基于纳米光子技术检测SARS-CoV-2研究进展※

doi:10.6023/A21100469

化学学报 ›› 2022, Vol. 80 ›› Issue (1): 80-88.DOI: 10.6023/A21100469 上一篇下一篇

所属专题：中国科学院青年创新促进会合辑

综述

基于纳米光子技术检测SARS-CoV-2研究进展^※

杨旭^a^,^b, 张泽英^a^,^b, 苏萌^a^,^b^,^*(), 宋延林^a^,^b^,^*()

^a中国科学院化学研究所绿色印刷重点实验室北京 100190
^b中国科学院大学北京 100049

投稿日期:2021-10-21 发布日期:2021-12-23
通讯作者: 苏萌, 宋延林

作者简介:

杨旭, 博士研究生. 2020年7月于中国科学院大学获理学学士学位. 现为中国科学院化学研究所宋延林研究员课题组直博生, 研究方向为微纳结构的绿色印刷与生物标志物的灵敏检测.

张泽英, 2016年于兰州大学获得学士学位, 2021年于中科院化学所获得博士学位. 目前在中科院化学所宋延林研究员课题组开展博士后研究, 主要从事于微纳结构的精细组装及其光学性质探究和生物检测.

苏萌, 博士, 中国科学院化学研究所副研究员, 北京市科技新星, 中国科学院青年创新促进会会员. 2017年在中国科学院化学研究所获得博士学位, 同年入选“博士后创新人才支持计划”, 现任中国科学院化学研究所副研究员. 提出了墨滴调控自成形的印刷微纳图案化方法, 实现了纳米级图案和器件的印刷制造. 已发表学术论文70余篇, 申请/授权发明专利15项, 参与起草制定国际标准1项.

宋延林, 中国科学院化学研究所研究员、绿色印刷重点实验室主任、博士生导师, 中国科学院大学长江学者特聘教授, 杰青. 主要从事光电功能材料、纳米材料与绿色印刷技术研究. 已发表SCI 收录论文400余篇, 被他人引用20,000余次, 并多次被Nature, Science 等作为研究亮点报道. 主持和参加编写英文专著10 部, 中文专著2部; 获授权中国发明专利100余项, 美国、日本、欧盟、韩国等授权发明专利26项.

^※ 庆祝中国科学院青年创新促进会十年华诞.

基金资助:
项目受国家重点研发计划(2018YFA0208501); 国家自然科学基金(51803217); 国家自然科学基金(51773206); 国家自然科学基金(91963212); 国家自然科学基金(51961145102); 国家自然科学基金(22075296); 中国科学院青年创新促进会(2020032); 北京分子科学国家研究中心(BNLMS-CXXM-202005); 北京市科技新星计划(Z201100006820037); 北京市科技新星计划(Z211100002121001)

Research Progress on Nano Photonics Technology-based SARS-CoV-2 Detection^※

Xu Yang^a^,^b, Zeying Zhang^a^,^b, Meng Su^a^,^b(), Yanlin Song^a^,^b()

^aKey Laboratory of Green Printing, Institute of Chemistry, Chinese Academy of Sciences (ICCAS), Beijing 100190, China
^bUniversity of Chinese Academy of Sciences, Beijing 100049, China

Received:2021-10-21 Published:2021-12-23
Contact: Meng Su, Yanlin Song
About author:
^※ Dedicated to the 10th anniversary of the Youth Innovation Promotion Association, CAS.
Supported by:
National Key R&D Program of China(2018YFA0208501); National Natural Science Foundation of China(51803217); National Natural Science Foundation of China(51773206); National Natural Science Foundation of China(91963212); National Natural Science Foundation of China(51961145102); National Natural Science Foundation of China(22075296); Youth Innovation Promotion Association CAS(2020032); Beijing National Laboratory for Molecular Sciences(BNLMS-CXXM-202005); Beijing Nova Program from Beijing Municipal Science & Technology Commission(Z201100006820037); Beijing Nova Program from Beijing Municipal Science & Technology Commission(Z211100002121001)

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摘要/Abstract

新型冠状病毒(SARS-CoV-2)的大规模爆发导致全球性大面积人员感染甚至死亡, 严重影响了人们的正常生活. 全球化贸易和便捷交通极大加速了疫情的传播速度, 使疫情防控困难重重. 因此, 快速准确地诊断感染者和筛查无症状感染者有重要意义. 目前使用最广泛的SARS-CoV-2检测方法是逆转录聚合酶链式反应(Reverse Transcription- Polymerase Chain Reaction, RT-PCR), 但是存在样品储运繁琐、检测步骤复杂等问题, 需要专业人员和设备, 难以满足疫情常态化形势下快速、简便、高效、大规模检测的要求. 近年来, 随着纳米光子学的快速发展和纳米制备技术的不断完善, 基于纳米光子学技术检测生物标志物的研究已成为新的研究热点. 最新研究的利用纳米光子结构检测生物标志物新方法, 包括表面等离子共振(Surface Plasmon Resonance, SPR)、表面增强拉曼散射(Surface Enhanced Raman Scattering, SERS)、回音壁模式(Whispering Gallery Mode, WGM)与比色法, 特异性强、检测速度快、简单高效. 这些检测技术为高灵敏快速生物检测提供了新的平台. 本综述对近年来发展的纳米光子学生物检测技术进行了总结与概述, 阐述了纳米光子学检测生物标志物的机制, 并分析其用于SARS-CoV-2检测的可能性. 针对目前纳米光子结构制造困难的问题, 提出了利用纳米绿色印刷微纳制造技术大面积制备纳米光子结构的新思路, 为实现疫情的精准有效防控提供理论和技术基础.

关键词: 纳米光子学, 生物标志物检测, SARS-CoV-2, 纳米绿色印刷

The worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the infection even death of people all over the world, which has gravely affected our daily life. Globalization of trade and convenient transportation immensely accelerate the propagation of the epidemic, which brings severe difficulties to prevent the epidemic. Therefore, rapid and accurate diagnosis of infected persons and screening of asymptomatic persons play an important role. At present, the most widely used method for the detection of SARS-CoV-2 is reverse transcription-polymerase chain reaction (RT-PCR), which still has some problems including complicated sample storage and transportation, complex operations and so on. These shortcomings cause the hindrances to achieve fast, simple, efficient diagnostic testing under the normalization of the epidemic. In the past few years, with the development of nanotechnology, bio-sensing methods based on nano photonics have become a research hotspot. Label-free optical methods have been widely explored for bio-sensing including virus detection, such as surface plasmon resonance (SPR), surface enhanced Raman scattering (SERS), whispering gallery mode (WGM) and colorimetry. These approaches offer available alternatives to improve the speed, sensitivity, and accuracy of optical bio-sensing, owing to the enhanced interaction between the nanostructure and the biomarkers. This review summarizes these nano photonics-based bio-sensing technologies for the detection of SARS-CoV-2. Moreover, the detection mechanism of biomarkers by nano photonics is explained, and the further development trends are discussed. In view of the difficulties in manufacturing nano photonics structures, a new strategy of large-area preparation of nano photonics structures using nano green printing technology is proposed, which provides theoretical and technical support for accurate and effective prevention and control of the epidemic diseases.

Key words: nano photonics, biomarkers detection, SARS-CoV-2, nano green printing

引用此文

杨旭, 张泽英, 苏萌, 宋延林. 基于纳米光子技术检测SARS-CoV-2研究进展^※[J]. 化学学报, 2022, 80(1): 80-88.

Xu Yang, Zeying Zhang, Meng Su, Yanlin Song. Research Progress on Nano Photonics Technology-based SARS-CoV-2 Detection^※[J]. Acta Chimica Sinica, 2022, 80(1): 80-88.

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图/表 7

图1. SPR技术进行生物标志物检测: (a) SPR技术检测CRP[31]; (b) SPR技术检测目标microRNA[32]; (c) SPR技术检测SARS-CoV-2[20]

Figure 1. Biomarkers detection by SPR technology: (a) detection of CRP by SPR technology[31]; (b) detection of microRNA by SPR technology[32]; (c) detection of SARS-CoV-2 by SPR technology[20] Reproduced with permission[31], Copyright 2016 Royal Society of Chemistry. Reproduced with permission[32], Copyright 2018 Elsevier. Reproduced with permission[20], Copyright 2020 American Chemical Society

图2. SERS技术检测生物标志物: (a) SERS技术检测CRP[57]; (b) SERS技术检测SARS-CoV-2[41]; (c) SERS即时检测模型[58]

Figure 2. Biomarkers detection by SERS technology: (a) detection of CRP by SERS technology[57]; (b) detection of SARS-CoV-2 by SERS technology[41]; (c) SERS real-time detection of SARS-CoV-2 model[58] Reproduced with permission[57], Copyright 2019 American Chemical Society. Reproduced with permission[41], Copyright 2021 Springer. Reproduced with permission[58], Copyright 2021 Elsevier

图3. WGM光学微腔检测病毒颗粒: (a) WGM光学微腔检测纳米颗粒[61]; (b) WGM光学微腔检测SARS-CoV-2[69]

Figure 3. Detection of virus particles by WGM optical microcavity: (a) detection of nanoparticles by WGM optical microcavity[61]; (b) detection of SARS-CoV-2 by WGM optical microcavity[69] Reproduced with permission[61], Copyright 2011 Nature Publishing Group. Reproduced with permission[69], Copyright 2021 Wiley

图4. 比色法检测生物标志物: (a)比色法测定双链DNA[73]; (b)比色法测定寨卡病毒[74]; (c)比色法测定胃癌生物标志物microRNA-148a[76]; (d)比色法测定SARS-CoV-2[77]

Figure 4. Biomarkers detection by colorimetry: (a) detection of dsDNA by colorimetry[73]; (b) detection of Zika virus by colorimetry[74]; (c) detection of gastric cancer biomarker microRNA-148a by colorimetry[76]; (d) detection of SARS-CoV-2 by colorimetry[77] Reproduced with permission[73], Copyright 2015 Elsevier. Reproduced with permission[74], Copyright 2018 Nature Publishing Group. Reproduced with permission[76], Copyright 2019 Institute of Physics Publishing. Reproduced with permission[77], Copyright 2020 American Chemical Society

图5. 利用印刷的纳米链直接比色检测生物液体中病毒颗粒[83]: (a)病毒检测流程图. i)羧基修饰的纳米粒子通过模板印刷技术自组装成纳米链阵列. ii, iii)通过羧基和氨基的偶联, 将特异性的抗体固定在纳米链上, 快速识别目标病毒. iv)在白光(黄色)斜照射下, 吸附的病毒颗粒会改变纳米链散射光的颜色(红色); (b)病毒颗粒的定量监测: 利用手机可以直接观察到纳米链的颜色变化; (c)纳米链与SARS-CoV-2假病毒颗粒结合前(橙色曲线)和结合后(蓝色曲线)的散射光谱; (d)纳米链结合不同数量的病毒后的磁场分布

Figure 5. Colorimetric detection of viruses directly from biological fluids using a printed nanochain assay[83]: (a) Flowchart of virus detection. i) The carboxyl-modified nanoparticles are self-assembled into nanochain arrays through the template-assisted printing technique. ii, iii) Specific antibodies are immobilized on nanochains on basis of the coupling of the carboxylic and amino groups for rapid identification of target viruses. iv) Under oblique illumination of white light (indicated by the yellow beam), the color of scattered light (indicaded by the red beam) changes with the viruses binding to nanochains; (b) Quantitative monitoring of virus particles: the color change of nano chains can be directly observed by mobile phone; (c) Measured scattering spectra of nanochains before (orange curve) and after (blue curve) binding pseudotyped SARS-CoV-2 viral particles; (d) Side view of magnetic field distribution of nanochains in response to binding different number of viruses Reproduced with permission[83], Copyright 2021 Wiley

图6. 雷达图比较了SPR、SERS、WGM和比色法作为光学检测技术在灵敏度、诊断可行性、操作简单性、设备成本和普适性方面的优缺点

Figure 6. The radar chart compares the advantages and disadvantages of SPR, SERS, WGM and colorimetry as optical detection technology in sensitivity, diagnostic feasibility, simplicity of operation, equipment cost and universality

检测方式	检测原理	检出限	检测时间
SPR	利用等离子光热效应放大SARS-CoV-2引起的局域等离子共振峰移动信号^[20].	0.22 pmol/L	15 min
SERS	金纳米针阵列特异性捕获SARS-CoV-2颗粒并大大增强其拉曼信号^[41]. 金纳米孔表面特异性捕获SARS-CoV-2颗粒后, SERS峰的强度发生改变^[42].	10^-17 mol/L^[41] 10 PFU/mL^[42]	5 min^[41] 15 min^[42]
WGM	监测SARS-CoV-2引起的WGM光学微腔谐振波长偏移^[69].	1 μg/mL	25 min
比色法	利用Au NP的聚集或近场增强等, 使体系颜色发生肉眼可见的改变^[77-78]. 一维纳米链特异性捕获SARS-CoV-2颗粒后, 共振峰位置与强度发生改变, 显示不同颜色^[83].	0.18 ng/mL^[77] C_t=36.5^[78] C_t(PCR循环阈值) 1 PFU/mL^[83]	10 min^[77] 3 min^[78] 15 min^[83]

表1. 基于纳米光子学的SARS-CoV-2检测技术

Table 1. Detection technologies of SARS-CoV-2 based on nano photonics

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基于纳米光子技术检测SARS-CoV-2研究进展^※

Research Progress on Nano Photonics Technology-based SARS-CoV-2 Detection^※

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[2]	苏莹莹, 彭天欢, 邢菲菲, 李迪, 樊春海. 纳米等离子体生物传感及成像[J]. 化学学报, 2017, 75(11): 1036-1046.

基于纳米光子技术检测SARS-CoV-2研究进展※

Research Progress on Nano Photonics Technology-based SARS-CoV-2 Detection※

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基于纳米光子技术检测SARS-CoV-2研究进展^※

Research Progress on Nano Photonics Technology-based SARS-CoV-2 Detection^※