Aggregation-Induced Emission Luminogens for Activity-Based Sensing

Article Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Aggregation-Induced Emission Luminogens for Activity-Based Sensing Published as part of the Accounts of Chemical Research special issue “Activity-Based Sensing”. Dong Wang*,† and Ben Zhong Tang*,‡

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†

Center for AIE Research, Shenzhen Key Laboratory of Polymer Science and Technology, Guangdong Research Center for Interfacial Engineering of Functional Materials, College of Materials Science and Engineering, Shenzhen University, Shenzhen 518060, China ‡ Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Institute of Molecular Functional Materials, State Key Laboratory of Neuroscience, Division of Biomedical Engineering and Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, China CONSPECTUS: Fluorescent sensing has emerged as a powerful tool for detecting various analytes and visualizing numerous biological processes by virtue of its superb sensitivity, rapidness, excellent temporal resolution, easy operation, and low cost. Of particular interest is activity-based sensing (ABS), a burgeoning sensing approach that is actualized on the basis of dynamic molecular reactivity rather than conventional lock-and-key molecular recognition. ABS has been recognized to possess some distinct advantages, such as high specificity, extraordinary sensitivity, and accurate signal outputs. A majority of ABS sensors are constructed by modifying conventional fluorogens, which are strongly emissive when molecularly dissolved in solvents but experience emission quenching upon aggregate formation or concentration increase. The aggregation-caused quenching (ACQ) phenomenon leads to a limited amount of labeling of the analyte with the sensor and low photobleaching resistance, which could impede practical applications of the ABS protocol. As an anti-ACQ phenomenon, aggregation-induced emission (AIE) provides a straightforward solution to the ACQ problem. Thanks to their intrinsic advantages, including high photobleaching threshold, high signal-to-noise ratio, fluorescence turn-on nature, and large Stokes shift, AIE-active luminogens (AIEgens) represent a class of extraordinary fluorogen alternatives for the ABS protocol. The use of AIEgen-involved ABS can integrate the advantages of AIEgens and ABS, and additionally, the AIE process offers some unique properties to the ABS approach. For instance, in some cases of water-soluble AIEgen-involved ABS, chemical reaction not only leads to a chang in the emission color of the AIEgens but also causes solubility variations, which could result in specific “light-up” signaling. In this Account, the basic concepts and mechanistic insights of the ABS approach involving the AIE principle are briefly summarized, and then we highlight the new breakthroughs, seminal studies, and trends in the area that have been most recently reported by our group. This emerging sensing protocol has been successfully utilized for detecting an array of targets including ions, small molecules, biomacromolecules, and microenvironments, all of which closely relate to human health, medical, and public concerns. These detections are smoothly achieved on the basis of various reactions (e.g., hydrolysis, boronate cleavage, dephosphorylation, addition, cyclization, and rearrangement reactions) through different sensing principles. In these studies, the AIEgen-involved ABS strategy generally shows good biocompatibility, high selectivity, excellent reliability and high signal contrast, strongly indicating its great potential for high-tech innovations in the sensing field, among which bioprobing is of particular interest. With this Account, we hope to spark new ideas and inspire new endeavors in this emerging research area, further promoting state-of-the-art developments in the field of sensing. lution, and so forth.1,2 The selection of proper fluorogens is vitally important to achieve efficient fluorescent sensing, and a vast variety of fluorogens have been developed to serve as sensors for analyzing various targets.3 However, conventional fluorogens, in particular organic fluorogens such as fluorescein,

1. INTRODUCTION Scientists are in enthusiastic pursuit of fluorescent sensors that allow for the effective detection of various analytes and for powerful visualization or even regulation of numerous biological/physiological processes, mainly benefiting from the intrinsic advantages of fluorescence techniques such as superb sensitivity, rapidity, technical simplicity, real-time and on-site responsiveness, noninvasiveness, high temporal−spatial reso© XXXX American Chemical Society

Received: June 7, 2019

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DOI: 10.1021/acs.accounts.9b00305 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

fragment and exploited for detection of many reactive chemical species, analysis of pH variation and light irradiation, and realtime signaling of biological processes in living systems. Moreover, the sensing principles of the reported AIEgenbased ABS approach are summarized as follows (Scheme 1):

rhodamine, indocyanine green, and cyanine, can emit strongly in solution but experience emission quenching upon aggregate formation or concentration increase. This phenomenon, notoriously known as aggregation-caused quenching (ACQ),4 is quite common and significantly limits the amount of labeling of the analyte with the sensor. Therefore, these sensors must be diluted in solution or dispersed in matrix materials, which causes complicated preparation processes, severe photobleaching, low signal-to-noise ratio, and significantly compromised sensitivity.5 Moreover, the ACQ effect has compelled many fluorescent sensors to be operated in a fluorescence turn-off mode, representing an unfavorable sensing protocol for practical applications. In a related context, the emergence of luminogens with aggregation-induced emission (AIE) characteristics thoroughly overcomes the difficulties confronted with ACQ fluorogens. As an anti-ACQ phenomenon, the concept of AIE, which was coined by our group in 2001,6 refers to a unique phenomenon that some fluorogens having both a twisted conformation and molecular rotators (or vibrators) are nonemissive or weakly emissive when molecularly dissolved in solution but highly fluorescent as aggregates/clusters.7,8 Restriction of intramolecular motions that can boost radiative decay has been rationalized as the mechanism of AIE. The intrinsic features of AIE luminogens (AIEgens) provide their great tolerance of high concentrations in solution or as nanoaggregates. Consequently, AIEgens generally exhibit higher photobleaching thresholds, and thus, they display superior photostability and higher signal reliability relative to conventional fluorogens, facilitating long-term tracing of biological processes. In addition, the AIE features endow AIEgens with a fluorescence turn-on nature when they are spontaneously aggregated in a hydrophilic environment or conjugated with analytes, showing high sensitivity and excellent signal-to-noise ratio.7,8 Furthermore, the turn-on nature of AIEgens is favorable for reducing the possibility of generating false positive/negative signals compared with their turn-off counterparts.9−11 As a result of these features in combination with other distinct advantages, including large Stokes shifts and structural diversity, the utilization of AIEgens has sparked intense research interest and opened an avenue to an array of possibilities with great potential for fluorescent sensing.12,13 The development of AIEgens provides a class of excellent fluorescent scaffolds for activity-based sensing (ABS), which is a burgeoning approach that uses dynamic molecular reactivity rather than conventional lock-and-key molecular recognition to achieve molecular-level selectivity in complex environments.2,14−17 The term “activity” refers to the ability of the moiety present in a sensor to confer reactivity with analytes. Compared with lock-and-key molecular recognition, ABS possesses some distinct advantages, such as high specificity, accurate signal outputs, and high tolerance to complex environments (especially for biological systems). It has been demonstrated that the use of AIEgen-involved ABS can combine the advantages of AIEgens (high signal contrast, high photostability, and efficient signal collection) and ABS (high specificity, extraordinary sensitivity, and accurate signal outputs),18−21 and meanwhile, simultaneous dual variations of the fluorescence signal originating from both chemical and physical changes can be visualized. By utilization of the AIEgen-involved ABS protocol with superior sensing amplification, a diverse array of sensors have been constructed through the integration of a reactive moiety with an AIE-active

Scheme 1. Schematic Illustration of the Working Principles of ABS Involving AIEgens: (A) Cleavage of DissolutionPromoting Moieties To Decrease Solubility; (B) Dequenching of Photophysical Quenching Processes; (C) Bioconjugation; (D) SCF-Chromism; (E) SCF-Switch

(A) cleavage of dissolution-promoting moieties to decrease solubility, (B) dequenching of photophysical quenching processes, (C) bioconjugation, (D) intrastructure change of fluorogens (SCF)-chromism, and (E) SCF-switch. Although some reviews of AIEgen-based sensing have appeared,12,13,22,23 there have been no previous reports specifically reviewing AIE sensors that perform on the basis of the ABS principle. In this Account, we briefly summarize recent research efforts on the development of ABS involving AIE principles. Basic concepts, seminal studies, new breakthroughs, and trends in the area are highlighted, and perspectives for further development are offered. The discussion is organized according to the type of sensing principle. Because of space limitations, the discussion is limited to representative examples of our own work that have most recently appeared, with the hope to stimulate new ideas and inspire new endeavors in this emerging research area.

2. CLEAVAGE OF DISSOLUTION-PROMOTING MOIETIES TO DECREASE SOLUBILITY The emitting centers of AIEgens usually possess high hydrophobicity, which causes aggregate formation in physiological environments or aqueous media, indicating the great potential as fluorescent light-up biosensors. Some watersoluble AIEgens consisting of an AIE-active unit, a hydrophilic fragment, and a cleavable linker between them have been synthesized. These molecularly dissolved fluorogens are B


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energy consumption of the excited state formed upon photoexcitation, which is caused by strong molecular motions. In the presence of ALP, the phosphate groups are cleaved through enzymatic hydrolysis, producing water-insoluble compounds 2 and 4, which are highly fluorescent in the green and red regions, respectively, as a result of aggregate formation. In the case of AIEgen 1,25 the linear fluorescent response enables quantification of ALP in the range of 0−30 units L−1 with a detection limit of 0.0077 unit L−1, which is much lower than those of most reported fluorescent sensors. Furthermore, the presented ABS approach has been incorporated into a dual-modality readout immunoassay platform for virus detection. As illustrated in Figure 1B, a virion-immune bridged hybrid consisting of magnetic beads, anti-VP1 monoclonal antibodies (mAbs), virus, rabbit polyclonal antibodies (P-Ab), biotinylated antibodies (Biotin-Ab), and the signal tags streptavidin-ALP (SA-ALP) was elaborately constructed and used for hydrolysis of AIEgen 3.26 The produced compound 4 aggregates and shows bright emission with about 380-fold intensity enhancement. Meanwhile, the hydrolysis process can mediate the reduction of Ag+ to generate a silver nanoshell on gold nanoparticles, yielding an obvious plasmonic color change that allows clear discrimination by the naked eye. This dual-modality readout strategy involving different conjugated antibodies performs well in the detection of the corresponding viruses, including EV71 virus, H7N9 virus, and Zika virus, showing exceptional accuracy and ultrahigh sensitivity. Taking EV71 virus as an example, the fluorescence modality endows the sensor with a very low detection limit down to 1.4 copies/μL, and a broad range from 1.3 × 103 to 2.5 × 106 copies/μL was determined by the naked eye.26 The high sensitivity of AIEgen 3 makes it one of the best fluorescent sensors for virus detection. The presented protocol would stimulate the development of high-accuracy clinical diagnosis of viruses. Significantly, the turn-on nature of these ALP sensors based on AIEgens endows them with distinct advantages in terms of signal reliability and sensitivity compared with ACQ-fluorogen-involved turn-off-type sensors,29,30 which exhibit detection limits much higher than that of these presented AIE sensors. β-Galactosidase has long been identified as an important enzymatic reporter for demonstrating transcription and transfection efficiencies as well as a biomarker related to primary ovarian cancers and cellular senescence.31 AIEgen 5, which was prepared by conjugating both a positively charged pyridinium fragment and a D-galactose unit to the TPE moiety, is barely emissive in aqueous solution because of its good water solubility, benefiting from the presence of the hydrophilic pyridinium and D-galactose groups.32 5 can be rapidly cleaved

nonemissive in aqueous media, and their emission is significantly boosted upon the formation of aggregates once the reaction of the AIEgen with reactive substrates is triggered. This strategy fully embodies the added value of AIE toward the ABS protocol and represents the most commonly used approach for realizing AIEgen-involved ABS. By means of this strategy, several analytes, including alkaline phosphatase (ALP), β-galactosidase, and thiols, can be determined and quantified, and in addition, cellular autophagy and apoptosis can be quantitatively monitored, allowing long-term tracing. ALP is an essential hydrolase for mediating dephosphorylation of various substrates. Abnormal levels of ALP have been proven to be a critical biomarker for cell viability and many diseases,24 and therefore, visualization of ALP using fluorescent sensors is supremely important and useful. Because ALP has the specific ability to remove phosphate groups, phosphorylated tetraphenylethylene (TPE) derivatives (e.g., 1 and 3)25−27 or chalcone derivatives28 were facilely prepared for detection of ALP (Figure 1). Both 1 and 3 are AIE-active and

Figure 1. ALP sensing. (A) Fluorescent turn-on sensing of ALP. (B) Virus detection using an AIEgen-based ABS approach. Reproduced from ref 26. Copyright 2018 American Chemical Society.

soluble in water, resulting from the aid of the waterdissolution-promoting phosphate groups. These AIEgens weakly emit light in aqueous solution because of the efficient

Figure 2. Schematic representation of β-galactosidase sensing. C


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Figure 3. Utilizing enzymatic cleavage of water-soluble AIE-active sensors for (A) real-time monitoring of cell apoptosis, (B) self-validated caspase3 detection, and (C) real-time monitoring of caspase cascade activation. Reproduced from ref 35. Published by The Royal Society of Chemistry.

by β-galactosidase in aqueous media, yielding phenolate compound 6, which spontaneously undergoes 1,6-elimination of p-quinone methide to produce hydrophobic compound 7 (Figure 2). Upon aggregation of 7, turn-on fluorescence can be observed for quantitative signaling of β-galactosidase, showing a good linear relationship between the fluorescence intensity and β-galactosidase concentration in the range from 0.8 to 4.8 units mL−1 as well as reaching a detection limit of 0.33 unit mL−1. The selectivity of AIEgen 5 toward β-galactosidase was then investigated by manipulating various biomolecules or enzymes. The results revealed a negligible effect of all other analytes, suggesting the excellent β-galactosidase targeting specificity. It was also demonstrated that AIEgen 5 with good biocompatibility is capable of selectively lighting up cells overexpressing β-galactosidase.32 Utilizing enzymatic cleavage of water-soluble AIE-active sensors to realize real-time monitoring of enzyme-related cellular processes is highly desirable, mainly because the aggregated AIEgens in the physiological environment are able to provide an accurate signaling location, extraordinary signal amplification, and stable signal output. To prepare sensors that perform well, hydrophilic peptides that can play crucial roles as both a water-solubility promoter and enzyme-responsive unit, have often been used as the linker to interconnect the AIE moiety, targeting ligand, and other functional units (Figure 3).33−35 A living-cell-permeable sensor (DEVDK-TPE) comprising a hydrophilic caspase-specific Asp-Glu-Val-Asp (DEVD) peptide and TPE moiety was prepared (Figure 3A). DEVDK-TPE is highly water-soluble and nonemissive in aqueous media or living cells but shows high fluorescence efficiency in response to caspase-3/-7, which can be activated in the apoptotic process and is able to cleave the DEVD moieties. This strategy allows real-time monitoring of cell apoptosis and evaluation of the apoptosis-associated drug efficacy.33 By utilization of the DEVD peptide, a coumarin fragment and an AIE-active unit were linked (Figure 3B).34 The obtained sensor, named Cou-DEVD-TPETP, is nonemissive in aqueous media as a result of fluorescence resonance energy transfer (FRET) from the coumarin fragment to the AIE-active unit, which is able to consume the accepted energy through free molecular motion. Cou-DEVD-TPETP can be decomposed by caspase-3 to generate the free coumarin unit and AIEgen, which synchronously exhibit strong green and red fluorescent signals, respectively. The fluorescence turn-on and

dual signal amplification feature make this sensor extraordinary for self-validated diagnosis, imaging, and drug screening applications.34 Later on, a fluorescent sensor consisting of two AIE-active fragments with different emission colors and a hydrophilic peptide (aspartic acid-valine-glutamic acid-aspartic acid-isoleucine-glutamic acid-threonine-aspartic acid, DVEDIETD) was synthesized and used for caspase cascade activation monitoring (Figure 3C).35 DVEDIETD can be successively cleaved by the apoptosis initiator caspase-8 and the effector caspase-3 in early apoptotic HeLa cells induced by H2O2. Meanwhile, these two orderly-produced AIE-active units TPS and TPETH accumulate in cells as a result of their high hydrophobicity, showing bright green and red fluorescence, respectively, upon photoexcitation at a single wavelength of 405 nm. The sequential dual signal turn-on endows the sensor with the function of tracing the caspase cascade activation during the apoptotic process, which is vitally useful for assessing the therapeutic efficiency.35 The protocol involving cleavage of dissolution-promoting moieties has also been demonstrated to be significantly effective for furin cleavage36 and autophagy-specific enzyme cleavage reactions,37 achieving the estimate of furin activity and quantitatively monitoring autophagy in living cells, respectively. Besides cleavage of dissolution-promoting moieties, in theory any reaction that can realize the transformation from well-dissolved AIEgen-containing compounds to insoluble AIE-active species could be employed for ABS, suggesting the great potential for signaling of a broad range of analytes.38

3. DEQUENCHING OF PHOTOPHYSICAL QUENCHING PROCESSES Photophysical quenching processes, including photoinduced electron transfer (PET), intramolecular charge transfer (ICT), and energy transfer (ET) are frequently used to reach a “fluorescence off” state, and fluorescence turn-on sensing can be realized through disruption of these processes. Moreover, excited-state intramolecular proton transfer (ESIPT) is a powerful principle for building light-up sensors. Blocking of the proton donor (usually hydroxyl or amino group) of the ESIPT sensor can lead to no emission, which is also considered as a photophysical quenching process, and deprotection of the blocked hydroxyl groups can activate the ESIPT process, D


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Figure 4. “AIE plus ESIPT” sensors.

Figure 5. Detection of amine vapors. Reproduced from ref 42. Copyright 2015 American Chemical Society.

offering fluorescence enhancement. The dequenching procedure is one of the most typical methods to achieve the ABS approach, and of particular interest is AIEgen-involved ABS, in which one or multiple photophysical quenching processes and the AIE principle can be synergistically integrated into a single sensor, endowing it with remarkable signal amplification. Disruption of the ICT process usually leads to an intrastructure change in the fluorescence-emitting center, and therefore, the related reports will be discussed in Intrastructure Change of Fluorogens. Fluorescent sensors with ESIPT characteristics have been proven to be highly emissive at high concentrations or in the

aggregate state. However, sensing media with high polarity could inhibit ESIPT emission. The combination of AIE and ESIPT perfectly solves this issue because AIE is favorable to ESIPT emission through the formation of aggregates. It is noteworthy that hydrophilic modification is not necessary for AIE−ESIPT sensors. Several AIE−ESIPT sensors have recently been exploited for detecting esterase, thiols, βgalactosidase, phosphatase, amine, reactive oxygen species, and perborate,39−44 showing superior photostability and longterm retention ability.45 Sensor 8 is a salicylaldazine derivative functionalized with acetoxy groups and morpholine moieties (Figure 4A).39 The E


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Accounts of Chemical Research esterase-reactive acetoxy groups block ESIPT through the destruction of the hydrogen bonding, and morpholine is a wellknown lysosome-specific targeting group. Experimental results reveal that the acetoxy groups are efficiently removed upon the appearance of lysosomal esterase, and strong green fluorescence of the produced compound 9 in the aggregated state is observed as a result of both the recovered ESIPT and the AIE effect. Sensor 8 performs well in esterase detection in terms of detection limit (2.4 × 10−3 unit mL−1) and selectivity. In addition, the application of 8 with low cytotoxicity can be successfully extended to in situ visualization of lysosomal esterase activity and tracking of lysosomal movements in living MCF-7 cells. By the use of other ESIPT blocking units, such as β-galactopyranoside and 2,4-dinitrophenyl groups, light-up sensors 10 and 11 with “AIE plus ESIPT” characteristics have also been developed for specific detection of β-galactosidase and hydrogen sulfide, showing detection limits of 0.014 unit mL−1 and 0.09 μM, respectively.40,41 An ABS approach using fluorescent sensors having “AIE plus ESIPT” characteristics has also been reported as an impactful strategy to detect amine vapors.42 AIE-active biosensor 12 was constructed on the basis of the fluorogen 2-(2-hydroxyphenyl)quinazolin-4(3H)-one. The acetyl group in the structure of 12 can be cleaved through an aminolysis reaction, and the fluorescence emission is then strongly enhanced to achieve turn-on signaling and quantitative determination of amine vapor (Figure 5). Aiming to conveniently use the sensor, filter paper was employed to load compound 12. The prepared filter paper carrying 12 was almost nonemissive under UV irradiation, but a rapid increase of fluorescence was observed upon exposure to ammonia vapor with increasing concentrations (Figure 5B), providing a detection limit as low as 8.4 ppm. Moreover, its high selectivity for amine vapor was solidly confirmed through comparison with various volatile organic compounds. Interestingly, it was observed that the presented sensor is capable of evaluating food spoilage by monitoring biogenic volatile amines from microbial growth. As displayed in Figure 5C, 12-loaded filter paper was weakly fluorescent under UV irradiation when it was placed in a plastic bag containing saury fish stored for 2 days at −20 °C, but in contrast, strong fluorescence was observed when saury fish was stored at room temperature for 2 days. Obviously, the efficient use of the sensor on filter paper benefits from the great tolerance for high concentrations resulting from the AIE property.42,46 In view of the strong relation of amines to food spoilage and many diseases, this fluorescent sensor with portability and high sensitivity has great potential for applications in many fields. Reactive oxygen species (ROS) are intimately involved in various disease and biological processes, but the study of ROS remains an important and challenging task with very limited success achieved to date because their reactive and transient nature. On the other hand, the high reactivity of ROS offers a unique opportunity for the development of powerful detection protocols based on the ABS approach.43 An AIE-active ABS sensor, namely, TPE-IPB, has been exploited for selective detection of hydrogen peroxide and in vivo monitoring of peroxynitrite at different pH values (Figure 6).44,47 Experimental results demonstrate that TPE-IPB is nonemissive in solution or the aggregate state, a reasonable result of the synergetic effects of PET, blocked ESIPT, and the CN cis− trans isomerization process. In the presence of hydrogen peroxide or peroxynitrite, bright yellow fluorescence was

Figure 6. Detection of ROS. (A) Working principle. (B) Schematic illustration of a TPE-IPB-PEG nanoparticle and its performance after incubation with peroxynitrite. (C) In vivo imaging of elevated peroxynitrite generation. Reproduced with permission from ref 47. Copyright 2016 Wiley-VCH.

clearly observed upon photoexcitation because of the generation of TPE-IPH via ROS-mediated oxidation of the phenylboronic pinacol ester. TPE-IPH performs well for sensing hydrogen peroxide at pH 9−10, showing a detection limit as low as 100 nM, but it is inefficient for sensing of hydrogen peroxide at pH < 9.44 As one of the highly reactive oxygen and nitrogen species, peroxynitrite plays fundamental roles in health and disease. Its elevated generation usually relates to chronic and acute inflammation or is an indicative omen of many major diseases. A nanosized sensor was prepared by encapsulating TPE-IPB in a lipid−poly(ethylene glycol) (PEG) matrix, and its fluorescence emission is considerably enhanced upon reaction with peroxynitrite at pH 7.4 (Figure 6B).47 Benefiting from the enhanced permeability and retention (EPR) effect, the presented nanosensor is capable of preferentially accumulating in the inflammatory region of inflammation-bearing mice over normal tissues. Remarkably, the inflammatory region was lit up upon photoexcitation 30 min after injection of the nanosensor because of the existence of a considerable amount of peroxynitrite in the inflammatory site, and the fluorescence intensity significantly increased over time, showing excellent signal contrast (Figure 6C). Notably, the efficient accumulation of the nanosensor in the inflammatory site was also verified by ex vivo imaging of isolated tissues.47 The findings in this work could stimulate the development of efficient theranostic anti-inflammatory agents for potential clinical applications. Apart from ESIPT, disruption of the PET process is also a useful strategy for realizing fluorescence turn-on sensing.48−50 Some tailored sensors (e.g., 14 and 15) were synthesized and F


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The great majority of AIEgen-based ABS involves the selfaggregation process of the AIEgen. On the contrary, the ABS approach based on accumulation of the AIEgen in/on a matrix via chemical reaction between reactive groups of the AIEgen and the matrix has rarely been reported. It has been demonstrated that a TPE-cored diboronic acid can detect Dglucose in aqueous media through the formation of an oligomeric matrix consisting of conjugated TPE-cored diboronic acid and D-glucose. In this process, the emission of the AIEgen is boosted by the restriction of the intramolecular rotations of the aryl rotors of TPE.51 Significantly, the ABS approach based on the accumulation of an AIEgen in/on a matrix would be particularly useful for labeling of biomacromolecules or biorelated species, which naturally own numerous reactive units (e.g., amine, hydroxyl, thiol groups) and large steric hindrance. A water-soluble AIEgen having a reactive functional group was shown to react with an antibody to generate a “turn-on” antibody−AIEgen conjugate, which performed well in wash-free specific cancer cell imaging with high a signal-to-noise ratio, enabling great potential of this new strategy for real-time tracking of cell dynamics and cancer theranostics.52 In another work, Tang’s group53 demonstrated that azide-functionalized AIEgens can be used to detect DNA synthesis and cell proliferation by labeling of 5-ethynyl-2′deoxyuridine (EdU)-decorated DNA. Comparison experiments show that AIE-active sensors exhibit a much wider working concentration range, superior photostability, and higher fluorescence efficiency than ACQ-active Alexa647azide dye, indicating that AIEgens would be promising alternatives to ACQ fluorophores for sensing.53 Theoretically, a great number of reactions can be used to mediating the accumulation of an AIEgen, but their harsh reaction conditions, limited reaction efficiency, and bioincompatibility characteristics have largely restricted their booming development. As one of the breakthroughs in the area of AIE sensing, catalyst-free click bioconjugation based on activated alkynes has recently appeared.54 The reaction of electronwithdrawing carbonyl group-activated alkynes with bionative amine, thiol, and hydroxyl groups proceeds smoothly (Figure 8). By the use of this protocol, various biorelated species,

utilized for hydrogen sulfide and thiols (Figure 7). The AIEactive sensor 15 was designed for detection of L-cysteine, an

Figure 7. Sensing based on disruption of the PET process. (A) Structure of sensor 14. (B) Structure of sensor 15 and selective detection of L-cysteine. Reproduced with permission from ref 49. Copyright 2010 Wiley-VCH.

amino acid containing a thiol group, and showed high sensitivity in a fluorescence turn-on manner.49 This sensor, which consists of TPE and maleimide components, is not fluorescent in either the single-molecule or aggregated state as a result of the PET effect. In the presence of L-cysteine, the spot of sensor 15 loaded on a TLC plate shows bright emission, which can be attributed to disruption of the PET process through the click reaction of the thiol with the pendent maleimide (Figure 7). It was observed that the thiol-activated detection protocol exhibits high sensitivity, allowing a nakedeye-visible fluorescence turn-on at L-cysteine concentrations as low as approximately 1 ppb. Moreover, sensor 15 barely emits upon exposure to other amino acids without a thiol fragment, strongly indicating the excellent thiol-specific signaling. This portable system is capable of sensing glutathione, which also contains a thiol group. Remarkably, the prominent thiol detection behavior enables sensor 15 to perform well as a visualization agent for mapping thiol distributions in living cells.49 Dequenching of photophysical quenching processes represents a rapid and reliable ABS strategy that shows analyteactivated light-up emission with good signal-to-noise ratio as well as high selectivity and high sensitivity. It is believed that this protocol will inspire new insights on the development of more advanced fluorescent sensors for visualizing and tracing biological processes.

4. BIOCONJUGATION Both self-aggregation of AIEgens and their accumulation in/on a matrix can achieve restriction of the intramolecular motions, further triggering fluorescent emission upon photoexcitation.

Figure 8. Schematic illustration of bioconjugation. Reproduced with permission from ref 54. Published by the American Association for the Advancement of Science. G


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Figure 9. Sensing based on SCF-chromism. (A) Fluorescent response of 16 to pH changes. (B) AIE sensor 17 for cyanide. (C) AIE sensor 18 for hydrogen sulfide. (D) AIE sensor 19 for homocysteine. Reproduced from ref 57. Copyright 2013 American Chemical Society.

Figure 10. Light-irradiation-responsive AIEgens. (A) AIEgens for light-irradiation sensing. (B) Structure of 22 and the energy balance of photophysics controlled by light exposure. FL: fluorescence. Reproduced from ref 61. Published by Nature Publishing Group.

constructed. The discussion in this section is organized according to the type of sensing principle: chromism of a single emitting center or fluorescence switching of two emitting centers.

including cells, Gram-positive bacteria, cell-penetrating peptides, PEG, proteins, and polysaccharides, are rapidly lit up, successfully achieving quick fluorescence labeling. Several attractive features of this bioconjugation strategy, such as 100% atom efficiency, mild reaction conditions, catalyst-free nature, and high reaction efficiency, make it potentially promising for modifying and signaling many biotargets and biotarget-related processes in vitro and in vivo. It is particularly necessary to point out that site- and target-specific bioconjugation in biological systems cannot be realized using this presented method because of the deficiency of selectivity for specific functional groups among amine, thiol, and hydroxyl groups.54

5.1. SCF-Chromism

Weakening or enhancement of the ICT strength is able to tune the emission wavelength, showing a blue or red emission shift, so as to achieve fluorescent sensing. It has been reported that several analytes exhibit high chemical activity for destruction of the π conjugation of AIEgens with a reactive double bond in the emitting center via addition reactions.55,56 In addition, some AIEgens have been determined to be responsive toward pH or light irradiation and showed obvious changes involving emission color, emission intensity, and AIE-to-ACQ conversion.57−61 The zwitterionic hemicyanine compound 16 is AIE-active, and its emission maximum is located in the red region showing a Stokes shift as large as 185 nm. Benefiting from the chemical reactivity toward OH−/H+, 16 significantly responds to pH variations, yielding dual emission changes of both the emission color and intensity.62 As depicted in Figure 9, strong to moderate red emission was observed in the pH range of 5−7, moderate intensity of red emission to no emission was obtained at pH 7−10, and an obvious blue fluorescence turnon process was visualized at pH 10−14. The reversible and

5. INTRASTRUCTURE CHANGE OF FLUOROGENS The above-mentioned ABS protocols are actualized on the basis of the structural transformation of functional groups of AIEgens, and the structures of the emitting centers are not changed in those cases. It has been demonstrated that some ABS strategies can also be established through intrastructure changes of the emitting centers of AIEgens. The intrastructure changes include destruction of π conjugation, expansion of π conjugation, alteration of electron donating−accepting (D−A) strength, photoactivated cycloaddition, and metal-mediated structural rearrangement. Through such intrastructure changes, a series of ratiometric fluorescent sensors have been H


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Accounts of Chemical Research reliable OH−/H+-switched red/blue emission can be attributed to the breakage/recovery of the overall conjugation. Considering that signaling by intracellular pH is vitally important for investigating proliferation, apoptosis, intracellular enzyme activity, and protein degradation, the biocompatible AIEgen 16 was further applied in imaging of intracellular pH and provided good performance in terms of pH range of detection and imaging resolution.57 The protocol of disrupting the ICT process has been proven to be useful for fluorescent sensing of several reactive analytes, such as cyanide, sulfite ion, amine, hydrogen sulfide, and homocysteine. For example, Duan et al.63 developed sensor 17 that is capable of detecting cyanide in aqueous solution, showing remarkable performance in terms of both selectivity and sensitivity with a detection limit as low as 0.1 μM (Figure 9B), which is comparable with the most sensitive sensors in the literature.15 Moreover, the cyanide monitoring strategy was successfully applied in both a paper test strip system and living cells. By a similar protocol, AIEgens 18 and 19 can be employed as ratiometric fluorescent sensors for detecting hydrogen sulfide and homocysteine through the efficient reactions between the reactive double bond and the analytes (Figure 9C,D).55,56 The detection limits for hydrogen sulfide and homocysteine are 0.5 and 0.346 μM, respectively, which are moderate and acceptable. Improvements in the sensitivity of AIE sensors would allow us to pursue such studies by lowering the detection limit. Some light-irradiation-responsive AIEgens have recently appeared, including 20, 21, and 22 (Figure 10).59−61,64 Upon light irradiation, various dramatic emission variations followed by intrastructure changes of the fluorogens were achieved, and these intrastructure changes smoothly proceeded through different reactions, such as photooxidative dehydrogenation, photoinduced Z/E isomerization, photocyclization, and photodimerization. Furthermore, these obtained compounds were successfully employed for lipid droplet- or mitochondria-specific living-cell fluorescent imaging59,60 and in vivo photoacoustic (PA) imaging with high spatial and temporal resolution.61 As shown in Figure 10B, compound 22 consisting of dithienylethene and 2-(1-(4-(1,2,2triphenylvinyl)phenyl)ethylidene)malononitrile moieties can exist in ring-closed and ring-open forms, which are switchable upon UV/visible-light irradiation. Benefiting from the good conjugation, the ring-closed form (RClosed-22) possesses remarkable ICT efficiency, resulting in long absorption wavelength and no emission, which indicates strong energy dissipation via thermal deactivation. The ring-opened form (ROpen-22) displays typical AIE properties with bright fluorescence emission and high ROS generation efficiency in aggregates (Figure 10B). The functionalized RClosed-22 nanoparticles are able to selectively target tumors and provide good PA signal output. Upon visible-light illumination, ROpen-22 is formed in situ and shows good performance in in vivo fluorescent imaging and photodynamic therapy (PDT).61

reaction driven by the analyte could lead to a solubility change of the sensor, which endows the AIEgen-based SCFswitch with superior sensitivity and reliability. Ratiometric Hg2+ sensing has been achieved through the SCF-switch strategy involving the use of sensor TPE-RNS, which is composed of a TPE unit and a precursor of rhodamine (Figure 11).65 TPE-RNS is emissive in 40% v/v

Figure 11. Schematic illustration of the Hg2+ sensing mechanism. Reproduced from ref 65. Published by The Royal Society of Chemistry.

CH3CN/H2O, peaking at 485 nm, as a result of the formation of nanoaggregates. The emission originates from the TPE moiety. In the presence of Hg2+, TPE-RNS is transformed to TPE-RNO containing a rhodamine moiety through Hgmediated structure rearrangement. TPE-RNO with enhanced hydrophilicity is well-dissolved in the solution, and it is believed that energy can be transferred from the TPE unit to the rhodamine moiety upon photoexcitation in this state via a dark through-bond energy transfer process. Therefore, the fluorescence emission was gradually switched to the ACQactive rhodamine unit, yielding strong red emission with a large emission change of 110 nm. By the use of this strategy, the ratiometric fluorescence enhancement reaches >6000-fold with a detection limit as low as 0.3 ppb, which is well below the limit for Hg2+ in drinking water regulated by the U.S. EPA (2 ppb), illustrating that TPE-RNO is one of the best fluorescent sensors for Hg2+ detection in terms of sensitivity compared with the others.14,15 Moreover, thanks to the high sensitivity and selectivity toward Hg2+, TPE-RNS can significantly visualize Hg2+-incubated cells.65

6. CONCLUSIONS The AIEgen-involved ABS approach has recently developed at a tremendous pace, benefiting from various distinct advantages of AIEgens in fluorescence emission as well as the good compatibility and synergism between the AIE principle and ABS. Through ingenious design of the sensor structure, the ABS protocol is smoothly achieved through several sensing principles, including cleavage of a dissolution-promoting moiety, disruption of photophysical quenching processes, bioconjugation, and intrastructure change of fluorogens. Indeed, the principles of cleavage of a dissolution-promoting moiety and bioconjugation are unique to AIE-active sensors. During the sensing processes involving these two principles, AIEgens undergo self-aggregation or accumulation in/on a matrix, and intramolecular motions can be efficiently restricted, further triggering dramatic emission enhancement and “lightup” signaling. In addition, other principles are also workable for sensors with ACQ characteristics. In those cases, AIEgens

5.2. SCF-Switch

SCF-switch refers to a sensing approach that involves a sensor containing two emitting centers, with one of the emission colors dominating through SCF triggered by an analyte. As one of ratiometric fluorescent sensing protocols, SCF-switch based on chemical activity is able to provide precise and quantitative determination of specific analytes. Furthermore, chemical I



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ACKNOWLEDGMENTS This work was partially supported by the National Natural Science Foundation of China (Grant 21801169), the Natural Science Foundation of Shenzhen University (2019004), the National Basic Research Program of China (973 Program) (2013CB834701 and 2013CB834702), and the University Grants Committee of Hong Kong (AoE/P-03/08).

can be competitive alternatives because of both their signal turn-on nature and efficient emission features in aggregates. Great progress has been witnessed in terms of successful signaling of a wide variety of analytes, analysis of microenvironment variation, and real-time visualization of biological processes in living systems. In these seminal studies, AIEgens significantly meet stringent requirements of ABS, generally showing good biocompatibility, high selectivity, excellent reliability, and extraordinary signal-to-noise ratio. Consequently, the AIE-involved ABS strategy holds great potential for high-tech innovations in the sensing field, with bioprobing being of particular interest . Although remarkable progress has been made, several aspects are deemed essential for formulating advanced ABSinvolving AIEgens. For instance, the examples covered in this Account mainly utilize AIEgens with short emission wavelengths, restricting their use for in vivo applications, which require deep penetration and low autofluorescence. Exploration of novel AIE-active sensors with long-wavelength absorption and emission is necessarily needed, which would stimulate the development of ABS in preclinical research and clinical applications. Considering that almost all sensing processes are realized by means of fluorescence, exploiting photoacoustic, ultrasonic, or photothermal signaling protocols will be supremely interesting. In view of the lack of selectivity of the AIE-based bioconjugation method, exploring a catalystfree bioconjugation strategy that allows high selectivity toward specific targets is particularly important. In addition, more efforts should be devoted to completely overcoming falsepositive or false-negative issues of real-sample assays in highaccuracy clinical diagnosis. Moreover, ABS involving the AIE principle is an emerging field, and extension of the diversity of AIEgens, analytes, and reactions is still needed. Nowadays, new breakthroughs are propelling the field by addressing these challenges. It is believed that the concept of AIE will provide plentiful added values to the ABS approach and significantly promote the development of sensing research.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Dong Wang: 0000-0001-5137-0771 Ben Zhong Tang: 0000-0002-0293-964X Notes

The authors declare no competing financial interest. Biographies Dong Wang received his Ph.D. degree from Bordeaux University and conducted his postdoctoral study at the University of Toronto and HKUST. He is currently an associate professor at Shenzhen University. His research focuses on the design of AIEgens for chemical sensing and biological applications. Ben Zhong Tang received his Ph.D. degree from Kyoto University and conducted his postdoctoral research at the University of Toronto. He joined HKUST in 1994 and was promoted to Chair Professor in 2008. He was elected to the Chinese Academy of Sciences in 2009. He is now serving as Editor-in-Chief of Materials Chemistry Frontiers. J


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Aggregation-Induced Emission Luminogens for Activity-Based Sensing

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