传感器技术在河豚毒素检测中的研究进展：从单模态到多模态

董秀秀; 李晓研; 王昊伟; 姜军; 吴世嘉; 徐振林

doi:10.7536/PC20260109

化学进展 ›› 2026, Vol. 38 ›› Issue (7) :1194-1221 DOI: 10.7536/PC20260109

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传感器技术在河豚毒素检测中的研究进展：从单模态到多模态

董秀秀 ¹ ,
李晓研 ¹ ,
王昊伟 ¹^,⁴ ,
姜军 ¹ ,
吴世嘉 ²^,^* ,
徐振林 ³^,^*

作者信息 +

Advances on the Sensors for Detection of Tetrodotoxin： From Single-Mode to Multi-Mode

Xiuxiu Dong ¹ ,
Xiaoyan Li ¹ ,
Haowei Wang ¹^,⁴ ,
Jun Jiang ¹ ,
Shijia Wu ²^,^* ,
Zhen-Lin Xu ³^,^*

Author information +

文章历史 +

摘要

河豚毒素（TTX）是一种高毒性小分子神经毒素，误食后会引发神经瘫痪，严重时可危及生命，因此开发高效且灵敏的TTX快速筛查技术对保障食品安全和人类健康至关重要。近年来，随着对光学传感和电化学传感机制研究的不断深入，众多研究者基于上述传感机制与功能性纳米材料、信号放大技术及特异性识别元件（适配体、抗体、多肽等）协同整合，建立了一系列检测体系，实现了对河豚毒素的快速、灵敏检测。本文重点阐述了以表面增强拉曼散射（SERS）传感器、表面等离子共振（SPR）传感器、比色与荧光传感器为代表的光学传感器和以阻抗型传感器、电流型传感器、电化学发光（ECL）传感器及光电化学（PEC）传感器等为代表的电化学传感器在TTX检测中的发展与应用现状。同时，探讨了多模式传感器（如荧光-SERS、电化学-SERS、电化学-比色双模式）的开发与性能特征，通过信号间的交叉验证，显著提升了检测结果的准确性与可靠性。特别是详细介绍了不同功能材料（如贵金属纳米颗粒、石墨烯、金属有机框架（MOFs）等纳米材料以及适配体、抗体等生物材料）修饰对传感器性能（线性范围、检测限（LOD）、稳定性等）的提升作用。在此基础上，本文指出当前TTX筛查技术面临的核心挑战，并展望了通过多技术融合推动TTX快速筛查技术从实验室走向实际应用的广阔前景，这将为降低TTX中毒事件的发生率、保障公众健康提供保障。

Abstract

Tetrodotoxin （TTX） is a small-molecule neurotoxin that is highly toxic. Accidental ingestion of TTX can cause neuroparalysis， with severe cases potentially life-threatening. Therefore， developing efficient， sensitive， and rapid screening techniques for TTX is crucial for safeguarding food safety. In recent years， with the intensive research on sensing mechanisms such as optical sensing and electrochemical sensing， numerous studies have integrated these sensing mechanisms with functional nanomaterials， signal amplification technologies， and specific recognition elements （aptamers， antibodies， peptides， etc.） to construct diverse detection systems that enable rapid， sensitive， and specific detection of TTX. This article focuses on the development process and application status in the detection of TTX by optical sensors， represented by surface-enhanced Raman scattering （SERS） sensors， surface plasmon resonance （SPR） sensors， and colorimetric and fluorescence sensors， as well as electrochemical sensors， represented by impedance sensors， amperometric sensors， electrochemiluminescence （ECL） sensors， and photoelectrochemical （PEC） sensors. Additionally， the development and performance characteristics of multi-modal sensors （such as fluorescence-SERS， electrochemical-SERS， and electrochemical-colorimetric dual-mode） are discussed， through cross-validation between signals， the accuracy and reliability of detection results have been improved. Especially the sensor performances （linear range， limit of detection （LOD）， stability） were optimized by using different functional materials （such as noble metal nanoparticles， graphene， metal organic frameworks （MOFs）， and biomaterials like aptamers and antibodies）. Finally， we point out the core challenges faced by current screening technologies of TTX. And the bright prospects of promoting the rapid screening technology of TTX from the laboratory to practical applications through the integration of multiple technologies were anticipated. In a word， these studies would make TTX poisoning incidents decrease and ensure public health.

Contents

1 Introduction

2 The developed analytical method based on optical sensing for the detection of TTX

2.1 SERS sensor

2.2 SPR sensor

2.3 Colorimetric sensor

2.4 Fluorescence sensor

3 The developed analytical method based on electrochemical sensing for the detection of TTX

3.1 Impedance sensor

3.2 Amperometric sensor

3.3 ECL sensor

3.4 PEC sensor

4 The developed analytical method based on multi-modal sensing for the detection of TTX

4.1 The fluorescence-SERS dual-modal sensor

4.2 The electrochemical-SERS dual-modal sensor

4.3 The electrochemical-colorimetric dual-modal sensor

4.4 The SERS-colorimetric dual-modal sensor

4.5 Multi-modal sensors based on other principles

4.6 The current status of multi-modal sensing for the detection of TTX

5 Challenges and outlook

6 Conclusion

Graphical abstract

关键词

河豚毒素 / 快速筛查 / 光学传感 / 电化学传感 / 多模传感

Key words

tetrodotoxin / rapid screening / optical sensing / electrochemical sensing / multi-modal sensing

引用本文

引用格式 ▾

董秀秀, 李晓研, 王昊伟, 姜军, 吴世嘉, 徐振林. 传感器技术在河豚毒素检测中的研究进展：从单模态到多模态[J]. 化学进展, 2026, 38(7): 1194-1221 DOI:10.7536/PC20260109

Xiuxiu Dong, Xiaoyan Li, Haowei Wang, Jun Jiang, Shijia Wu, Zhen-Lin Xu. Advances on the Sensors for Detection of Tetrodotoxin： From Single-Mode to Multi-Mode[J]. Progress in Chemistry, 2026, 38(7): 1194-1221 DOI:10.7536/PC20260109

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1 Introduction

Tetrodotoxin （TTX）， whose molecular formula is C₁₁H₁₇O₈N₃， is an alkaloid that exists in pufferfish （commonly known as blowfish） and various other organisms. As an amino-perhydroquinazoline compound， TTX has extremely high neurotoxicity^[1]. It has a local stimulating effect on the intestine. After being absorbed， TTX can quickly act on nerve endings and nerve centers. TTX can block the sodium ion channel on the nerve excitatory membrane and the conduction of nerve signals can be hindered， which will result in nerve paralysis and eventually lead to death^[2-3]. TTX has no specific antidote， and for mice via intraperitoneal injection， its median lethal dose （LD₅₀） is 8~10 μg/kg^[4]， posing TTX an extreme threat to human health. The residual accumulation property of TTX is a key factor causing poisoning. The toxin is slowly metabolized in organisms and is not easily biotransformed or degraded， resulting in persistent residues in tissues^[5]. For the bioaccumulation pathway， after low-trophic-level organisms ingest TTX-containing bacteria or algae， the toxin initially accumulates in their bodies. It is then transferred to higher-trophic-level organisms via predation， with a stepwise increase in concentration^[6]. TTX is not exclusive to pufferfish. It has been detected in marine organisms such as blue-ringed octopuses， xanthid crabs， and gastropods^[7-8]. TTX is also found in terrestrial organisms such as newts， frogs， and certain worms^[9-10]. Furthermore， some bacteria have been confirmed to be capable of synthesizing TTX， which enters host organisms through the food chain^[11-12]. Table 1 contains the information on the sources of TTX.

As reported in China， from 2011 to 2020， there were 92 nationwide cases of TTX poisoning， with 339 people poisoned and 15 deaths， resulting in a case fatality rate of 4.4%^[33]. Since TTX has high toxicity， TTX products require mandatory testing. As early as 2016， China had set a TTX limit of 2200 μg/kg for dolphin products^[34]. For the edible muscle tissue of pufferfish， the control limit is less than 10 μg/kg^[35]. However， there are still many accidents occurred in China. In December 2024， a poisoning incident of TTX associated with pufferfish consumption occurred in Nan’ao County， Shantou City， resulting in two cases， including one death. In March 2025， two people in Changzhou City， Jiangsu Province suffered from poisoning after consuming pufferfish. In addition， multiple poisoning cases of TTX have been reported in coastal provinces， including Zhejiang， Fujian， Guangdong， and Guangxi recently. Besides， Japan stipulates that the equivalent limit of TTX in edible pufferfish tissue is 2000 μg/kg^[36]， while the European Union European Food Safety Authority recommends that the TTX safety threshold in shellfish is less than 44 μg/kg^[37-38]. The US FDA （Food and Drug Administration） prohibits the illegal import of pufferfish， and requires legal imported varieties to pass liquid chromatography-tandem mass spectrometry （LC-MS/MS） testing and verification^[39]. Due to the extremely high toxicity of TTX and the lack of a specific antidote， it is necessary to develop detection technologies for quantitative analysis of TTX. Traditional techniques for the detection of TTX rely on instrument-based analytical methods， such as liquid chromatography （LC）^[40]， liquid chromatography-mass spectrometry （LC-MS）^[41]， and LC-MS/MS^[42]. Although these methods are highly accurate and widely recognized， they are costly， complex to operate， and have long detection times， making it difficult to meet the needs of rapid on-site screening and large-scale sample testing. In recent years， with the rapid development of detection technologies based on principles such as optical sensing and electrochemical sensing， the detection of TTX has surpassed traditional methods to achieve higher sensitivity， shorter detection times， and the capability for rapid on-site screening. As shown in Fig.1， this review discusses three types of sensors for the detection of TTX， including optical sensors， electrochemical sensors， and multimodal sensors. Based on the analysis of existing research reports， the differences and advantages of each technology are compared in detail， and the challenges and prospects of the rapid screening technology of TTX are discussed. Compared with existing reviews on the detection of TTX， the unique contributions of this review are primarily reflected in three aspects. 1） This review systematically traces the evolution of sensing technologies from single-modal to multi-modal sensing techniques， covering all technical branches within the two mainstream sensing systems， optical and electrochemical. 2） It illustrates the sensor performance improvement originated from the functional nanomaterial， and recognition element. And the key indicators of the different sensors such as detection time and sample pretreatment complexity were quantified for giving a reference for government， enterprises， and so on. 3） It systematically investigates the optimization pathways and application potential of the sensors， which would hold certain academic value and practical significance for promoting the prevention and control of TTX contamination， safeguarding food safety， and protecting public health.

2 The developed analytical method based on optical sensing for the detection of TTX

Optical methods^[43]， with the core of the interaction between light and matter， constitute a category of non-contact detection technologies^[44]. Because of their high sensitivity， these methods hold a crucial position in the analysis of TTX. The principles of optical methods encompass multiple mechanisms， including optical absorption， emission， scattering， and diffraction， etc. Specifically， molecules can absorb light of a specific wavelength through electronic transitions， and when excited， they emit fluorescence or phosphorescence （such as fluorescence spectroscopy） or produce scattering signals through collisions with light （such as Raman scattering）. These characteristic signal changes lay a foundation for the qualitative or quantitative analysis of TTX. Surface-enhanced Raman scattering （SERS） can enhance Raman signals by a factor of 10¹⁰~10¹⁵ to enable the analytical detection of individual molecules using Raman spectroscopy^[45]. Surface plasmon resonance （SPR） technology is based on the phenomenon of metal surface plasma resonance^[46]. When polarized light hits the surface of the metal film at a specific angle （resonance angle）， the photon energy is transferred to the free electrons of the metal， causing collective oscillations （surface plasma） and causing a sharp drop in the intensity of the reflected light^[47]. Colorimetry can convert the concentration information of an analyte into measurable changes in color intensity， allowing for the quantitative detection of a target substance by measuring the absorbance or transmittance of the colored solution. Fluorescence is an analytical method based on the phenomenon of fluorescence emission of substances. When the sample is irradiated by light of a specific wavelength， the molecules in the sample absorb photon energy and transition to an excited state. They then return to the ground state by emitting photons with lower energy. Table 2 shows a performance analysis of four types of sensors that are based on optical sensing principles.

2.1 SERS sensor

The SERS sensor uses the hot spot effect of precious metal nanoparticles （e.g.， gold and silver^[48]） to enhance the Raman signal of TTX. However， characteristic peaks of TTX are susceptible to interference from the sample matrix， so the introduction of Raman reporter molecules combined with internal standard correction is thus necessary to mitigate such interference^[49]. For example， Yin et al.^[50] developed a SERS-based self-assembled bimolecular calibrated aptasensor. The Au@4-Mercaptobenzonitrile （MBN） located in the Raman silent region （1800~2400 cm^-1） is used as the Raman reporter molecule， effectively avoiding interference from biomolecules. The silicon （Si） molecules in the nanoparticle-modified silicon-based components exhibit a characteristic peak at 520.7 cm^-1， which can be used for real-time calibration of SERS signals， not only improving detection accuracy but also ensuring the excellent uniformity of the sensor which has a relative standard deviation （RSD） of 8.8%. MBN@Ag nanoparticles （Ag NPs） functionalized TTX complementary chain nanoparticles function as signal labeling and conduction elements. Fig.2a shows its detection mechanism. The high affinity between TTX and aptamers induces the detachment of Au@MBN@Ag nanoparticles， which in turn triggers changes in SERS signaling. Innovatively， this study combines self-assembled nanoparticle monolayers with bimolecule calibration to overcome the long-standing problems of poor uniformity and substrate interference associated with traditional SERS sensors. Furthermore， Wei et al. ^[51] developed a ratiometric SERS biosensor based on three-way junction catalytic hairpin assembly. In this sensor， Prussian blue （PB） is used as the Raman reporter molecule， with characteristic peaks located in the silent region （1800~2800 cm^-1）， effectively avoiding interference from other signals. PB embedded in the core-shell gap not only exhibits high stability but also allows real-time calibration of the SERS signal， significantly improving detection reproducibility， with an RSD of only 3.66%. Quantitative analysis of TTX concentration is realized through the Raman peak intensity ratio. This sensor is operated without the involvement of enzymes， with a limit of detection （LOD） as low as 0.0027 ng/mL and a linear range of 0.01~500 ng/mL， and good practicality is demonstrated by it in actual samples. Compared with the study by Yin et al.^[50]， Wei et al.^[51] is also based on the reporter molecules and internal standard calibration in silent regions， which further integrates enzyme-free signal amplification technology， overcoming the limitation of insufficient sensitivity of traditional SERS sensors for trace detection of TTX， achieving an integration of high sensitivity， strong anti-interference capability， and good reproducibility. Therefore， developing more Raman reporter molecules located in the Raman silent region of TTX can provide additional ways for improving the accuracy of sensors. At the same time， spectral recognition and background correction can be quickly achieved by artificial intelligence （AI）， which also improves the accuracy of measurements in complex samples^[52-54].

2.2 SPR sensor

Besides SERS sensors， which rely on plasmon-enhanced Raman scattering signals for detection， SPR sensors achieve detection based on refractive index changes at the metal-dielectric interface induced by molecular interactions. When the TTX binds to antibodies or aptamers immobilized on the metal film surface， the local refractive index changes， resulting in a shift of the SPR resonance angle^[55]. The offset is linearly related to the concentration of TTX. For example， Yakes et al.^[56] pioneered the development of an SPR-based method to detect TTX using an inhibitory format. This experimental process achieves the transition from prototype instruments to the commercial chip （Bia IPE， Bia Ref）. By immobilizing TTX on the surface of a chip modified with a mixed thiol monolayer， they estimated the toxin concentration based on the degree of signal inhibition. The signal inhibition is caused by free TTX competing with immobilized TTX for binding to anti-TTX antibodies. The preparation time of the Bia Ref chip was reduced from 4 d to 1 d. In the experiment， the higher the concentration of free TTX， the fewer antibodies bind to the surface of the chip， and the smaller the wavelength shift of SPR. The character of this method is that it allows TTX to be detected in complex matrices such as pufferfish， milk， and apple juice. Building on this foundational work， Vaisocherová et al.^[57] shows the collaboration of three laboratories of the Sciences. They aim to preliminarily validate a method for detecting TTX using an inhibitory SPR sensor， which is also based on the principle of competition. The results confirmed that the method could detect TTX in pufferfish matrix over a broad concentration range of 2~9000 ng/mL， and the LOD and the limit of quantitation are both below 10 ng/mL in the fugu fish matrix， and the matrix interference is small. The inter-laboratory recovery rate was 101%~119% in naturally contaminated samples. This sensor upgrades the lab-scale method to a standardized candidate method， which serves as a reasonable reference for evaluating the sensor.

For SPR sensors， analyzing the inhibited level of the SPR signal is not the only method to detect the concentration of TTX. In 2014， Yakes’ team^[58] developed the first SPR sensor that directly detects TTX， breaking through the limitations of traditional inhibitory assays. Instead of relying on competitive binding， this sensor immobilizes anti-TTX antibodies on two types of sensor chips： high-density CM7 chips and low-density CM5 chips， and the direct binding of TTX to the fixed antibody on the chip triggers the signal changes of SPR. As shown in Fig.2b， during the detection， the TTX analyte was injected directly through the sensor surface. The advantage of this direct method is that the detection speed is fast， and the full cycle is only 3.5 min， which is 2 times faster than the suppression method. The sensitivity is higher， and the LOD of the CM5 chip in HBS-EP is as low as 0.09 ng/mL， which is 4 times higher than that of the suppression method （0.38 ng/mL）. The SPR sensor can be used for real-time monitoring during the processing of pufferfish， integrating the sensor into the production line to detect the liver and muscle samples of pufferfish online， and automatically alarming when the concentration of TTX exceeds a certain limit to ensure food safety. To achieve the goal of further rapid on-site screening of TTX， SPR sensors can be combined with microfluidic technology. This method may enable automatic sample pretreatment， develop continuous online detection capabilities， and promote the development of SPR sensors to achieve portability， miniaturization， and intelligence.

2.3 Colorimetric sensor

Colorimetric sensors rely on the color changes induced by the reaction during the process^[59]. It features ease of operation and low cost， and is usually visible to the naked eye， making it suitable for on-site detection. As a classic technique of colorimetric detection， enzyme-linked immunosorbent assay （ELISA） achieves quantitative measurement of TTX through antigen-antibody specific binding and enzyme-catalyzed color development. Its core advantages lie in high specificity and manageable cost， but its application is limited by issues such as matrix interference and cumbersome operation. By fixing the antigen or antibody on a solid-phase carrier， it uses enzyme-labeled antibodies or antigens for color development^[60]. For example， Reverté et al.^[61] developed a maleimide-based ELISA for the detection of TTX in oysters and mussels. This method uses cysteamine instead of dimercaptans to construct self-assembled monolayers （SAMs） and is validated by LC-MS/MS. The use of cysteamine reduces the experimental time and costs， while TTX-coated maleimide plates can be stored reliably for 3 months at 4 ℃ and -20 ℃. Its minimum eLOD is as low as 20 μg/kg （for oyster samples not cleaned by SPE）， and the test results are not significantly different from those of LC-MS/MS， making it suitable for routine shellfish monitoring. Maleimide-based ELISA laid the technical foundation for the immunodetection of TTX， but there are still matrix interference issues in analysis. The subsequently developed magnetic bead （MB）-based colorimetric immunoassay has significantly improved the resistance of this method to matrix interference by optimizing the solid-phase carrier and reaction system. For example， Campàs et al.^[62] developed a MB -based colorimetric assay based on enzyme-catalyzed colorimetry. As shown in Fig.3a， the construction of the sensor is clear. TTX is first immobilized on maleimide-activated MBs to form MB-TTX conjugates. In the presence of TTX， anti-TTX monoclonal antibodies （mAbs） compete for binding sites between the immobilized MB-TTX and free TTX in the sample. Finally， the mAbs combined with horseradish peroxidase-labeled secondary antibodies （IgG-HRP） can catalyze the colorimetric response of the substrate. By summarizing and analyzing the colorimetric response results， quantitative analysis of the analyte （TTX） can be achieved. In the experiment， the effective LOD （eLOD） of the method was 1 μg/kg for oysters and razor clams， and 3.3 μg/kg for mussels. To further improve anti-interference capability， an antibody-aptamer hybrid ELISA strategy is used. Shkembi et al.^[63] developed a hybrid antibody-aptamer sandwich assay for the detection of TTX in pufferfish. TTX aptamers were screened out via systematic evolution of ligands by exponential enrichment （SELEX） combined with next-generation sequencing. As shown in Fig.3b， an anti-TTX monoclonal antibody is used as the capture element， and a biotinylated aptamer is used as the detection element. The aptamers screened had a LOD as low as 0.310 ng/mL without interference from other marine toxins such as algaetoxins and okadaic acid （OA）， which is also shown in Fig.3b. TTX in pufferfish tissue extracts has a detection recovery of 93.5%~109.1% and correlates well with the results of competitive ELISA and LC-MS/MS. Future efforts should focus on developing rapid ELISA kits to reduce operational difficulty and testing time. In addition， the introduction of materials such as magnetic particles can enhance the efficiency and separation of detection， thereby improving the sensitivity of ELISA. However， the stability of biological enzymes is easily influenced by the environment. Therefore， the stability and color intensity of the sensors can be enhanced by developing nanozymes or new colorimetric substrates^[64-66].

Colloidal gold immunochromatographic technology， which is based on lateral flow chromatography， is also a traditional colorimetric technology. It fixes antigens or antibodies on the test strips and uses colloidal gold as a marker^[67]. The test strips appear with specific color bands through the combination of antigens and antibodies， achieving rapid qualitative or semi-quantitative detection^[68]. For instance， Ling et al.^[69] developed dual-channel competitive colloidal gold test strips， achieving the detection of TTX and OA at the same time. As shown in Fig.4a， they use approximately 40 nm colloidal gold nanoparticles （Au NPs） to develop a dual-detection immunoassay strip. The strip adopts highly specific anti-OA and anti-TTX monoclonal antibodies and takes 40 nm Au NPs as signal amplification vectors. For seafood substrates like clam， green mussels， and razor clam， the strip only needs simple pre-treatment， and the visual detection limits （vLOD） for OA and TTX are 1.5 μg/kg and 30 μg/kg， respectively. The detection results of the strip are consistent with LC-MS results， and the whole detection process can be completed within 10 min. To address the issues of insufficient sensitivity and susceptibility to matrix interference in traditional competitive technologies， Li et al.^[70] achieved a technological upgrade through antibody screening and optimization of reaction conditions. The sensor uses a highly specific 3H3 monoclonal antibody （which does not cross-react with other toxins such as saxitoxin （STX）， pectenotoxin （PTX）， etc.）， and uses 20 nm Au NPs as the signal amplification vector. For crucian carp and clam substrates， the sensor does not require complex pre-treatment， and the LOD for TTX in both substrates is 10 μg/kg. The detection results of the sensor are consistent with LC-MS/MS results， and the entire inspection process can be completed in less than 10 min. Further， Tang et al.^[71] developed an antibody-aptamer sandwich-structured sensor that is signal-on. TTX-specific monoclonal antibodies are fixed on the test line （T line） of the test strip， while biotin-modified complementary DNA （cDNA） is fixed on the control line （C line）. The AuNP-aptamer probes bind to TTX to form a complex. The complex migrates to the T line through capillary action and is captured by the antibody， forming a sandwich structure that causes AuNP aggregation and color development. The remaining probes are captured by the cDNA to form a second color band， ensuring the test is valid. Experiments indicate that the detection range of this method is 8~100 ng/mL， with an LOD of 8 ng/mL. In future research， the morphology and modification methods of Au NPs should be further optimized to improve the sensitivity of the sensor. For example， developing gold nanorods， gold nanoshells， and other nanostructures with SPR effects can further enhance the signal strength^[72]. More advanced chromatographic matrices should be developed to accommodate the application of these new Au NPs labels or other markers， to improve accuracy and sensitivity. By combining machine learning with software on smartphones， the accuracy of colorimetric sensors can be further improved， fully leveraging their visibility and low-cost advantages^[73-74].

2.4 Fluorescence sensor

The Fluorescent Sensor achieves qualitative or quantitative detection of target substances based on changes in fluorescence signals^[75].The performance optimization of the fluorescence sensor mainly relies on the specific binding of the recognition elements and the design of signal amplification strategies. For example， Lan et al.^[75] developed a fluorescent sensor based on the specific recognition of TTX and TTX-apt， using berberine as the fluorescent reporter molecule to detect TTX. During the detection， TTX combined with aptamers to transform its conformation into a tight structure of a neck ring， providing a more rigid environment for berberine and further enhancing fluorescence. Fig.5a shows the concentration response of the sensor. The advantages of this system are that it can be detected in less than 5 minutes， has a LOD of 7.4×10^-11 mol/L， a linear range of 1.0×10^-10~5.0×10^-7 mol/L， and a recovery rate of 96.54%~106.40% in human serum spiked samples， with strong specificity and low cost. In 2020， Lan et al.^[76] further developed an exonuclease I （Exo I）-assisted fluorescent sensor， using Exo I as a background quencher. Exo I was added to the sensor to degrade TTX-Apt， releasing berberine， which caused fluorescence quenching. As Fig.5b illustrates， TTX-Apt forms a stable stem-loop structure that resists Exo I degradation and enhances berberine fluorescence when TTX binds to the aptamer. The sensor has the advantages of a low LOD of 1.1×10^-11 mol/L， a linear range of 3.0×10^-8~6.0×10^-6 mol/L， and a recovery of 99.63%~105.51% in human serum spiked samples， with high specificity and low background interference. With the development of fluorescent sensing technology， the integration of signal amplification strategies has been introduced to improve detection performance. Zhang et al.^[77] developed a triple-cycle amplification detection method based on the MB-aptamer competition system. As shown in Fig.5c， in the experiment， free TTX competed with cDNA to bind MNPs-Apt， and the magnetically separated cDNA was amplified as a triple cycle amplification composed of primer-triggered strand displacement amplification （SDA） and catalytic hairpin CHA. The amplification product was combined with a fluorescent reporter probe to restore fluorescence. The advantage of this method is that the LOD is as low as 2.65×10^-4 ng/mL， and the recovery rates are 100%~107.33% and 99.67%~116.67% in clam and shellfish samples， respectively， and the results are consistent with commercial ELISA kits， with high sensitivity and strong reliability. Moreover， novel functional materials^[78]， such as metal-organic frameworks （MOFs）^[79]， have also been applied for performance optimization of fluorescent sensors. Dou et al.^[80] developed aptamer-functionalized nanometal-organic framework （NMOF） fluorescence sensors for the detection of TTX. As shown in Fig.5d， zirconium-based nano-MOFs （NMOF 1/2） are energy donors （green/blue fluorescence， respectively） and Carboxytetramethylrhodamine （TAMRA）-labeled TTX-Apts are energy acceptors （reddish fluorescence）， with aptamers fixed on the surface of NMOF by Zr-O-P bonds. In the experiment， TTX combined with aptamers to change its conformation， donor-recipient distance is shortened， the fluorescence resonance energy transfer （FRET） effect is enhanced， and NMOF fluorescence is weakened， and TAMRA fluorescence is enhanced. The sensor has the advantage of a LOD of 3.07 ×10^-9mol/L， a recovery of 84.79%~103.31% in shellfish spiked samples， and good pH independence， stability （fluorescence attenuation ≤8% at 21 d）， and specificity. Novel materials would provide many ways for further optimization of fluorescent sensors. Therefore， more stable fluorescent probes with low background interference （such as rare-earth-doped nanomaterials and carbon quantum dots） could be developed， with the aim of achieving higher sensitivity. In addition， by combining ratiometric fluorescence technology^[81-82]， detection of TTX can be achieved based on the ratio of dual signals to enhance the accuracy of the sensor.

As a typical and practical subclass， fluorescent immunochromatographic sensors are based on lateral flow chromatography technology， with antigens or antibodies immobilized on the test strip. Different from colloidal gold immunochromatography， fluorescent immunochromatographic sensors use fluorescent substances （such as fluorescent microspheres， quantum dots， or fluorescent dyes） as labels. Through the specific binding interaction between antigens and antibodies， a specific fluorescent signal band is generated on the test strip， enabling rapid qualitative， semi-quantitative， and even quantitative detection of target substances. Fluorescent immunochromatographic sensors have a more significant advantage in detection sensitivity. For instance， Shen et al.^[83] developed a membrane-based fluorescence quenching immunochromatographic sensor for the detection of TTX， using ordinary fluorescent microspheres as fluorescent labeling material. Bovine serum albumin-TTX labeled with fluorescent microspheres （FM-BSA-TTX） and FM-BSA were fixed on the nitrocellulose membrane as T line and C line， respectively， and Au NPs-mAbs were loaded on the binding pad as quenching agents. The sensor can complete the detection in less than 12 min， with a LOD as low as 0.78 ng/mL （more than 20 times lower than colloidal gold test strips）， a linear range of 3.13~50 ng/mL， and a recovery rate of 61.3%~70.4% in pufferfish spiked samples， achieving fast and highly sensitive detection of TTX. The fluorescent immunoassay analyzer in Fig.6a is used in their research. To get better effects， as shown in Fig.6b， Shen et al.^[84] further optimized the fluorescent immunochromatographic test strip by combining quantum dot nanobeads with gold nanoflowers （Au NFs）， constructing a signal-on competitive fluorescence immunochromatographic test strip. The entire detection process takes only 8 minutes， with a LOD as low as 0.2 ng/mL for TTX and a quantitative range of 1.56~100 ng/mL. In addition， the test strip has excellent signal brightness and low background interference， and the recovery rate in the spiked sample is 85.5%~119.7%， which is not interfered with by the sample matrix. The sensor prepared by Shen relies on anti-mouse IgG antibodies as the C line， which is a traditional design method and has certain instability. Introducing a streptavidin-biotin system into the fluorescent immunochromatographic sensor provides higher resistance to interference and greater stability^[85]. For example， Sun et al.^[86] developed a highly sensitive quantitative fluorescent test strip immunosensor based on an independent control system for the rapid detection of TTX in shellfish. The detection probe is prepared with Eu³⁺ time-resolved fluorescent microspheres as markers， and the streptavidin-biotin system is introduced as an independent quality control system. Biotin-bovine serum albumin （Biotin-BSA） is coated on the C line to stabilize the fluorescence signal. Fig.6c shows its responses to the concentration gradient of TTX. In experiments， the sensor detected TTX in 20 min， with LOD as low as 0.05 ng/mL， a linear range of 0.5~40 ng/mL， and spiked recovery of 97%~102%. The C line has a CV value of less than 5%， excellent stability and accuracy， which can be used for on-site point-of-care screening of TTX in shellfish. Fluorescent markers have significant potential for the development of fluorescent immunochromatographic sensors. One promising direction is exploring the application of time-resolved fluorescent microspheres. The time-resolved fluorescent microspheres can avoid interference from background fluorescence through fluorescence lifetime measurement， with the aim of ultra-sensitive detection of TTX.

3 The developed analytical method based on electrochemical sensing for the detection of TTX

Electrochemical methods are technologies that use the electrochemical properties （such as impedance， current， voltage， etc.） of substances to analyze target. Electrochemical sensors have the advantages of high sensitivity， fast response speed， and instrument miniaturization^[87]. Their core principle is that TTX either undergoes redox reactions on the electrode surface or specifically interacts with modified substances on the electrode surface， resulting in changes in the electrochemical properties of the electrode^[88]. These changes in electrical signals are then detected by electrochemical workstations and other equipment to achieve the qualitative and quantitative detection of TTX. As shown in Table 3， there are mainly four kinds of sensors that are based on electrochemical methods， including impedance sensors， amperometric sensors， electrochemiluminescence （ECL） sensors， and photoelectrochemical （PEC） sensors.

3.1 Impedance sensor

The electrochemical impedance-based sensor detects the concentration of TTX by measuring the change in charge transfer resistance （R_ct） at the electrode interface^[89]. The core structure of the sensor is a three-electrode system （working electrode， reference electrode， and pair electrode）^[90]. The surface of the working electrode is mostly decorated with recognition elements. When the analyte binds to the recognition element， the formation of an insulating layer inhibits the transfer of electrons， resulting in altered electrode impedance^[91]. This amount of R_ct variation is linearly related to the concentration of the analyte， allowing for quantitative detection of the analyte.

The cell impedance sensor， which is a typical impedance sensor， uses living cells as the sensitive element and reflects the concentration of toxins by monitoring changes in the physiological state of the cells^[92]. Wang et al.^[93] developed a cardiomyocyte-based impedance biosensor for the detection of marine toxins such as STX and TTX. The sensor system combines primary neonatal SD rat cardiomyocytes with an impedance sensor array. It uses label-free real-time monitoring technology to monitor the growth dynamics and contraction behavior of cardiomyocytes. Fig.7a illustrates the construction of the cardiomyocyte-based biosensor. The core innovation of the sensor is the use of cardiomyocyte pulsation frequency as a sensitive parameter for detecting STX and TTX. The experimental results showed that the LOD for STX could reach 0.087 ng/mL and 89 ng/mL for TTX. At the same time， it has high throughput and non-invasiveness， providing a reliable tool for the quantitative analysis of marine toxins. As for aptamer-based impedance sensors， their high molecular recognition specificity enables lower LOD. For instance， Fomo et al.^[94] developed an electrochemical aptasensor for TTX detection based on a glassy carbon electrode modified with a poly（4-styrenesulfonic acid）- doped polyaniline membrane （PANI/PSSA）. Through covalent crosslinking with glutaraldehyde， an amino-terminal functionalized TTX-binding aptamer （NH₂-Apt） is immobilized on the electrode surface. Signal acquisition was performed using cyclic voltammetry （CV） and electrochemical impedance spectroscopy （EIS）.

When TTX binds to the aptamer， it causes a change in the R_ctof the film layer， and this change is used as the detection signal output， which is illustrated in Fig.7b. The sensor has a dynamic linear range of 0.23~1.07 ng/mL， a sensitivity of （134.88±11.42） Ω‧mL/ng， and a LOD as low as 0.199 ng/mL. The above two cases demonstrate the application of electrochemical impedance platforms in the detection of toxins at both the biological and molecular levels. Both sensors are highly specific and user-friendly， thus effectively addressing the core detection requirements in food safety and environmental monitoring. For the sake of accuracy and the analysis speed， machine learning could be applied to identify impedance spectra of the sensor， promoting their widespread application in the detection of TTX.

3.2 Amperometric sensor

The amperometric sensor takes the change of current generated by electrochemical reactions as the core detection principle^[95]. The amount of current change correlates with the concentration of TTX， allowing for quantitative detection of TTX. When TTX specifically binds to the recognition element on the electrode surface^[96]， it will interfere with the electron transfer process of redox probes （such as [Fe（CN）₆]^3-/4- pairs）， and eventually lead to a change in the current signal. Initially， researchers regulated the electrochemical signals of enzyme labels through antigen-antibody specific binding. Zhang et al.^[96] developed an amperometric immunosensor with a composite electrode based on single-walled carbon nanotubes （SWCNTs） and an ionic liquid （OPFP， i.e.， n-octylpyridinium hexafluorophosphate）， specifically for the detection of TTX in pufferfish. The sensor design integrates the classic principle of ELISA， uses alkaline phosphatase as the labeling enzyme， and achieves antigen （BAS-TTX） immobilization through magnetic particles to form a complete detection system. Experimental data show that the amperometric immunosensor detects TTX in a linear range of 2~45 ng/mL， with a LOD as low as 5 ng/mL. The detection efficiency is excellent， and a single inspection process can be completed within 20 min. In the analysis of actual puffer fish samples， the sensor achieved a spiked recovery rate of 98.16%. Further modifying the electrode can improve the performance of the sensor. For example， Reverté et al.^[97] developed an amperometric immunosensor array based on dithiol SAMs for the detection of TTX in pufferfish. The array is based on a gold electrode array and forms a directional， stable sensing platform through the self-assembly of carboxylate-containing dimercaptans. After the immobilization of TTX， the sensor performs a competitive immunoassay with HRP-labeled secondary antibodies as enzyme markers and 3，3'，5，5'- tetramethylbenzidine （TMB） as substrates. The sensor has a LOD of 2.6 ng/mL and can detect TTX as low as 70 μg/kg in tissue samples. The results are in good agreement with those obtained by methods such as SPR immunosensors and liquid chromatography-high resolution mass spectrometry （LC-HRMS）， which fully demonstrates its reliability in the detection of real samples. In addition， optimizing the carrier can also enhance the sensitivity and specificity of the sensor. Leonardo et al.^[98] developed an MB-based amperometric immunosensor for the detection of TTX in juvenile pufferfish （Lagocephalus sceleratus） from the North Aegean region. The sensor uses maleimide-activated MBs to achieve TTX immobilization through the self-assembly of cysteine， constructing a competitive immunoassay system. This system is combined with a screen-printed carbon electrode array to complete the detection. Fig.8a illustrates the process. Experimental data show that the sensor has a linear detection range of 1.2~52.7 ng/mL and a LOD of 1.2 ng/mL. MBs reduce matrix interference while improving the reaction kinetic efficiency.

In recent years， the introduction of new materials has also driven the development of amperometric sensors for the rapid detection of TTX. For example， Rocha et al.^[99] developed an electrochemical sensor based on a molecularly imprinted polymer （MIP） for the detection of TTX in seafood. In this sensor， o-phenylenediamine is used as the functional monomer， and voglibose is used as the dummy template. On a screen-printed gold electrode， an MIP is synthesized via electropolymerization， which is characterized with CV. The signal is measured using differential pulse voltammetry （DPV） combined with a redox probe （[Fe（CN）₆]^3-/4-）. As shown in Fig.8b， experimental data showed that the sensor has a linear detection range of 5×10³~2.5×10⁴ ng/mL， with a LOD of 1.14×10³ ng/mL. Compared to the non-imprinted polymer （NIP） sensor， the MIP enhances the selectivity and stability of the sensor while improving analytical efficiency. The sensor achieved recoveries of 81.0%~110.2% （RSD less than 15%） in spiked mussel samples. Besides MIP， the peptides have also been introduced into the development of the sensor. For example， Kim et al.^[100] developed a peptide-based electrochemical sensor. The sensing platform is constructed by sequentially electrodepositing polypyrrole （PPy） and Au NPs， and detection is carried out using potentiometry and CV. Cysteamine is modified at the C-terminus of the peptide， and the peptide is immobilized on the electrode via Au—S bonds. PPy and Au NPs enhance the conductivity of the carbon fiber screen-printed electrodes and provide ample immobilization sites for the receptor. Experimental data show that the sensor has a linear detection range of 2×10³~1×10⁶ ng/mL， with a LOD of 2.8×10³ ng/mL. Future research could further explore more nanomaterials （such as MXene， MOF， etc.） to improve the efficiency of electron transfer， develop more advanced enzyme-free amperometric sensors， and enhance the stability and reproducibility of amperometric sensors.

3.3 ECL sensor

ECL sensors combine the dual characteristics of electrochemistry and luminescence， and their detection principle is that the ECL reagent is stimulated by an electrochemical reaction to produce luminescence^[101-102]. The luminescence intensity is correlated with the concentration of TTX. This type of sensor combines the high controllability of electrochemistry with the high sensitivity of luminescence detection， showing significant advantages in rapid and accurate detection of TTX. Early ECL sensors mostly improved detection performance by simply modifying electrodes with composites. In 2016， Shang et al.^[103] developed a simple-structured ECL sensor， which uses a glassy carbon electrode modified with a Nafion-graphene-Ru(bpy)₃²⁺ composite film as the core detection element for the detection of TTX. Fig.9a is a simple depiction of the sensor construction process. Nafion enables the one-step synchronous immobilization of graphene and Ru(bpy)₃²⁺. Graphene enhances electron transfer efficiency， while Ru（bpy）₃²⁺ acts as the core ECL signal molecule. As shown in Fig.9b， the luminescence intensity of the ECL sensor is enhanced when TTX is present. Experimental results show that the sensor detects TTX with a linear range of 5.0×10^-1~5.0×10³ ng/mL and a LOD as low as 0.1 ng/mL. In addition， the TTX in the sample is enriched by solid-phase microextraction technology， which further improves the detection stability and accuracy of the sensor. In the actual pufferfish sample recovery experiment， the recovery rate of the sensor ranged from 96%~107%， proving its suitability for sensitive detection scenarios of TTX in the field of food safety. To further enhance the specificity and anti-interference ability of the sensor， researchers introduced an immunoassay to construct a sandwich-type ECL sensor. In 2017， Shang et al.^[104] further developed an ECL immunosensor for the detection of TTX. As shown in Fig.9c， the sensor uses branched polyethyleneimine （BPEI）-functionalized graphene Fe₃O₄-Au composites as magnetic capture probes to achieve the immobilization of the primary antibody （Ab₁）. At the same time， luminol-AuNPs are used as signal markers and conjugated to secondary antibodies （Ab₂） to construct sandwich immune complexes. The core advantages of the design are that BPEI enhances the ECL signal strength of luminol， Fe₃O₄-Au enables fast magnetic separation， and luminol-AuNPs provide stable signal output. Experimental results show that the sensor has a linear detection range of 0.01~100 ng/mL and a LOD as low as 0.01 ng/mL. When analyzed on actual samples， the recovery of the sensor ranged from 96.0% to 107.3%， with strong specificity and excellent stability. Therefore， more ECL luminophores （such as MOFs， quantum dots， etc.） should be developed to enhance the luminescence efficiency of sensors. At the same time， magnetic separation technology can be applied to sensors to simplify preprocessing steps and optimize sensor performance characteristics.

3.4 PEC sensor

PEC sensors operate based on the principle of photogenerated carrier separation and transfer^[105]. Photoelectrodes （e.g.， titanium dioxide （TiO₂）^[106]， zinc oxide （ZnO）^[107]） are the core of PEC sensors. Under the light， photoelectrodes produce electron-hole pairs. When TTX binds to the recognition element， the separation efficiency of carriers is regulated， and the photocurrent signal is changed. For example， to address co-contamination of TTX and OA in aquatic products， Zheng et al.^[108] developed a near-infrared responsive PEC immunosensor based on a multi-channel paper-based electrode， achieving simultaneous detection of the two toxins. which is shown in Fig.10. The sensor immobilizes the primary antibody of TTX on the paper-based screen-printed electrode （PSPEG） through electrostatic adsorption and introduces Ag₂S quantum dots labeled with the secondary antibody of TTX， constructing a sandwich-type PEC immunosensor. The Au NPs on the PSPEG surface enhance electrode conductivity and provide active sites for antibody loading， while the porous fibrous structure of the paper-based substrate facilitates rapid diffusion of TTX. Additionally， the near-infrared-responsive Ag₂S quantum dots can reduce phototoxicity and enhance sample penetration， thereby minimizing matrix interference. Experimental data indicate that under optimal conditions， the sensor has a linear detection range for TTX of 0.001~100 ng/mL， with a LOD of 0.005 ng/mL. Building upon the analysis of the modification materials， the development of PEC sensors can focus on developing more NIR-responsive photosensitive materials. At the same time， combining paper-based electrodes with microfluidics^[109-110] can achieve low-cost and disposable detection of TTX， which can expand the application of sensors in biological samples and in vivo detection.

4 The developed analytical method based on multi-modal sensing for the detection of TTX

Multi-mode integrated sensing technology integrates two or more detection principles. The detection accuracy and anti-interference capability are improved through signal cross-verification^[111]， and common combined modes include fluorescence-SERS， electrochemistry-SERS， etc. Detecting TTX in real food and environmental samples often faces challenges such as complex matrix interference and the need for rapid on-site detection. Although the optical and electrochemical sensing technologies described in the above two chapters have achieved certain successes in sensitivity， detection speed， and portability， single-mode sensing systems still have technical limitations in practical applications.

Specifically， optical sensors represented by SERS and fluorescence sensors have high sensitivity. However， the detection performance of SERS sensors is easily interfered with by complex sample matrices and strong background noise， and the signal reproducibility of SERS remains unsatisfactory due to the uneven distribution of hotspots on the substrate. And for fluorescence sensors， they are prone to interference from autofluorescence of samples and ambient light， resulting in a low signal-to-noise ratio. As for electrochemical sensors， they usually have the advantages of portability and fast response， but their ability to resist interference in complex matrices is limited， and a single electrical signal can be prone to false positives due to environmental effects. Furthermore， detection technologies are required for the detection of on-site screening to balance sensitivity， accuracy， speed， and operability， which is challenging to fully achieve with single-modal sensors.

In order to overcome the above limitations of single-mode sensing， multi-modal integrated sensing technology has become a research hotspot in the field of detection of TTX in recent years. Multi-mode integrated sensing technology integrates two or more detection principles， and improves detection accuracy and anti-interference ability through signal cross-verification or self-calibration^[112-113]. The core design concept of multimodal sensors for the detection of TTX is to integrate the technical advantages of different single-modal sensors and offset their respective limitations. For example， the combination of electrochemistry and SERS includes the portability and fast response of electrochemical sensors， as well as the high sensitivity and immunity of SERS. The combination of fluorescence with SERS leverages the visibility of fluorescence and the accurate quantification of the content of TTX by SERS. At the same time， the multi-modal sensing system can effectively reduce the interference of complex matrices and environmental factors on the detection results through the mutual correction of multiple signals， and improve the accuracy， reliability， and anti-interference ability of the detection， making it more suitable for the actual needs of on-site rapid screening of TTX in complex samples. At present， the multimodal sensors detected by TTX are mainly dominated by bimodal sensing systems， and the common fusion modes include fluorescence SERS， electrochemical SERS， electrochemical colorimetry， and SERS colorimetry. These multimodal sensors use functional nanomaterials （such as precious metal nanoparticles， MOFs， and MXenes） as the core signal transduction and recognition carriers^[114-115]， combined with specific recognition elements， to achieve simultaneous acquisition of multiple signals in a detection system （as shown in Table 4）. This chapter focuses on the development and performance characteristics of mainstream multimodal sensing systems in the detection of TTX， expounds the signal generation mechanism， material modification strategy and detection process of different multimodal sensors， analyzes the advantages of multimodal sensing compared with single-modal sensing in practical applications， and summarizes the current development progress， existing problems and future development direction of multimodal sensing technology， to provide technical reference for the development of more practical on-site TTX rapid screening technology.

4.1 The fluorescence-SERS dual-modal sensor

The fluorescence-SERS dual-modal sensor can combine the advantages of both^[116]. The fluorescence-SERS dual-modal detection method has received widespread attention from researchers^[117-119]. This method not only allows visualization of analytes through fluorescence but also provides accurate quantitative results from SERS analysis^[119-120]. For example， Liu et al.^[121] developed a fluorescence-SERS dual-modal aptasensor based on Au NPs@MIL-101 nanohybrids for the ultrasensitive detection of TTX. As shown in Fig.11a， the sensor consists of two parts. On the one hand， it uses Au NPs@MIL-101 nanohybrids as the fluorescence quencher and SERS substrate， which combine the high adsorption capacity of MIL-101 with the optical properties of Au NPs. On the other hand， TTX-specific aptamers labeled with the fluorescent and Raman reporter molecule Cy3 （Cy3-aptamers） are used as recognition elements and signal probes. In the presence of TTX， the high affinity between TTX and Cy3-aptamers causes the two to form rigid complexes and detach from the surface of the nanohybrids， resulting in the recovery of the fluorescence signal and the attenuation of the SERS signal. The advantage of this sensor is that it is easy to operate. The fluorescence and SERS signals show a good linear relationship， respectively， with LODs as low as 0.006 ng/mL （fluorescence） and 0.008 ng/mL （SERS）. When detecting spiked pufferfish and clam samples and naturally contaminated samples， the recovery rate and coefficient of variation performed excellently， effectively improving the reliability and accuracy of detection. In this sensor， the fluorescence signal and the SERS signal are detected under different light sources， reducing potential signal interference from a single light source. Therefore， the overall anti-interference capability of the detection is enhanced. This type of dual-modal sensor exhibits considerable potential. For example， Cy3-aptamers can be replaced with rare-earth-doped fluorescent probes （such as Eu³⁺/Tb³⁺ time-resolved fluorescent nanoparticles）， further enhancing the anti-interference ability and reproducibility of the fluorescence signal. Additionally， constructing Au nanoshell structures can further enhance SERS signals， which improve the sensitivity of the sensor.

4.2 The electrochemical-SERS dual-modal sensor

The electrochemical-SERS dual-modal sensor also combines the advantages of both methods^[122-123]. The total electrochemical peak intensity and SERS signals are quantified to reduce environmental interference， achieving more precise and stable targets. As shown in Fig.11b， Yao et al.^[124] developed an electrochemical-SERS dual-modal aptasensor based on Ag@Cu₂O NPs for the accurate detection of TTX. The sensor uses Ag@Cu₂O NPs as dual-signal probes， which can generate characteristic electrochemical signals at Cu⁺ oxidation and Ag⁰ oxidation. MXene nanosheets （NSs） are carriers of the sensor. Their high specific surface area allows them to load Ag@Cu₂O NPs， and their inherent Raman peak can be used as an internal reference. During the experiment， the specific binding of TTX to the aptamers causes Ag@Cu₂O NPs to detach from MXene NSs， resulting in attenuation of the dual signals. The environmental interference can be reduced by quantifying the total electrochemical peak intensity in the SERS ratio signal. The results showed that the linear results were good in the TTX concentration range of 0.1 ng/mL to 1×10⁴ ng/mL， with LODs as low as 0.0316 ng/mL （electrochemical） and 0.0383 ng/mL （SERS）， and the detection recovery rate for actual fish samples reached 97.8%~99.1%， with excellent specificity and stability. In this sensor， the quantitative analysis of TTX is achieved by quantifying the total electrochemical peak intensity and the SERS ratio signal， which provides a great reference value for other similar sensors. In addition， the selection of alternative materials with higher electrical conductivity and more stable Raman signals to replace MXene NSs could also be regarded as an effective strategy for enhancing the performance of sensors.

4.3 The electrochemical-colorimetric dual-modal sensor

Electrochemical-colorimetric dual-modal sensors are also notable sensors^[125-127]. They combine the high sensitivity of electrochemical sensors with the advantages of colorimetric sensors， such as low cost， visual detection， and ease of operation^[128]. For example， Li et al. ^[129] developed an electrochemical-colorimetric dual-modal immunosensor for the detection of TTX. The HRP/anti-TTX mAb@ZIF-8 composite material serves both recognition and signal probe functions. The phage-displayed mimotope peptide （CDEMWPHYC） is modified on the gold electrode surface. The CDEMWPHYC can specifically bind the anti-TTX mAb and compete for the TTX binding site， enabling a non-toxic detection strategy that replaces conventional toxic TTX antigens. During detection， varying concentrations of TTX were mixed with HRP/anti-TTX mAb@ZIF-8 and added to the modified electrode. The specific binding between TTX and mAb would reduce the amount of complex material bound to the electrode， leading to a dual-signal change， which is shown in Fig.11c. The advantage of this sensor lies in the mutual verification and self-calibration of the dual signals. The electrochemical mode uses DPV， and the colorimetric mode is combined with a smartphone app to analyze the RGB values （especially the B value）， enabling rapid on-site screening. Both modes can effectively reduce environmental interference. The experimental results showed that the sensor has excellent specificity and good reproducibility. When applied to the detection of actual seafood samples such as pufferfish and whelk， the recovery in electrochemical mode was 89.5%~109.5%， and 81.9%~117.5% for colorimetric mode， with results consistent with the LC-MS/MS method， confirming its practical application value in TTX detection in food samples. Electrochemical and colorimetric signals are obtained in different detection systems （an electrochemical workstation and a smartphone）. The potential signal interference caused by a single detection environment or instrument is reduced. Based on this sensor， HRP can be replaced with other enzymes with stronger catalytic activity （such as AP to further amplify the signal and enhance detection sensitivity. Alternatively， new optical materials like quantum dots can be used instead of TMB as a colorimetric substrate to improve the stability and visualization of the signal.

4.4 The SERS-colorimetric dual-modal sensor

The SERS-colorimetric dual-modal sensors can achieve more precise and stable detection of TTX by synchronously quantifying the intensity of SERS characteristic peaks and colorimetric absorbance signals， effectively reducing environmental interference and matrix effects^[130-131]. As shown in Fig.12， Peng et al.^[132] constructed a dual-modal sensor using Fe₃O₄@Cu nanozyme as the catalytic core and a TTX aptamer as the specific recognition element for sensitive detection of TTX. The Fe₃O₄@Cu nanozyme exhibits excellent peroxidase-like activity， which can catalyze the oxidation of TMB to oxTMB in the presence of hydrogen peroxide （H₂O₂）. A synergistic signal basis for both detection modes is provided. The aptamer specifically binds to TTX and detaches from the nanozyme surface， causing the catalytic activity of Fe₃O₄@Cu to recover， thereby regulating the production of oxTMB. During detection， the formation of oxTMB triggers dual signal changes. In the SERS mode， after enhancement with Au NPs， oxTMB exhibits a characteristic Raman peak at 1610 cm^-1， with an intensity positively correlated to TTX concentration. In the colorimetric mode， oxTMB produces a strong absorbance peak at 652 nm， with the absorbance significantly increasing with the concentration of TTX. At the same time， the sensor developed an image processing channel to quantify the color change of oxTMB with RGB values. The LOD for the SERS mode is as low as 0.055 ng/mL， while the LOD for the colorimetric mode is 2.127 ng/mL. The sensor shows almost no response to interfering marine toxins such as OA， demonstrating excellent anti-interference capability. Furthermore， Peng et al.^[133] also constructed a dual-modal sensor using hairpin probes （HPs） as specific recognition elements and Au/Au@Ag NPs as signal transduction cores for sensitive detection of TTX. The Au NPs possess unique localized surface plasmon resonance properties， which have distinct UV-visible absorption changes. Au@Ag NPs can enhance the hot spot effect of SERS， providing a synergistic signal basis for both detection modes. The HP specifically binds to TTX and undergoes conformational changes， exposing flexible single-stranded DNA （ssDNA） ends that adsorb onto the surface of 4-mercaptopyrimidine （4-MPY）-functionalized Au NPs， thereby inhibiting salt-induced AuNP aggregation. This regulation of aggregation state further modulates the signal output of both detection modes. The LOD for the SERS mode is as low as 0.0947 ng/mL， while the LOD for the colorimetric mode is 1.077 ng/mL.

4.5 Multi-modal sensors based on other principles

There are some sensors that are not only based on optical and electrochemical methods. For instance， the colorimetric-photothermal dual-modal sensor can integrate the advantages of both detection modes^[134]. This dual-signal detection method has garnered significant attention in analysis as well， as it not only enables visual judgment of analytes through color changes but also provides precise quantitative results via photothermal temperature readouts. For example， Raza et al.^[135] developed a colorimetric-photothermal dual-modal sensor for the detection of TTX. The sensor constructs a competitive immunoassay system with fourier transform infrared-assisted Au@prussian blue （FTAN@PB） composites serving as dual-functional nanozymes/photothermal agents and immunoprobes， and TTX-BSA as the capture antigen. In the presence of TTX， the binding of immunoprobes to TTX-BSA is inhibited， leading to weakened colorimetric and photothermal signals. Featuring simplified antibody conjugation and portability， the sensor achieves LODs of 0.26 ng/mL （colorimetric） and 0.44 ng/mL （photothermal）， with acceptable recovery rates （82.0%~111.8% and 79.1%~99.6%） and low variation coefficients in spiked samples. The dual-modal design minimizes signal interference and enhances the reliability of the detection. In a similar manner， as shown in Fig.13， Li et al.^[136] developed a colorimetric， catalytic-enhanced colorimetric and photothermal triple-modal aptamer-based lateral flow assay for the detection of TTX. In the presence of TTX， MB@poly-Apts disassemble due to high target affinity， releasing complementary linkers that hybridize with onion flower-like gold-palladium nanoparticles （MOGP） probes， leading to signal accumulation at the T line and turn on of three signals， which are colorimetric output from the intrinsic optical absorption of MOGPs， catalytically amplified colorimetry via their nanozyme activity， and photothermal readout based on their high photothermal conversion efficiency. The assay achieves vLODs of 1 ng/mL （colorimetric）， 0.01 ng/mL （catalytic-enhanced colorimetric）， and 0.025 ng/mL （photothermal）， with good recovery rates （89.8%~121.4%） and low relative standard deviations （RSD less than 11.7%） in spiked pufferfish samples. This triple-modal design not only broadens the detection linear range but also verifies signals mutually， minimizing interference and significantly improving the reliability and flexibility of TTX on-site detection.

4.6 The current status of multi-modal sensing for the detection of TTX

Compared to single-modal sensing， dual-modal sensing has significant advantages. In complex matrices， the reliability of the detection is improved. The detection range and sensitivity are also enhanced compared to single-modality sensors. At the same time， multi-modal and single-modal sensing are complementary. The low cost and speed of single-mode sensing are irreplaceable in certain scenarios. Multi-mode is more suitable for high-demand scenarios. Taking these dual-modal methods into account， more multifunctional nanocomposites or probes can be developed to provide a reference for the further improvement of dual-modal sensors. In the future， machine learning models can be established to explore the relationship between the two mode signals， calibrating one signal with the other to improve the accuracy of detection. At the same time， portable dual-modal devices can be developed to adapt to complex field environments， along with supporting smartphone apps， to promote the widespread use of dual-modal sensors in in-site detection^[137-139]. In addition， constructing multi-modal sensors that integrate optical sensing and electrochemical sensing principles can further overcome the detection limitations of a single modal sensor. By obtaining and analyzing three or more characteristic signals， the multimodal sensor enables the detection of TTX more accurately and reliably. However， when integrating three or more types of sensors， the signals are easily prone to mutual interference， which may require the design of special nanocomposite materials （such as multifunctional nano-tags） to achieve signal isolation. Multi-modal data also faces the problem of spatiotemporal asynchrony， making it difficult to balance real-time performance and accuracy. Additionally， in miniaturized scenarios， the volume and energy consumption could be increased by integrating three types of signals， posing significant challenges for on-site applications. In the future development of multi- modal sensors， the above issues should be given priority.

5 Challenges and outlook

However， the current rapid screening technology of TTX is still faced with four core challenges （Fig.14）.

1） The matrix interference of complex samples is prominent. Although some techniques reduce interference through strategies such as Raman reporter molecules and matrix matching， matrix effects still restrict the accuracy of detection for real samples with multiple components coexisting.

2） The standardization of the testing process is not sufficient. The sensors developed by different laboratories have differences in the modification of the sensing surface， reagent ratio， operating parameters， etc.， resulting in poor comparability of the results on different detection platforms. A unified industry standard has not yet been formed.

3） The datasets of TTX lack completeness， consistency， and reference values. Existing studies mostly rely on small-scale datasets built in laboratories， with a single source of data and an insufficiency of standardized methods and quality control standards. This situation makes it difficult to cross-validate and integrate data from different studies， preventing the sensors from further improvement.

4） The widespread adoption of technology faces significant challenges. High-sensitivity technologies（e.g.， SERS， ECL sensors） rely on precious metal nanomaterials （gold and silver nanoparticles） and precision instruments. For instance， electrochemical readers are often cheaper than Raman spectrometers for SERS. Therefore， it is difficult for Grassroots regulatory departments to bear the costs of equipment and consumables. The balance among the technical adaptability， cost， and applicability of on-site testing equipment is hard to control.

To deal with these challenges， the future development of rapid screening technology for TTX should focus on the following aspects. To improve anti-interference technology and sample pre-processing techniques， probe materials with stronger targeted recognition capabilities can be developed， or signal amplification technologies can be applied^[140]. High-affinity aptamers can be screened through SELEX technology， or antibodies can be genetically engineered （such as single-chain antibodies）， to enhance the specific binding ability of TTX and reduce matrix interference^[141]. Moreover， AI algorithms can be used for intelligent signal correction to efficiently reduce matrix interference^[142]. For example， convolutional neural network can be trained to recognize features of various matrix interferences in Raman spectra， such as noise and baseline drift， thereby reducing the impact of these interferences on detection in one step^[143]. Apart from signal correction， AI， especially machine learning， can be used to directly predict the toxicity of TTX from untargeted data， providing a new path for the integration of detection technology and toxicity assessment. For example， the MS2Tox machine learning framework^[144]， can capture unknown chemical signals in complex environments through a non-targeted LC-HRMS sensor. The machine learning model is trained on mass spectrometry data， enabling direct prediction of the acute toxicity endpoints of TTX without relying on reference standards or a targeted detection process. In addition， through the analysis of results from multiple laboratories， using large AI models to establish an evaluation system for screening method performance can promote the standardization and normalization of technology. Besides， AI-enabled microfluidic technology could be integrated into the system， which can further promote the standardization and regulation of the technology^[145]. Integrated microfluidic chips can be used to achieve rapid sample separation， enrichment， and detection in one system. The preprocessing time can be reduced， and human operational errors are minimized.

At the same time， using a machine learning model， it is possible to predict more reliable data based on existing small samples， thereby enhancing the scale and coverage of the dataset^[146]. Specifically， multi-technique response data （optical， electrochemical， multi-modal） should be collected. The data collection should be conducted under different matrices （pufferfish， shellfish， serum， urine）， various contamination concentrations （0.001~1000 ng/mL）， and different environmental conditions^[140]. Recording different sensor performance parameters， sample information， testing environment， and raw signal data can help complete the dataset and provide support for technology optimization and cross-study validation. As for technical and cost issues， researchers can further develop portable and intelligent detection devices， utilizing wireless data transmission to achieve on-site real-time detection and remote monitoring， providing more affordable and efficient technical support for the food safety production chain， market supervision， and emergency response.

6 Conclusion

The various rapid screening techniques developed based on the principles of optical sensing， electrochemical sensing， and multi-mode sensing for detection of TTX were comprehensively discussed. These technologies enable the sensitive and rapid detection of TTX in aquatic products， food processing chains， and emergency response scenarios.

In summary， various sensing methods have developed distinct advantageous features. For optical sensing methods， SERS enables single-molecule detection with EF ranging from 10⁶ to 10¹⁰. SPR technology reduces detection times to 3.5 minutes through real-time analysis. Colorimetric sensors use color changes as visual signals， enabling simple and low-cost detection， while fluorescent sensors introduce materials for modification in multiple ways to lower the LOD to the pg/mL level. Meanwhile， electrochemical sensing technology has sensitivity and portability. impedance， amperometric， ECL， and the PEC sensor covers a detection range from nanograms per milliliter to femtograms per milliliter. Electrochemical methods analysis through charge transfer impedance changes， redox current responses， and low background luminescence signals， which makes the method particularly suitable for analyzing trace TTX in complex matrices.

Multimodal sensing technology， represented by fluorescence-SERS， electrochemistry-SERS， and other technologies， effectively reduces matrix interference and takes detection reliability to a new level with the help of signal cross-validation （such as bilinear correlation between fluorescence and SERS signals）.

At present， challenges such as matrix interference， insufficient standardization of detection procedures， and incomplete datasets still exist. In the future， the rapid screening technology for TTX should center on the exploration of artificial intelligence-enabled （AI-enabled） microfluidic systems and machine learning models. More efficient materials and miniaturized sensing devices should be developed to facilitate on-site applications of rapid TTX screening technologies.

In general， the rapid screening technology for TTX has progressed from a stage of solely improving sensitivity to a stage of coordinated development in sensitivity， accuracy， and practicability. With continuous innovations in materials， microfluidics， and AI， these technologies will play an increasingly crucial role in reducing poisoning incidents and ensuring food safety， with the aim of safeguarding public health.

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基金资助

国家自然科学基金项目(62201230)

国家自然科学基金项目(32061160473)

国家自然科学基金项目(32572707)

江苏省自然科学基金项目(BK20220546)

江苏高校优势学科建设工程（四期）资助项目(PAPD-2023-87)

中国博士后基金(2021M691314)

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Received	Published
2026-01-06	2026-07-24
Online Date
2026-05-23

摘要

Abstract

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引用本文

1 Introduction

2 The developed analytical method based on optical sensing for the detection of TTX

2.1 SERS sensor

2.2 SPR sensor

2.3 Colorimetric sensor

2.4 Fluorescence sensor

3 The developed analytical method based on electrochemical sensing for the detection of TTX

3.1 Impedance sensor

3.2 Amperometric sensor

3.3 ECL sensor

3.4 PEC sensor

4 The developed analytical method based on multi-modal sensing for the detection of TTX

4.1 The fluorescence-SERS dual-modal sensor

4.2 The electrochemical-SERS dual-modal sensor

4.3 The electrochemical-colorimetric dual-modal sensor

4.4 The SERS-colorimetric dual-modal sensor

4.5 Multi-modal sensors based on other principles

4.6 The current status of multi-modal sensing for the detection of TTX

5 Challenges and outlook

6 Conclusion

参考文献

基金资助