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Review
. 2021 Nov 13:16:7575-7608.
doi: 10.2147/IJN.S333969. eCollection 2021.

Progress in Nanomaterials-Based Optical and Electrochemical Methods for the Assays of Exosomes

Xiaohua Ma  1 , Yuanqiang Hao  1 , Lin Liu  1   2
Affiliations
Review

Progress in Nanomaterials-Based Optical and Electrochemical Methods for the Assays of Exosomes

Xiaohua Ma et al. Int J Nanomedicine. .

Abstract

Exosomes with diameters of 30-150 nm are small membrane-bound vesicles secreted by a variety of cells. They play an important role in many biological processes, such as tumor-related immune response and intercellular signal transduction. Exosomes have been considered as emerging and noninvasive biomarkers for cancer diagnosis. Recently, a large number of optical and electrochemical biosensors have been proposed for sensitive detection of exosomes. To meet the increasing demands for ultrasensitive detection, nanomaterials have been integrated with various techniques as powerful components. Because of their intrinsic merits of biological compatibility, excellent physicochemical features and unique catalytic ability, nanomaterials have significantly improved the analytical performances of exosome biosensors. In this review, we summarized the recent progress in nanomaterials-based biosensors for the detection of cancer-derived exosomes, including fluorescence, colorimetry, surface plasmon resonance spectroscopy, surface enhanced Raman scattering spectroscopy, electrochemistry, electrochemiluminescence and so on.

Keywords: circulating tumor biomarkers; electrochemical biosensor; exosomes; nanomaterials; optical biosensor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic of SMC-MB platform. (A) Construction of SMC-MB platform. (B) Procedure of SMC-MB platform in exosomes analysis. (C) Principle of nonenzymatic amplification cycle. (D) Exosomes purification by restriction enzyme. Reprinted with permission from Li P, Yu X, Han W, et al. Ultrasensitive and reversible nanoplatform of urinary exosomes for prostate cancer diagnosis. ACS Sens. 2019;4:1433–1441. Copyright 2019 American Chemical Society.
Figure 2
Figure 2
(A) Schematic of magnetic and fluorescent bio-probes (MFBP) constructing process and sensing principle of MFBP-based quantification of exosomes. Reprinted with permission from Wu M, Chen Z, Xie Q, et al. One-step quantification of salivary exosomes based on combined aptamer recognition and quantum dot signal amplification. Biosens Bioelectron. 2021;171:112733–112742. Copyright 2021 Elsevier B.V. (B) Schematic of photonic crystals-assisted signal amplification for measurement of tumor-derived exosomes. Reprinted with permission from Zhang J, Zhu Y, Shi J, et al. Sensitive signal amplifying a diagnostic biochip based on a biomimetic periodic nanostructure for detecting cancer exosomes. ACS Appl Mater Interfaces. 2020;12:33473–33482. Copyright 2020 American Chemical Society. (C) Schematic of the proposed method for exosome detection based on a copper-mediated signal amplification strategy. Reprinted with permission from He F, Wang J, Yin BC, Ye BC. Quantification of exosome based on a copper-mediated signal amplification strategy. Anal Chem. 2018;90:8072–8079. Copyright 2018 American Chemical Society. (D) Schematic of design and sensing mechanism of ASPNC. (a) Synthetic route of ASP. Reagents and conditions: i) tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3], tri(p-tolyl)phosphine (TPTP), chlorobenzene, 100°C, 24 h; ii) trimethylamine, tetrahydrofuran (THF), methanol, 24 h. (b) Illustration of the formation of ASPNC and the afterglow detection of exosomes. Reprinted with permission from Lyu Y, Cui D, Huang J, Fan W, Miao Y, Pu K. Near-infrared afterglow semiconducting nano-polycomplexes for the multiplex differentiation of cancer exosomes. Angew Chem Int Ed. 2019;58:4983–4987. Copyright 2019 Wiley-VCH.
Figure 3
Figure 3
(A) Schematic of the exosome-triggered enzyme-powered DNA motors for exosome detection. Reprinted with permission from Yu Y, Zhang WS, Guo Y, Peng H, Zhu M, Miao D, Su G. Engineering of exosome-triggered enzyme-powered DNA motors for highly sensitive fluorescence detection of tumor-derived exosomes. Biosens Bioelectron. 2020;167:112482–112490. Copyright 2020 Elsevier B.V. (B) Schematic of paper-supported aptasensor based on the LRET between UCNPs and AuNRs for the determination of exosomes. Reprinted with permission from Chen X, Lan J, Liu Y, et al. A paper-supported aptasensor based on upconversion luminescence resonance energy transfer for the accessible determination of exosomes. Biosens Bioelectron. 2018;102:582–588. Copyright 2018 Elsevier B.V.
Figure 4
Figure 4
(A) Schematic of enzyme-aided fluorescence amplification based on GO-DNA aptamer interactions for exosome detection. Reprinted with permission from Wang H, Chen H, Huang Z, Li T, Deng A, Kong J. DNase I enzyme-aided fluorescence signal amplification based on graphene oxide-DNA aptamer interactions for colorectal cancer exosome detection. Talanta. 2018;184:219–226. Copyright 2018 Elsevier B.V. (B) Schematic of homogeneous magneto-fluorescent nanosensor for tumor-derived exosome isolation and analysis. (a) Tumor-derived exosomes are specifically captured by GPC-1 antibody coated magnetic beads and subsequently bind with extended CD63 aptamers, forming a bead−exosome−aptamer complexes. (b) Captured exosomes are detected in a homogeneous solution by aptamer-triggered DNA TWJs cyclic assembly strategy along with TPE-TA and the GO-based “turn-on” fluorescent system. Reprinted with permission from Li B, Pan W, Liu C, et al. Homogenous magneto-fluorescent nanosensor for tumor-derived exosome isolation and analysis. ACS Sens. 2020;5:2052–2060. Copyright 2020 American Chemical Society. (C) Schematic of Cy3-CD63 aptamer was mixed with MXenes aqueous solution and then added exosomes. Reprinted with permission from Zhang Q, Wang F, Zhang H, Zhang Y, Liu M, Liu Y. Universal Ti3C2 MXenes based self-standard ratiometric fluorescence resonance energy transfer platform for highly sensitive detection of exosomes. Anal Chem. 2018;90:12737–12744. Copyright 2018 American Chemical Society.
Figure 5
Figure 5
(A) Schematic of the colorimetric method for exosome detection by a combination of immunoaffinity separation and cholesterol-based signal amplification. Reprinted with permission from He F, Liu H, Guo X, Yin BC, Ye BC. Direct exosome quantification via bivalent-cholesterol-labeled DNA anchor for signal amplification. Anal Chem. 2017;89:12968–12975. Copyright 2017 American Chemical Society. (B) Schematic of magnetic capture of exosomes, HRP-mediated PDA engineering of exosomes and urease immobilization for point-of-care testing. Reprinted with permission from Yang Y, Li C, Shi H, Chen T, Wang Z, Li G. A pH-responsive bioassay for paper-based diagnosis of exosomes via mussel-inspired surface chemistry. Talanta. 2019;192:325–330. Copyright 2019 Elsevier B.V.
Figure 6
Figure 6
(A) Schematic of nanoplasmonic assay for probing by eye protein contaminants (single and aggregated exogenous proteins, SAP) in EV preparations. Reprinted with permission from Maiolo D, Paolini L, Di Noto G, et al. Colorimetric nanoplasmonic assay to determine purity and titrate extracellular vesicles. Anal Chem. 2015;87:4168–4176. Copyright 2015 American Chemical Society. (B) Schematic of the aptamer/AuNP complex for molecular profiling of exosomal proteins. (a) Schematic of the displacement of aptamers from gold nanoparticles by binding with exosome surface protein and the concomitant aggregation of gold nanoparticles. (b) Profiling of different exosome surface proteins with the aptamer/AuNP complex. Reprinted with permission from Jiang Y, Shi M, Liu Y, et al. Aptamer/AuNP biosensor for colorimetric profiling of exosomal proteins. Angew Chem. 2017;129:12078–12082. Copyright 2017 Wiley-VCH. (C) Schematic of the PLA-RPA-TMA assay. Reprinted with permission from Liu W, Li J, Wu Y, et al. Target-induced proximity ligation triggers recombinase polymerase amplification and transcription-mediated amplification to detect tumor-derived exosomes in nasopharyngeal carcinoma with high sensitivity. Biosens Bioelectron. 2018;102:204–210. Copyright 2018 Elsevier B.V.
Figure 7
Figure 7
(A) Schematic of the mechanism for multicolor visual detection of exosomes based on HCR and enzyme-catalyzed metallization of Au NRs. Reprinted with permission from Zhang Y, Wang D, Yue S, et al. Sensitive multicolor visual detection of exosomes via dual signal amplification strategy of enzyme-catalyzed metallization of Au nanorods and hybridization chain reaction. ACS Sens. 2019;4:3210–3218. Copyright 2019 American Chemical Society. (B) Schematic of the visible detection of exosomes based on ssDNA-enhanced Fe3O4 NPs nanozyme activity. Reprinted with permission from Chen J, Xu Y, Lu Y, Xing W. Isolation and visible detection of tumor-derived exosomes from plasma. Anal Chem. 2018;90:14207–14215. Copyright 2018 American Chemical Society. (C) Schematic of DNA aptamer accelerating the intrinsic peroxidase-like activity of g-C3N4 NSs for the detection of exosomes. Reprinted with permission from Wang YM, Liu JW, Adkins GB, et al. Enhancement of the intrinsic peroxidase-like activity of graphitic carbon nitride nanosheets by ssDNAs and its application for detection of exosomes. Anal Chem. 2017;89:12327–12333. Copyright 2017 American Chemical Society. (D) Schematic of the detection mechanism for the visible detection of exosomes based on ssDNA-enhanced Fe3O4 NPs nanozyme activity. Reprinted with permission from Zhang Y, Su Q, Song D, Fan J, Xu Z. Label-free detection of exosomes based on ssDNA-modulated oxidase-mimicking activity of CuCo2O4 nanorods. Anal Chim Acta. 2021;1145:9–16. Copyright 2021 Elsevier B.V.
Figure 8
Figure 8
Schematic of dual AuNP-assisted signal amplification for SPR determination of exosomes. Reprinted with permission from Wang Q, Zou L, Yang X, et al. Direct quantification of cancerous exosomes via surface plasmon resonance with dual gold nanoparticle-assisted signal amplification. Biosens Bioelectron. 2019;135:129–136. Copyright 2019 Elsevier B.V.
Figure 9
Figure 9
(A) Schematic representation of detection process and design inspiration of the Au-coated TiO2 MIO SERS probe. Reprinted with permission from Dong S, Wang Y, Liu Z, et al. Beehive-inspired macroporous SERS probe for cancer detection through capturing and analyzing exosomes in plasma. ACS Appl Mater Interfaces. 2020;12:5136–5146. Copyright 2020 American Chemical Society. (B) Schematic representation of preparation of three types of SERS nanotags and molecular phenotype profiling of exosomes using SERS nanotags and CD63 antibody-functionalized MBs. Reprinted with permission from Zhang W, Jiang L, Diefenbach RJ, et al. Enabling sensitive phenotypic profiling of cancer-derived small extracellular vesicles using surface-enhanced Raman spectroscopy nanotags. ACS Sens. 2020;5:764–771. Copyright 2020 American Chemical Society. (C) Schematic of exosomes engineering based on a hydrophobic insertion strategy with DSPE-PEG-Mal. Reprinted with permission from Di H, Zeng E, Zhang P, et al. General approach to engineering extracellular vesicles for biomedical analysis. Anal Chem. 2019;91:12752–12759. Copyright 2019 American Chemical Society. (D) Schematic representation of assembling AuNPs in triangular pyramid DNA. Reprinted with permission from Zhang X, Liu C, Pei Y, Song W, Zhang S. Preparation of a novel Raman probe and its application in the detection of circulating tumor cells and exosomes. ACS Appl Mater Interfaces. 2019;11:28671–28680. Copyright 2019 American Chemical Society.
Figure 10
Figure 10
(A) Schematic representation of the electrochemical aptasensor for exosomes capture and release based on specific host-guest interactions between cucurbit[7]uril and Fc. Reprinted with permission from Liu Q, Yue X, Li Y, et al. A novel electrochemical aptasensor for exosomes determination and release based on specific host-guest interactions between cucurbit [7]uril and ferrocene. Talanta. 2021;232:122451–122458. Copyright 2021 Elsevier B.V. (B) Schematic representation of the construction process and application of a dual-signal and intrinsic self-calibration aptasensor of exosomes based on a functional hybrid thin-film sensing platform aptamer-BPNSs/Fc/ZIF-67/ITO. Reprinted with permission from Sun Y, Jin H, Jiang X, Gui R. Assembly of black phosphorus nanosheets and MOF to form functional hybrid thin-film for precise protein capture, dual-signal and intrinsic self-calibration sensing of specific cancer-derived exosomes. Anal Chem. 2020;92:2866–2875. Copyright 2020 American Chemical Society.
Figure 11
Figure 11
(A) Schematic of the electrochemical aptasensor for exosomes detection by using AuNPs and enzyme for amplification. Reprinted with permission from Jiang J, Yu Y, Zhang H, Cai C. Electrochemical aptasensor for exosomal proteins profiling based on DNA nanotetrahedron coupled with enzymatic signal amplification. Anal Chim Acta. 2020;1130:1–9. Copyright 2020 Elsevier B.V. (B) Schematic of the fabrication process of MB@UiO-66-based nanoprobe and the electrochemical biosensor for the detection of GBM-derived exosomes. Reprinted with permission from Sun Z, Wang L, Wu S, et al. An electrochemical biosensor designed by using Zr-based metal-organic frameworks for the detection of glioblastoma-derived exosomes with practical application. Anal Chem. 2020;92:3819–3826. Copyright 2020 American Chemical Society. (C) Schematic of identification of PD-L1+ exosomes based on HRCA-responsive PVP@HRP@ZIF-8. Reprinted with permission from Cao Y, Wang Y, Yu X, Jiang X, Li G, Zhao J. Identification of programmed death ligand-1 positive exosomes in breast cancer based on DNA amplification-responsive metal-organic frameworks. Biosens Bioelectron. 2020;166:112452–112460. Copyright 2020 Elsevier B.V. (D) Schematic of the fabrication process of COFs-based nanoprobes and the mechanism of the EC biosensor for exosomes detection. Reprinted with permission from Wang M, Pan Y, Wu S, et al. Detection of colorectal cancer-derived exosomes based on covalent organic frameworks. Biosens Bioelectron. 2020;169:112638–112645. Copyright 2020 Elsevier B.V.
Figure 12
Figure 12
(A) Schematic of the assay for direct exosome isolation and detection from cell culture media based on Au-NPFe2O3NC. Reprinted with permission from Boriachek K, Masud MK, Palma C, et al. Avoiding pre-isolation step in exosome analysis: Direct isolation and sensitive detection of exosomes using gold-loaded nanoporous ferric oxide nanozymes. Anal Chem. 2019;91:3827–3834. Copyright 2019 American Chemical Society. (B) Schematic of the electrochemical biosensor for exosomes activity detection signal amplification strategy by using in situ generation of Prussian blue. Reprinted with permission from Zhang H, Wang Z, Wang F, Zhang Y, Wang H, Liu Y. Ti3C2 MXene mediated Prussian blue in situ hybridization and electrochemical signal amplification for the detection of exosomes. Talanta. 2021;224:121879–121886. Copyright 2021 Elsevier B.V. (C) Schematic representation of the two-step isolation and analysis of exosomes and microsomes: (a) capture step where vesicles are immobilized on aptamer-modifi ed sensors, (b) electrochemical detection of the captured exosomes/microsomes with Cu and AgNPs. Reprinted with permission from Zhou YG, Mohamadi RM, Poudineh M, et al. Interrogating circulating microsomes and exosomes using metal nanoparticles. Small. 2016;12:727–732. Copyright 2016 Wiley-VCH.
Figure 13
Figure 13
(A) Schematic of the integrated immuno-magneto- electrochemical sensor for exosomes detection. Reprinted with permission from Jeong S, Park J, Pathania D, et al. Integrated magneto-electrochemical sensor for exosome analysis. ACS Nano. 2016;10:1802–1809. Copyright 2016 American Chemical Society. (B) Schematic of the Exo PCD-chip and the electrochemical Sensor on the Surface of ITO Electrode. Reprinted with permission from Xu H, Liao C, Zuo P, Liu Z, Ye BC. Magnetic-based microfluidic device for on-chip isolation and detection of tumor-derived exosomes. Anal Chem. 2018;90:13451–13458. Copyright 2018 American Chemical Society.
Figure 14
Figure 14
(A) Schematic of the highly sensitive electrochemical biosensor for exosomes detection based on aptamer recognition-induced multi-DNA release and cyclic enzymatic amplification. Reprinted with permission from Dong H, Chen H, Jiang J, Zhang H, Cai C, Shen Q. Highly sensitive electrochemical detection of tumor exosomes based on aptamer recognition-induced multi-DNA release and cyclic enzymatic amplification. Anal Chem. 2018;90:4507–4513. Copyright 2018 American Chemical Society. (B) Schematic of the ratiometric electrochemical biosensor for the detection of exosomes by target-triggered 3D DNA walker and Exo III-assisted cyclic enzymatic amplification. Reprinted with permission from Zhao L, Sun R, He P, Zhang X. Ultrasensitive detection of exosomes by target-triggered three-dimensional DNA walking machine and exonuclease III-assisted electrochemical ratiometric biosensing. Anal Chem. 2019;91:14773–14779. Copyright 2019 American Chemical Society. (C) Schematic of the ratiometric immobilization-free electrochemical sensing system for tumor exosome detection in the absence (a) and in the presence (b) of the tumor exosomes. Reprinted with permission from Yang L, Yin X, An B, Li F. Precise capture and direct quantification of tumor exosomes via a highly efficient dual-aptamer recognition-assisted ratiometric immobilization-free electrochemical strategy. Anal Chem. 2021;93:1709–1716. Copyright 2021 American Chemical Society.
Figure 15
Figure 15
(A) Schematic of the ECL biosensor for exosomes based on multivalent recognition and signal amplification strategy by anti-GPC1-g-C3N4@Galinstan-PDA nanoprobe. Reprinted with permission from Zhang Y, Wang F, Zhang H, Wang H, Liu Y. Multivalency interface and g-C3N4 coated liquid metal nanoprobe signal amplification for sensitive electrogenerated chemiluminescence detection of exosomes and their surface proteins. Anal Chem. 2019;91:12100–12107. Copyright 2021 Elsevier B.V. (B) Schematic of the prepared process of CdS QDs-loaded DNA microcapsules integrated with target recycling amplification for homogeneous ECL detection of tumor exosomes. Reprinted with permission from Guo Y, Cao Q, Zhao C, Feng Q. Stimuli-responsive DNA microcapsules for homogeneous electrochemiluminescence sensing of tumor exosomes. Sens Actuat B Chem. 2021;329:129136–129142. Copyright 2019 American Chemical Society. (C) Schematic of the dual-mode biosensor for exosomes detection based on MXenes and black phosphorus quantum dots. Reprinted with permission from Fang D, Zhao D, Zhang S, Huang Y, Dai H, Lin Y. Black phosphorus quantum dots functionalized MXenes as the enhanced dual-mode probe for exosomes sensing. Sens Actuat B Chem. 2020;305:127544–127552. Copyright 2020 Elsevier B.V.
Figure 16
Figure 16
Schematic of the ECL biosensor for exosomes detection based on in situ formation of AuNPs decorated MXenes nanoprobes Reprinted with permission from Zhang H, Wang Z, Wang F, Zhang Y, Wang H, Liu Y. In situ formation of gold nanoparticles decorated Ti3C2 MXenes nanoprobe for highly sensitive electrogenerated chemiluminescence detection of exosomes and their surface proteins. Anal Chem. 2020;92:5546–5553. Copyright 2020 American Chemical Society.
Figure 17
Figure 17
Schematic of CuS-microgel synthesis and the CuS-microgel-based assay for exosome quantification. Reprinted with permission from Jiang Q, Liu Y, Wang L, Adkins GB, Zhong W. Rapid enrichment and detection of extracellular vesicles enabled by cus-enclosed microgels. Anal Chem. 2019;91:15951–15958. Copyright 2019 American Chemical Society.
Figure 18
Figure 18
Schematic of ultrasensitive inductively coupled plasma−mass spectrometry method for the detection of exosomes by using UCNPs as element labels. Reprinted with permission from Zhang XW, Liu MX, He MQ, Chen S, Yu YL, Wang JH. Integral multielement signals by DNA-programmed UCNP-AuNP nanosatellite assemblies for ultrasensitive ICP-MS detection of exosomal proteins and cancer identification. Anal Chem. 2021;93:6437–6445. Copyright 2021 American Chemical Society.
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Grants and funding

This research was funded by the Program for Innovative Research Team of Science and Technology in the University of Henan Province (21IRTSTHN005), the National Natural Science Foundation of China (21804085), and the Research Funds for the Henan Key Laboratory of Biomolecular Recognition and Sensing (HKLBRSK1902).