有机框架（Zr-MOFs）与固定有ssDNA 的 AuNPs 复合	识别蛋白质和人类精液样本	[41]
2017	基于蛋白质和DNA 之间的相互作用	蛋白质识别	[42]
2017	基于AuNPs在H2O2 存在下可催化3,3,5,5-四甲基联苯胺（TMB）产生蓝色，使用三种DNA 修饰的AuNPs	蛋白质识别	[43]
2015	AuNPs 和非特异性染料标记的DNA	蛋白质的区分	[44]
2019	AuNPs 与三个染料标记的ssDNA 序列复合	区分正常细胞与病理性细胞	[45]
2016	AuNPs-DNA复合物	检测并区分重金属离子	[46]
2019	以DNA为模板的Cu纳米颗粒和金属介导的碱基对	区分生物硫醇	[51]
2012	GO和荧光染料标记的非特异性DNA序列	对蛋白质、细胞和细菌进行定性和定量分析	[55]
2017	纳米氧化石墨烯（nGO）和荧光团修饰的单链DNA共轭	确定抗体降解途径	[56]
2017	nGO和三个表现出不同序列和荧光团的（ssDNA）共轭	识别蛋白质	[57]
2015	表面固定有核酸适配体的磁性纳米粒子	检测氯霉素	[58]
2019	核酸适配体共轭磁性纳米粒子	检测广泛存在的食源性病原体副溶血弧菌	[59]
2020	适配体和抗体结合的双重识别单元	检测单核细胞增生李斯特菌	[60]
2021	吸附三种靶向外泌体蛋白的核酸的C₃N₄纳米片	检测和诊断癌症	[62]
2009	使用阳离子共轭低聚电解质（COE）与6-羧基荧光素（6-FAM）标记的ssDNA聚集体	蛋白质识别	[63]
2021	ssDNA 苝复合物	进行蛋白质的区分	[64]
2010	共轭聚电解质和荧光素（FAM）标记的 ssDNA 的复合物	检测细菌	[65]
2017	DNA和两种染料的复合物	区分金属离子	[66]
2017	苯并呋喃尿苷荧光团标记的RNA	RNA 结构模式识别分析	[68]
2019	市售染料	DNA 的高通量二级结构分析	[72]
2020	核酸的自身荧光	探索 DNA 的二级结构	[73]
2018	包含各种化学支架的30个已知核酸黏合剂库	筛选特定核酸结构的选择性配体	[74]
2018	三种荧光蛋白（H-mTagBFP-H、H-EGFP-H、H-sfCherry-H）	在水溶液中实现了对9种金属离子的区分	[101]
2009	绿色荧光蛋白（GFP）和五种纳米颗粒形成的复合物	检测缓冲液和人血清中生物相关浓度的蛋白质	[102]
2010	纳米粒子与GFP	有效识别多种哺乳动物癌细胞	[103]
2020	由金纳米粒子（AuNPs）和高效绿色荧光蛋白（EGFP）组成	低剂量条件下快速检测细胞异常的早期迹象	[104]
2018	由功能化金纳米粒子（BenzNP）和三个荧光蛋白（EGFP, EBFP, tdTomato）组成	快速区分乳腺癌干细胞和非肿瘤干细胞	[105]
2017	功能化的金纳米粒子（BenzNP）作为识别元件，GFP作为荧光报告传感器	在超低浓度下（兆分之一和千万亿分之一摩尔水平）检测细胞的雌激素EDC反应	[106]
2018	聚亚苯基乙炔（PPE）和改性GFP（GFP-K72）的复合物	在25 mmol浓度下以100%的准确度识别20种天然氨基酸	[107]
2016	由一系列共轭聚合物（CPs）和GFP构成的静电复合物	识别16种不同的细胞类型，并区分健康细胞、癌细胞和转移细胞	[108]
2017	共轭荧光聚电解质与三种荧光蛋白（GFP、GFP-K36、GFP-E36）构建成传感元件	识别威士忌的关键品质信息，如麦芽状态、酒龄、原产地甚至口味等	[109]
2021	胶溶蛋白（Gelsolin）修饰的Ag-NTs和Ag-NRs	同时识别和检测复杂脑样本中的Aβ₄₀和Aβ₄₂	[110]
2020	带负电的PPE与四种带正电的抗菌肽（AMPs）形成的静电复合物	准确识别和区分14种细菌	[111]
2010	抗菌肽Ib-AMP4融合GFP形成的重组IGP蛋白	识别10种最常见的临床分离菌	[112]
2011	基于GO猝灭的聚组氨酸适配器与AMPs融合体	细菌识别	[113]
2017	基于肽单元和荧光团	识别溶解在水中的合成聚合物	[114]
2019	由荧光肽和氧化石墨烯（GO）复合组成	可以靶向病毒半胱氨酸上的糖蛋白，利用主成分分析促进埃博拉病毒、马尔堡病毒和水泡性口炎病毒的鉴别	[115]
2020	由1个含组氨酸的短肽、1个二价金属离子和1个pH比色指示剂组成	区分和预测红酒混合物成分	[116]
2020	结合有β-半乳糖苷酶的AuNPs	蛋白质的识别	[117]
2015	结合有β-半乳糖苷酶的端基为季铵盐的AuNPs	检测微生物污染	[118]

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基于核酸和蛋白质生物分子阵列传感器的构建及检测应用的研究进展

Research progress in the construction of nucleic acid and protein biomolecular sensor arrays and their applications for rapid detection

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