Fluorescent Sensors Based on Aggregation ... - ACS Publications

Fluorescent Sensors Based on Aggregation...

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Fluorescent Sensors Based on Aggregation-Induced Emission: Recent Advances and Perspectives Meng Gao† and Ben Zhong Tang*,†,‡ †

Guangdong Innovative Research Team, State Key Laboratory of Luminescent Materials & Devices, South China University of Technology, Guangzhou 510640, China ‡ Department of Chemistry and Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, The Hong Kong University of Science & Technology, Clear Water Bay, Kowloon, Hong Kong, China ABSTRACT: Fluorescent sensors with advantages of excellent sensitivity, rapid response, and easy operation are emerging as powerful tools in environmental monitoring, biological research, and disease diagnosis. However, conventional ﬂuorophores featured with πplanar structures usually suﬀer from serious self-quenching in the aggregated state, poor photostability, and small Stokes’ shift. In contrast to conventional aggregation-caused quenching (ACQ) ﬂuorophores, the newly emerged aggregation-induced emission ﬂuorogens (AIEgens) are featured with high emission eﬃciency in the aggregated state, which provide unique opportunities for various sensing applications with advantages of high signal-to-noise ratio, strong photostability, and large Stokes’ shift. In this review, we will ﬁrst brieﬂy give an introduction of the AIE concept and the turn-on sensing principles. Then, we will discuss the recent examples of AIE sensors according to types of analytes. Finally, we will give a perspective on the future developments of AIE sensors. We hope this review will inspire more endeavors to devote to this emerging world. KEYWORDS: sensor, aggregation-induced emission, ions, small molecules, microenvironment, stimuli response, biological macromolecules, cellular processes, pathogens

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luorescent sensors with advantages of excellent sensitivity, rapidness, and easy operation have found broad applications in various ﬁelds.1,2 However, the conventional ﬂuorophores, such as ﬂuorescein, rhodamine, and cyanine, can only emit brightly in dilute solution and will undergo serious self-quenching at high concentration or in the aggregated state.3 Therefore, they are only suitable for sensing in dilute solution and suﬀer from poor photostability, small Stokes’ shift, and low signal-to-noise ratio. It is thus highly desirable to develop new ﬂuorescent sensors that can eﬃciently conquer the aggregationcaused quenching (ACQ) drawbacks. In contrast to ACQ ﬂuorophores, aggregation-induced emission ﬂuorogens (AIEgens) are nonemissive in dilute solution but emit intensely upon aggregate formation. Since the concept of AIE was proposed in 2001,4 various hypotheses have been suggested on AIE mechanisms, including the restriction of intramolecular motion (RIM),5,6 excimer formation,7 J-aggregates,8,9 inhibition of TICT process,10 and excited state intramolecular proton transfer (ESIPT).11 Among these hypotheses, the restriction of intramolecular motion, including restriction of intramolecular rotation and vibration, is proved by intensive experimental and theoretical studies.12,13 With PDHA molecule as an example (Figure 1), the vibration of dihydroanthracene backbone and rotation of phenyl peripheries in the solution state can eﬃciently consume the excited energy and almost no emission was observed, while the intramolecular motion is eﬃciently restricted in the aggregated © XXXX American Chemical Society

Figure 1. PDHA molecule is nonemissive when dissolved but becomes highly emissive when aggregated through restriction of intramolecular motion. Adapted with permission from ref 14. Copyright 2015 American Chemical Society.

state and an intensive ﬂuorescence was observed through blocking of the nonradiative decay pathways.14−16 Thanks to the enthusiastic eﬀorts of scientists worldwide, many AIEgens have been developed based on the RIM mechanism, such as tetraphenylethene (TPE), tetraphenylpyrazine (TPP),17 silole,18 quinoline-malononitrile (QM),19 cyanostilbene,20 9,10-distrylanthracene (DSA),21 and organoboron complexes.22,23 Beneﬁting from the strong emission in the aggregated or solid state, AIEgens are featured with large Stokes’ shift, strong photostability, and low background noise in dilute solution.24 Based on the unique advantages of AIEgens, several turn-on sensing principles are summarized as follows (Figure 2): (A) self-assembly with analytes to form highly Received: August 8, 2017 Accepted: September 13, 2017

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Figure 2. Schematic illustration of the turn-on sensing principles of AIE sensors: (A) self-assembly with analytes to form aggregates; (B) speciﬁc recognition with analytes to restrict intramolecular motion; (C) cleavage of dissolution-promoting ligands to decrease solubility leading to aggregates formation; (D) disruption of the photophysical quenching processes. Figure 3. (A) Schematic illustration of sensor AIE-L for detection of Zn2+ based on complexation to disrupt the PET process and further assembly to form aggregates. Adapted with permission from ref 32. Copyright 2016 American Chemical Society. (B) Schematic illustration of the complexation between TPEN and Ag+ to restrict intramolecular motion and turn-on ﬂuorescence. Adapted with permission from ref 34. Copyright 2017 American Chemical Society. (C) Ratiometric sensing of Hg2+ based on p/m-TPE-RNS via DTBET strategy. Adapted with permission from ref 36. Copyright 2017 Royal Society of Chemistry. (D) Schematic illustration of Pb2+-induced aggregation of GSH-AuNCs and light-up ﬂuorescence. Reprinted with permission from ref 41. Copyright 2015 Royal Society of Chemistry.

emissive aggregates through various noncovalent interactions, including electrostatic, hydrogen bonds, van der Waals, and metal−ligand interactions; (B) conjugation of AIEgens with targeting ligands to recognize analytes and turn-on ﬂuorescence by restriction of intramolecular motion; (C) reaction with enzymes or speciﬁc chemical species to cleave dissolutionpromoting ligands and decrease solubility to form aggregates; (D) disruption of the photophysical quenching processes, such as photoinduced electron transfer (PET), intramolecular charge transfer (ICT), and energy transfer (ET) processes. These diﬀerent sensing principles can also be synergistically integrated in a single sensor. Considering several comprehensive reviews on AIEgens and their applications which have been recently reported,25−29 herein we will discuss some representative examples of AIE sensors in the past three years according to the types of analytes, including metal ions, anions, small molecules, microenvironment, mechano- and photostimulus, biological macromolecules, cellular processes, and pathogens. We will also give a perspective on the future developments of AIE sensors.

Silver ion (Ag+) has been extensively utilized in medical industries as an antimicrobial agent.33 Based on the metal chelating ability of naphthyridine moiety, Goel et al. developed an AIE-active sensor TPE-naphthyridine (TPEN) for selective detection of silver ions (Figure 3B).34 The chelating ratio between TPEN and silver ion was calculated to be 2:1 and an obvious bathochromic shift emission from 492 to 525 nm was observed. The detection limit (0.25 μM) is much lower than the environmentally permissible level (0.93 μM) set by the USEPA.35 Mercury ion (Hg2+) is highly toxic to human health. Tang et al. developed a highly sensitive and ratiometric sensor composed with rhodamine spirolactam-conjugated TPE for Hg2+ detection based on the dark through-bond energy transfer (DTBET) strategy.36 Before treating with Hg2+, the sensor tends to form aggregates in water and only the blue emission of TPE was observed (Figure 3C). After treating with Hg2+, the spirolactam ring was opened and positively charged rhodamine was generated accompanied by intensive red emission. This can be due to the fast DTBET process between TPE and rhodamine and the nonradiative decay of TPE with increased water solubility. As a result, a low detection limit of 0.3 ppb and a large pseudo-Stokes shift of up to 280 nm was achieved for Hg2+ detection. To further make the sensing of Hg2+ in a portable manner, Li et al. developed a Hg2+ probe TPE-S based

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IONS Detection and quantiﬁcation of biologically essential or toxic metal ions is important in biological study and environmental inspection.30,31 For example, zinc ion (Zn2+) is one of the most abundant in vivo transition metal ions and is involved in many biological processes. Misra et al. synthesized an AIE-L probe for sensitive and light-up detection of Zn2+ based on formation of AIE-L-Zn chelating complex to disrupt the photoinduced electron transfer (PET) process and further self-assembly into aggregates to restrict the intramolecular motion (Figure 3A).32 The detection limit was as low as 1.1 × 10−7 M, which is far below the permissible level of Zn2+ (70 μM) in drinking water according to the United States Environmental Protection Agency (USEPA). Moreover, the probe can be loaded on a portable paper for convenient on-site detection of Zn2+. B

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ACS Sensors on Hg2+-catalyzed thioacetal deprotection and subsequent keto−enol isomerization reaction. The reaction proceeds very fast with color change from colorless to deep purple and ﬂuorescence change with signiﬁcant turn-on ratio. The portable test strip can be easily fabricated by immersing a ﬁlter paper into the TPE-S solution, which is very convenient for on-site detection with detection limit as low as 1 × 10−7 M.37 Recently, M(I)−thiolate complexes (M = Au, Ag, Cu, etc.) have emerged as a promising class of sensors due to their molecular-like behavior and intriguing AIE properties.38−40 Hu and Pei et al. reported that glutathione (GSH) capped Aunanoclusters could be used for light-up detection of lead ions (Pb2+) through GSH−Pb2+ interaction induced aggregation (Figure 3D).41 A good selectivity and a linear wide response range from 5.0 to 50 μM was observed. The successful on-site detection of Pb2+ in lake water demonstrated its potential for practical applications. Based on the similar strategy, the M(I)− thiolate complexes have also been successfully used for detection of various metal ions with excellent sensitivity and selectivity, such as Ca2+, Al3+, and Cu2+.42−44 Like metal ion sensing, the detection of anions has also attracted much attention due to their biological signiﬁcance and environmental concern. For example, anionic surfactants have wide applications in daily life and various industries, but their residues can cause serious threats to the environment and hazards to human health.45 Tang et al. developed an AIE-active HBT-C18 probe for sensitive detection of anionic surfactant sodium dodecylbenzenesulfonate (SDBS) (Figure 4A).46 HBT-

C18 can form highly emissive catanionic aggregates or micelles with SDBS by restriction of intramolecular motion and protection of the intramolecular hydrogen bond from disruption of the aqueous environment. The formation of HBT-C18/SDBS catanionic aggregates is thus accompanied by increasing keto/enol emission ratio through ESIPT process and can be used for quantitative determination of SDBS concentration. This AIE-active probe can eﬃciently avoid the interference of small anions and can be used for selective detection of anionic surfactant SDBS with a low detection limit of 0.051 μM, which is lower than the standard colorimetric methylene blue method (about 0.144 μM).47 Sensors with the intramolecular charge transfer (ICT) eﬀect may undergo signiﬁcant quenching in aqueous solution due to the increased environmental polarity.48 The disruption of ICT eﬀect can lead to blue-shift and turn-on emission. For example, Duan et al. reported a turn-on AIE sensor for CN− detection based on the addition of CN− to terthienyl-cyanine conjugate to eﬃciently disrupt the ICT eﬀect (Figure 4B). As a result, a low detection limit of 0.1 μM was achieved and the sensor could also be loaded on a portable paper strip for on-site detection.49 Based on the similar strategy, Upadhyay et al. developed a pyrene-benzthiazolium conjugate AIE-R1 with red emission, which exhibits high speciﬁcity toward HSO3− by addition reaction to produce a large blue shift emission. The lowest detection limit for this ratiometric sensor was found to be 8.90 × 10−8 M.50 Citrate ion is a crucial metabolite in the citric acid cycle and its level in bioﬂuid is associated with many diseases, such as kidney dysfunctions and prostate cancer.51 Hua et al. developed two NIR-emissive diketopyrrolopyrrole (DPP) derivatives, DPP-Py1 and DPP-Py2, for, respectively, ratiometric and turn-on sensing of citrate ion through multiple hydrogen bonds and electrostatic interactions (Figure 4C).52 Compared with DPP-Py2, DPP-Py1 shows a better pH tolerability and a lower detection limit of 1.8 × 10−7 M. Peroxynitrite (ONOO−) is generally overexpressed during acute and chronic inﬂammation.53 Ding and Tang et al. reported a nanoprobe TPE-IPB-PEG based on lipid-PEG encapsulated imine-functionalized TPE derivative of TPE-IPB (Figure 4D).54 The nanoprobe is nonﬂuorescent in aqueous solution but emits intense yellow ﬂuorescence after reaction with ONOO− by recovery of the intramolecular hydrogen bond. The probe can thus be used for light-up detection of ONOO− with a high sensitivity (about 100 × 10−6 M) and high-contrast imaging of in vivo inﬂammatory region.

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SMALL MOLECULES AIE sensors have been developed for detection of various small molecules, such as CO2,55,56 explosives,57 glucose,58,59 and nerve agents.60 In this section, we will discuss some recent examples of AIE sensors for detection of small molecules, including amines, H2S, volatile organic compounds (VOCs), H2O2, creatinine, and thiol-containing amino acids. Amines play vital roles in agriculture and industries, but volatile amine vapors are serious threats to human health. Tang et al. recently developed a ﬂuorescent and portable sensor HPQ-Ac for light-up detection of amine vapors (Figure 5A). The reaction with amine vapors could eﬃciently cleave the Oacetyl bond through aminolysis reaction and restore the intramolecular hydrogen bond to recover the ﬂuorescence. With ammonia vapor as an example, the detection limit was as low as 8.4 ppm. The HPQ-Ac sensor can also be deposited on

Figure 4. (A) Light-up detection of anionic surfactant SDBS by formation of HBT-C18/SDBS catanionic aggregates. Reprinted with permission from ref 46. Copyright 2016 Wiley-VCH. (B) Light-up detection of CN− via addition reaction to disrupt the ICT eﬀect. Reprinted with permission from ref 49. Copyright 2016 Elsevier. (C) Schematic illustration of the complexation between DPP-Py derivatives and citrate ion and further self-assembly into nanoaggregates. Adapted with permission from ref 52. Copyright 2016 American Chemical Society. (D) Light-up detection of ONOO− based on TPE-IPB-PEG nanoprobe. Adapted with permission from ref 54. Copyright 2016 Wiley-VCH. C

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Figure 5. (A) Schematic illustration of sensor HPQ-Ac for light-up detection of amine vapors via aminolysis reaction. Reprinted with permission from ref 61. Copyright 2014 American Chemical Society. (B) Schematic illustration of sensor TPE-NP for light-up detection of H2S based on thiolysis of dinitrophenyl ether. Adapted with permission from ref 63. Copyright 2015 American Chemical Society. (C) Schematic illustration of TPE-CDs for detection of VOCs. Reprinted with permission from ref 65. Copyright 2016 American Chemical Society. (D) Schematic illustration of the energy-relay between the encased molecules in CLNP-PPV/BDP nanoparticle for light-up detection of H2O2. Reprinted with permission from ref 68. Copyright 2016 Elsevier. (E) Schematic illustration of the formation of emissive aggregates between the AIE-active IDATPE and creatinine. Reprinted with permission from ref 70. Copyright 2017 Royal Society of Chemistry. (F) Schematic illustration of the light-up detection of thiolcontaining amino acids by destruction of the Pt(II) metallacage to yield emissive aggregates of the TPE-based precursor. Adapted with permission from ref 72. Copyright 2017 American Chemical Society.

ﬁlter paper to detect biogenic amine vapors (e.g., NH3 and NMe3) to monitor food spoilage.61 Hydrogen sulﬁde (H2S) is increasingly regarded as an important signaling molecule in biology.62 Li and Tang et al. developed a dual signaling molecule sensor for selective and instantaneous monitoring of intracellular hydrogen sulﬁde (H2S) level based on the cleavage of TPE−OH and dinitrophenyl ether (Figure 5B). Through removal of the ﬂuorescence quenching 2,4-dinitrobenzene moiety, the ﬂuorescence intensity increases signiﬁcantly and the solution color changes from colorless to brown with a low detection limit of 12.8 nM. Moreover, the sensor was successfully applied to imaging of intracellular H2S in C. elegans.63 Detection of organic pollutants is crucial for guaranteeing the safety of water and atmosphere.64 Inspired by dog noses, Liang and Tang et al. constructed self-assembled ﬂuorescent nanosheets based on TPE decorated cyclodextrins (TPE-CDs) for rapid and sensitive detection of VOCs. The TPE moieties are packed and solidiﬁed into TPE-β-CD nanosheets to emit intense ﬂuorescence emission through restriction of intramolecular motions of TPE. The organic pollutants as good solvents of TPE can transport through the hydrophobic cavity of outer cyclodextrin layers to the inner TPE layers and eﬃciently quench the ﬂuorescence through dissolving of TPE moieties to activate the intramolecular motion. Such nanosheets allow rapid detection of xylene within seconds and a low detection limit of 5 μg/L was achieved (Figure 5C).65 To further realize turn-on sensing of VOCs, Tang and Zhao et al. reported a 2D layered metal−organic framework (MOF) named NUS-1 with TPE-2CO2H as the ligand unit.66 The turn-on sensing can be due to the restriction of the motion of partially ﬁxed TPE units in MOF after contact with VOCs, such as benzene, toluene, and p-xylene.

H2O2 plays an important role as an intracellular signaling molecule and is overgenerated during inﬂammation.67 Kim et al. developed a nanoprobe for detection of inﬂammatory H2O2 by integration of H2O2-responsive peroxalate to generate electronic excitation energy, a green-emissive BODIPY dye as the energy relay molecule, and an AIE-active polymer DPACN-PPV as the NIR emitter (Figure 5D).68 Due to the nanoscopic close packing in the nanoparticle and optimal spectral matching between BODIPY and DPA-CN-PPV, a greatly enhanced NIR chemiluminescence was observed from the “nanophotonic energy relay” nanoprobe with a low detection limit of 10−9 M for H2O2. This nanoprobe can also be used for in vivo imaging of inﬂammation generated H2O2 in murine models of arthritis and peritonitis with a high tissue penetration ability (>12 mm). Small molecules as disease biomarkers are attractive sensing targets and require sensitive detection methods. For example, the urine creatinine and human serum albumin (HSA) level is related with progressive kidney and cardiovascular diseases.69 Tang and co-workers developed an AIE-active probe IDATPE for detection and quantitation of creatinine (Figure 5E).70 An excellent correlation between ﬂuorescence intensity and creatinine concentration (0−100 μM) is achieved in artiﬁcial urine. Combined with the AIE probe of BSPOTPE for HSA quantitation,71 the combination of IDATPE/BSPOTPE can potentially be used for diagnosis of the related kidney diseases. Biological thiols such as cysteine and GSH play vital roles in maintaining homeostasis of protein function. To detect thiolcontaining amino acids, Stang et al. prepared a tetragonal prismatic Pt(II) metallacage with benzoate-TPE groups as the metallacage faces. The metallacage is nonemissive in methanol/ water (1/1, v/v), while the same solution shows a great emission enhancement via destruction of the MOF by thiolD

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of the silica shell. To develop a rapid and sensitive method for detection of the pore size of silica shell, Xie et al. developed Au(I)-SG@SiO2 NPs and found that metal ions smaller than the pore size of the silica shell, such as Pb2+ (8.02 Å), Cd2+ (8.52 Å), and Zn2+ (8.6 Å), were able to pass through the silica shell and turn-on the inner Au(I)-SG complexes, while metal ions larger than the pore size, such as Ce3+ (9.04 Å) and Al3+ (9.5 Å), could not enter into the particle and showed no eﬀect. This pore size determination method based on the high sensitivity of AIE-active Au(I)-SG to metal ions has advantages of rapidness, preciseness, and high sensitivity (Figure 6B).79 The visualization of gelation process is important for development of hydrogel materials. Wang et al. prepared TPE-labeled chitosan (TPE-CS) with an optimal labeling ratio of 1.54 mol % for in situ monitoring the gelation process in LiOH-urea aqueous system (Figure 7A). Under confocal

containing amino acids to yield highly emissive aggregates of the TPE-based precursor with detection limits of 2.78 × 10−7 and 1.89 × 10−7 M for cysteine and glutathione, respectively (Figure 5F).72 Qu et al. reported a label-free method for turnon detection of GSH with a low detection limit of 200 nM.73 The amino-functionalized and positively charged SiO2 NPs were ﬁrst coated with negatively charged MnO2 nanosheets, which could be reduced by GSH to expose the positively charged surface of SiO2NPs. The AIE-active BSPOTPE could then form aggregates on the surface of SiO2 NPs to emit strong ﬂuorescence.

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MICROENVIRONMENT SENSING Microenvironment sensing plays a pivotal role in reﬂecting and controlling the physical system properties. AIE sensors are able to change their luminescent properties in response to microenvironmental changes, such as pH,74 temperature,75 hydrophobic eﬀect,76 and viscosity.77 In this section, we will discuss the applications of AIE sensors to detect the microstructures of organic−inorganic composites,78,79 and monitor the gelation processes of chitosan80 and the micelle transition processes of surfactants.81 The dispersion of inorganic ﬁllers in organic−inorganic composites is of great importance for manipulating the properties of organic−inorganic composites.82 While the TEM image only shows the lateral information on morphology and macrodispersion from a slice, the 3D ﬂuorescence visualization has ultrafast and noninvasive advantages for organic−inorganic composite dispersion study. However, the ﬂuorescence imaging of inorganic ﬁllers has been impeded by the ACQ properties of conventional ﬂuorophores in the aggregated state. Lu and Tang et al. developed an AIE-active amphiphilic molecule of TPE-DTAB to image macrodispersion of montmorillonite in polyvinyl chloride (PVC) polymer matrix (Figure 6A).78 The 3D ﬂuorescence imaging reveals a real and impartial distribution of the dispersion state of MMT particles in the PVC matrix, which provides a new avenue for the visualization of inorganic ﬁller macrodispersion. Porous silica nanoparticles (NPs) with core−shell structure have broad applications in imaging and drug delivery. However, there is still no rapid method for determination of the pore size

Figure 7. (A) (a) Chemical structure of TPE-CS; (b) digital images of TPE-CS solution and gel taken under day light and UV (365 nm) illumination; (c−f) confocal images of the gelation process of TPE-CS. Reprinted with permission from ref 80. Copyright 2016 The Nature Publishing Group. (B) Chemical structure of TPE-SDS and schematic illustration of micelle-transition processes in solutions with diﬀerent salt concentration. Reprinted with permission from ref 81. Copyright 2015 Wiley-VCH.

ﬂuorescence microscope, the heat initiated gelation of the TPE-CS solution with a high concentration (10−2 g mL−1) ﬁrst led to formation of some bright emission areas, which further subdivided and contracted through rinsing to remove LiOH and urea from the gelation system. The convenient ﬂuorescence monitoring of the entire gelation process based on unique AIE features clearly veriﬁed the hypothesis of two distinct but integrated thermal gelation and rinse gelation stages.80 The in situ monitoring of micelle transition process of surfactants is critical for their various technical applications. However, the ﬂuorescent visualization of micelle transitions by conventional ﬂuorophores is greatly hampered due to the ACQ eﬀect upon micellar aggregates formation. Lu and Tang et al. developed an AIE-active surfactant TPE-SDS, which showed a CMC concentration at around 30 μM. The micelle-transition processes (spherical, rodlike, and wormlike micelles) induced by adding neutral electrolyte of NaCl can be directly monitored by ﬂuorescence microscopy (Figure 7B).81 Moreover, the size variation of microemulsion droplets (MEDs) composed with

Figure 6. (A) Chemical structure of TPE-DTAB and schematic illustration of the 3D visualization of macrodispersion of montmorillonite in organic−inorganic composites. Reprinted with permission from ref 78. Copyright 2016 The Nature Publishing Group. (B) Schematic illustration of metal ion-induced AIE luminescence of Au(I)-SG@SiO2 NPs for detection of the pore size of silica shell. Adapted with permission from ref 79. Copyright 2016 Wiley-VCH. E

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ACS Sensors TPE-SDS could also be directly observed through inverse changes of ﬂuorescence intensity with the MEDs size.

Chi et al. further developed an asymmetric molecule SFPC, which could integrate the properties of AIE, mechanoluminescence (ML), and delayed ﬂuorescence (DF) (Figure 8B). A high photoluminescence quantum yield of 93.3% and a long ﬂuorescence lifetime of 1.23 ms were observed for its powder form. Moreover, when the powder sample of SFPC was scratched under pressure, a strong green luminescence could be observed even under daylight. This study provides a strategy to integrate the features of AIE, ML, and DF into one compound, which facilitate its potential applications as sensors.88 Li et al. recently reported an AIEgen (DPP-BO) with ﬂuorescence−phosphorescence dual emission under mechanical stimulation (Figure 8C).89 In the ML spectrum of DPP-O, the ﬂuorescence peak is at about 350 nm, while the phosphorescence peak is at about 450 nm. The lifetimes of phosphorescence decay at 450 nm were measured to be 5.5 and 2.2 s in solution and solid state at low temperature (77 K), respectively. The ﬂuorescence−phosphorescence dual emission of DPP-BO can be explained by the multiple intermolecular C−H···O and C−H···π interactions in the crystal and the small reorganization energy for the transition from S1 to Tn states at low temperature. The light-emitting performance of AIE ML materials can eﬃciently overcome the limitations set by ACQ eﬀect and will expand the applications as mechanical stimuli responsive sensors. Recently, Tang et al. developed a mitochondria-speciﬁc photoactivatable probe o-TPE-ON+, which can undergo photocyclodehydrogenation reaction to yield highly emissive c-TPE-ON+ by locking the rotation of peripheral aryl groups (Figure 9A). Because the oxidative dehydrogenation of o-TPE-

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STIMULI RESPONSE AIEgens are “smart” materials as they are able to change their emission properties in response to diﬀerent stimuli, such as thermal heating or cooling, vapor fuming, mechanical force, and photon irradiation.82−86 Herein, we select some examples of newly developed mechanoluminescence and photoactivated ﬂuorescence systems for discussion. Chi et al. constructed a TPE derivative P4TA with two crystalline polymorphs (Cg and Cb). The block-like crystal (Cg-form) exhibited a strong green emission upon pressing or grinding, while the prism-like crystal (Cb-form) completely lost the ML activity (Figure 8A). Single crystal X-ray analysis of the

Figure 8. (A) Molecular structure of P4TA and its mechanoluminesence in the dark and mechanochromic behavior with UV irradiation under pressure stimulus. Adapted with permission from ref 87. Copyright 2015 Royal Society of Chemistry. (B) Molecular structure of SFPC and its PL and ML spectra. Inset: ML image of SFPC sample upon grinding. Reprinted with permission from ref 88. Copyright 2015 Wiley-VCH. (C) (a) PL spectra of solid DPP-BO at 298 and 77 K, and its mechanoluminescent (ML) spectrum. Inset: ML image of asprepared DPP-BO sample upon grinding with a spatula in daylight. (b) Phosphorescence decay at 450 nm of DPP-BO at 77 K in solution and solid state. Reprinted with permission from ref 89. Copyright 2017 Wiley-VCH.

Figure 9. (A) Photocyclodehydrogenation of o-TPE-ON+ to yield cTPE-ON+ (left); ﬂuorescent, epiﬂuorescent, and STORM superresolution imaging of mitochondria in ﬁxed HeLa cells based on oTPE-ON+ (right). Reprinted with permission from ref 90. Copyright 2016 Wiley-VCH. (B) Photooxidative dehydrogenation of dihydro-2azaﬂuorenones to aﬀord AIE-active 2-azaﬂuorenones (left); sequential photoactivation of lipid droplets in selected HCC827 cells based on dihydro-2-azaﬂuorenone (NR2 = morpholinyl) (right). Reprinted with permission from ref 91. Copyright 2017 Royal Society of Chemistry.

two polymorphs suggested that the Cg polymorph has larger net-dipole moments and smaller ΔEg (HOMO → LUMO) values as compared with the Cb polymorph. As a result, the mechanoluminescence can be achieved for the Cg polymorph with stronger piezoelectric eﬀect. Moreover, bathochromic shifts were observed for both Cb and Cg polymorphs under a mechanical stimulus and UV irradiation, which indicate a special mechanochromic eﬀect. This work provides a unique design strategy for ML materials by combining of the piezoelectric and AIE properties.87

ON+ is promoted by oxygen, external oxygen-scavenging agents are not needed. The cyclized product c-TPE-ON+ exhibits pH/environment-insensitive strong ﬂuorescence under long excitation wavelength (>500 nm). This photoactivatable probe can be used for monitoring of the dynamic movement of mitochondria in live cells at the nanoscale level based on STORM super-resolution imaging.90 F

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ACS Sensors Tang et al. further developed photoactivatable and lipid droplet-speciﬁc probes dihydro-2-azaﬂuorenones, which can undergo photooxidative dehydrogenation reaction to yield AIEactive 2-azaﬂuorenones (Figure 9B). Dihydro-2-azaﬂuorenones with diﬀerent amine substituents are generally applicable for LD-speciﬁc imaging with an excellent photoactivation eﬃciency (up to 265-fold turn-on ratio). They can also be used for selective photoactivation of a single cell in complex environment. The photoactivatable AIE probes are expected to have broad applications in biological studies of LDs due to their high speciﬁcity for LDs and excellent photoactivation eﬃciency.91

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BIOLOGICAL MACROMOLECULES Fluorescent sensing for biological macromolecules has attracted intensive attention due to the strong requirement in clinical diagnostics. AIE sensors have been developed for sensing of various biological macromolecules, such as cholera toxin,92 lectin,93 γ-globulins,94 and G-quadruplex DNAs.95 In this section, we will represent some typical examples of AIE sensors for detection of polysaccharides, nucleic acids, nonenzymatic proteins, and enzymes. Heparin is a highly negatively charged polysaccharide and a widely used anticoagulant, thus the quantitative detection of heparin is important for clinical use.96 Yang et al. developed discrete organoplatinum(II) metallacycles decorated with trisTPE for light-up detection of heparin through multiple electrostatic interactions-induced aggregation (Figure 10A). A linear relationship within 0−28 μM was obtained for heparin detection, which completely covers the clinical dosing range (1.7−10 μM). Moreover, the structurally similar polymers with negatively charges, such as chondroitin 4-sulfate and hyaluronic acid, led to much less ﬂuorescence increase than heparin. Therefore, the AIE-active metallacycle provides a new platform for detection of heparin with high selectivity.97 To further fabricate an easily available sensor for heparin detection, Tang et al. recently developed an AIE probe HPQ-TBP-I, which can form HPQ-TBP/heparin complex via electrostatic interactions and synergistic displacement of the ﬂuorescence quencher iodide ion. As a result, a low detection limit of 22 nM and a linear relationship from 0 to 14 μM was achieved.98 Nucleic acids carry genetic information on all living organisms. Xu and Tian et al. used ssDNA aptamer, graphene oxide (GO) together with AIE-active DSA derivatives (DSAC2N, DSAC4N, and DSAC6N) for detection of ssDNA with a speciﬁc sequence (Figure 10B).99 When GO binds with the complex of ssDNA aptamer and AIE probes, the ﬂuorescence will be quenched through ﬂuorescence resonance energy transfer (FRET) from AIE probes to GO. The hybridization with target ssDNA will detach the probes from the surface of GO and recover the ﬂuorescence based on the strong binding between AIE probes and dsDNA. Through optimizing and tuning molecular interactions of AIE probes and GO with ssDNA, an excellent sensitivity (LOD: 0.17 × 10−9 M) was achieved. The abnormal aggregation and ﬁbrillation of α-synuclein (αSyn) play central roles in Parkinson’s disease (PD).100 To monitor α-syn ﬁbrillation processes, Tang et al. developed an AIEgen based on triphenylphosphonium decorated TPE derivative (TPE-TPP).101 Compared with most frequently used probe Thioﬂavin T (ThT), the AIE probe TPE-TPP exhibits a higher sensitivity and faster response to diﬀerentiate monomeric and ﬁbrillar α-Syn (Figure 10C). The dissociation constants (Kd) of TPE-TPP and ThT for α-Syn ﬁbrils were

Figure 10. (A) Schematic illustration of the detection of heparin by electrostatic interaction induced aggregation between tris-TPE metallacycle and heparin. Reprinted with permission from ref 97. Copyright 2015 American Chemical Society. (B) Schematic illustration of the DNA sensing based on GO and cationic silole derivatives. Adapted with permission from ref 99. Copyright 2016 Wiley-VCH. (C) Comparison between the light-up detection of TPE-TPP and ThT for α-Syn ﬁbrillation. Inset: photographs of mixtures of TPE-TPP and ThT with ﬁbrillar forms of α-Syn taken under UV irradiation (365 nm). Reprinted with permission from ref 101. Copyright 2015 Royal Society of Chemistry. (D) Molecular structure of RGKLVFFGR peptide decorated TPE and its “switch-on” detection of Aβ1−40 ﬁbrils. Adapted with permission from ref 104. Copyright 2015 American Chemical Society. (E) AIE-SiO2 NP-based label-free aptasensor for turn-on detection of PSA. Reprinted with permission from ref 105. Copyright 2017 Springer Berlin Heidelberg.

measured to be 4.36 μM and 8.48 μM, respectively. TPE-TPP is thus potential for sensitive monitoring the ﬁbrillation process of α-Syn and detection of early stage PD. The extracellular accumulation of β-amyloid (Aβ) peptides in the form of Aβ ﬁbrils is a major pathological feature of Alzheimer’s disease (AD).102 In order to diagnose AD early, it is critical to develop probes for sensitive detection of Aβ ﬁbrils and monitor the ﬁbril formation kinetics. Tang et al. previously reported an AIE-active probe BSPOTPE, which can act as both an ex situ monitor and an in situ inhibitor for protein ﬁbrillation with bovine insulin as an example.103 Recently, Ghorai and Jana et al. reported a ﬂuorescent “switch-on” probe for detection of amyloid ﬁbrils. The probe consists of an AIEgen of TPE and a G

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ACS Sensors

highly emissive aggregates. The detection limit can be as low as 11.4 pM or 0.2 U/L.107,108 Tang et al. further developed a phosphorylated chalcone derivative for ratiometric detection of ALP activity. The sensor is soluble in water and emits greenish-yellow in aqueous buﬀers. In the presence of ALP, the emission gradually changes to deep red with a ratiometric ﬂuorescent response due to formation and aggregation of enzymatic product with smooth ﬂow of the ESIPT and AIE processes (Figure 11B). The linear detection of ALP activity is in a range of 0−150 mU/mL with a detection limit of 0.15 mU/mL. Moreover, the probe also shows an excellent biocompatibility and is thus suitable to study the ALP activity in living cells.109 Caspases are critically important in the initiation and regulation of proteolytic events during apoptosis. Liu et al. recently reported a self-validating probe composed of coumarin (Cou) as the energy donor and an AIEgen of tetraphenylethenethiophene (TPETP) as the energy quencher linked through a caspase-3 responsive DEVD peptide (Figure 12A). In aqueous

peptide component (RGKLVFFGR) for speciﬁc binding with amyloid structure (Figure 10D). This probe is nonﬂuorescent in the presence of amyloid monomer peptide, but will “switchon” its ﬂuorescence by binding with amyloid ﬁbrils. Compared with conventionally used probe ThT, this AIE-active probe oﬀers an approximately 4-fold stronger signal for sensitive detection and monitoring of amyloid ﬁbrillation.104 Prostate-speciﬁc antigen (PSA) is the most important biomarker for diagnosis of prostate cancer. Qu et al. developed a label-free method for turn-on detection of PSA (Figure 10E).105 The amino-functionalized SiO2 NPs with positive charges were ﬁrst coated with single-stranded PSA aptamer via electrostatic interactions. The speciﬁc binding of the aptamer with PSA would lead to a release of aptamer from the surface of SiO2 NPs and the positively charged surface of SiO2NPs could then bind with the negatively charged AIEgen of BSPOTPE to form highly emissive aggregates. Based on this sensitive method with simple operation, a low detection limit of 0.5 ng/mL was achieved for PSA detection. The detection of enzyme activity has values signiﬁcant to biological research and clinical diagnosis of disease. AIE sensors have been used for detection of various enzymes, including acetylcholinesterase (AChE), 106 alkaline phosphatase (ALP),107−109 esterase,110,111 caspases,112−114 chymase,115 furin,116 β-galactosidase,117,118 hyaluronidase,119 methyl parathion hydrolase (MPH),120 monoamine oxidases,121,122 NAD(P)H: quinone oxidoreductase-1 (NQO1),123 sirtuin type 1 (SIRT1),124 and telomerase.125,126 In this section, we will represent some recent examples of AIE sensors for enzyme detection. Alkaline phosphatase (ALP) is a group of enzymes that plays important roles in regulating diverse cellular functions. Zhang and Liu et al. independently reported TPE-based probes for sensitive detection of ALP based on decoration of the TPE core with phosphate groups to endow the probe with good water solubility (Figure 11A). In the presence of ALP, the phosphate groups are cleaved through enzymatic hydrolysis, yielding

Figure 12. (A) Schematic illustration of the self-validated caspase-3 detection based on FRET process between coumarin and AIEgen of TPETP. Reprinted with permission from ref 113. Copyright 2016 Royal Society of Chemistry. (B) Schematic of a single ﬂof TPETP probe with two AIEgens of diﬀerent emissive colors for real-time monitoring of the caspase cascade activation. Reprinted with permission from ref 114. Copyright 2017 Royal Society of Chemistry.

solution, the probe is nonemissive due to the energy transfer between Cou and TPETP, and further dissipation of the acceptor energy through free intramolecular motion. Through cleavage of the peptide linker with caspase-3 to disrupt the energy transfer process, strong green and red ﬂuorescence signals from Cou and TPETP are simultaneously activated. This dual ﬂuorescence turn-on detection mode allows selfvalidation with a high accuracy.113 Liu et al. further reported an AIE probe TPETHDVEDIETD-TPS for real-time and cascade detection of caspase-8 and caspase-3 activity in living cells.114 This probe consists of two AIEgens with distinct green and red emission

Figure 11. (A) Schematic illustration of the light-up detection for ALP. Reprinted with permission from ref 107. Copyright 2013 American Chemical Society. (B) Schematic illustration of the ratiometric detection of ALP activity. Adapted with permission from ref 109. Copyright 2014 American Chemical Society. H

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ACS Sensors colors and a hydrophilic peptide (DVEDIETD) linker as the substrate of caspase-8 (IETD) and caspase-3 (DVED) (Figure 12B). The probe is nonﬂuorescent in aqueous solution due to its good solubility. During apoptosis, the initiator caspase-8 and activator caspase-3 will sequentially cleave the corresponding peptide substrate and release green emissive TPS and red emissive TPETH, respectively. This sequential turn-on detection mode allows real-time monitoring of the caspase cascade activation during apoptosis. The enzyme furin is a kind of trans-Golgi protein convertase that is overexpressed in diﬀerent tumors.127 Liang et al. developed a TPE-based probe Ac-Arg-Val-Arg-Arg-Cys(StBu)Lys(TPE)-CBT for sensitive detection of furin enzyme based on formation of TPE-Dimer and TPE-NPs with “‘Dual AIE’” eﬀect (Figure 13).116 The 1,2-aminothiol group can be in situ

Figure 14. Fluorescent probes of (A) SA-Gal and (B) TPE-Gal for light-up detection of β-galactosidase. (A) is reprinted with permission from ref 117. Copyright 2015 Royal Society of Chemistry. (B) is reprinted with permission from ref 118. Copyright 2017 Royal Society of Chemistry.

to turn on the ﬂuorescence of the TPE-Py molecule by decreased water solubility and formation of aggregates. Compared with the SA-βGal probe, a wider linearity range (0.8 to 4.8 U mL−1) was achieved, but the detection limit is higher (0.33 U mL−1).118 Telomerase can add speciﬁc DNA sequence (TTAGGG)n to the end of a telomere. Due to its high activity in cancer cells, telomerase can act as a biomarker of cancer.129 Lou and Xia et al. reported a series of AIE sensors for detection of telomerase. For example, the AIE-active and positively charged sensor Silole-R is nonemissive when dissolved in solution, but its ﬂuorescence can greatly increase by binding on the DNA strand elongated by telomerase with an intensity increase of 586% (Figure 15A).125 Furthermore, a much higher sensitivity was

Figure 13. Schematic illustration of furin activity sensing with “dual AIE” eﬀect. Reprinted with permission from ref 116. Copyright 2017 Royal Society of Chemistry.

generated through reduction of the disulﬁde bond linked on the cysteine motif by intracellular glutathione and cleavage of the Ac-Arg-Val-Arg-Arg peptide moiety by furin enzyme. The 1,2aminothiol group could then react with the cyano group to yield the TPE-Dimer with higher hydrophobicity, which then form nanoaggregates at the locations of activated furin. The conversion of Cys-Lys(TPE)-CBT to TPE-Dimer and TPENPs with “Dual AIE” eﬀect could eﬃciently improve the signalto-noise ratio (up to 109-fold). As a control, the TPE-based probe decorated with an Ac-Arg-Val-Arg-Arg peptide but without cysteine and CBT groups exhibited only a 63-fold signal-to-noise ratio. β-Galactosidase cannot only act a reporter to evaluate transfection eﬃciency, but also is a very important biomarker for cellular senescence.128 Liu et al. reported an AIE probe SAβGal for light-up detection of β-galactosidase via cleavage of the β-galactopyranoside group to restore intramolecular hydrogen bond and further form highly emissive aggregates (Figure 14A). The probe SA-βGal exhibits an excellent sensitivity with a low detection limit of 0.014 U mL−1 and a linear response range of 0−0.1 U mL−1.117 Tang et al. further developed a TPE based light-up sensor TPE-Gal for detection of β-galactosidase. The probe bears a positively charged pyridinium pendant and further conjugated with a β-galactose residue (Figure 14B). In the presence of β-galactosidase, the β-galactose group was cleaved and spontaneously underwent an elimination reaction

Figure 15. Schematic illustration of diﬀerent strategies for detection of telomerase activity. (A) Direct turn-on sensing by binding of AIEgens to the elongated DNA strand. Adapted with permission from ref 125. Copyright 2016 American Chemical Society. (B) Quencher-labeled TS primer to eliminate the background noise and improve the turn-on sensing ratio. Adapted with permission from ref 126. Copyright 2015 American Chemical Society. (C) Ratiometric detection through parallel detection of dual ﬂuorescence signals from Cy5-labeled primer and Silole-R labeled DNA strand. Adapted with permission from ref 125. Copyright 2016 American Chemical Society. I

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ACS Sensors achieved with a signal increase of 1424% through combination of Silole-R and a quencher (DABCYL acid) decorated TS primer (Figure 15B).126 This can be due to the FRET process between Silole-R and the quencher-labeled TS primer, which would eﬃciently eliminate the background noise in the absence of telomerase. However, the sole turn-on signal can be easily perturbed by experimental conditions. To tackle this challenge, they further reported a ratiometric probe design through parallel detection of dual ﬂuorescence signals of Cy5 and SiloleR, which are respectively labeled on the template strand primer (TS primer) and the elongated DNA strand (Figure 15C). In the presence of telomerase, the blue emission of Silole-R is enhanced through aggregation induced emission, while the red emission of Cy5 is almost unchanged as a stable internal reference. As a result, a much lower standard deviation (SD = 0.055) was observed for the ratiometric probe than the solely turn-on probe (SD = 0.305).125 This facile and fast-responsive telomerase detection method based aggregation-induced emission has great potentials in clinical diagnosis and therapeutic monitoring of cancer.

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CELLULAR PROCESSES The real time monitoring of cellular processes (e.g., growth, diﬀerentiation, apoptosis, and autophagy) is important to understand their mechanisms. For example, based on the incorporation of 5-ethynyl-2′-deoxyuridine (EdU) into newly synthesized DNA, Tang et al. utilized AIEgens (TPE−Py−N3 and Cy−Py−N3) decorated with an azide group for labeling of EdU to detect the DNA synthesis during S-phase in the cell cycle (Figure 16).130 With longer incubation time, the nuclei of HeLa cells become more emissive, which indicates that the AIE-active probes can quantitatively monitor the of DNA synthesis process. Compared with the ACQ dye of Alexa647azide, the AIEgens exhibited a much wider working concentration range (10 to 100 μM), higher brightness, and much stronger photostability. Therefore, the AIEgens are promising alternatives to the commercial Alexa-azide dyes. Autophagy is a lysosome-dependent metabolic process to clear dysfunctional cellular components, which is closely related with various diseases.131 As lysosomes play critical roles in autophagy execution, Tang et al. developed an AIE-active and lysosome-speciﬁc probe AIE-LysoY, which can selectively accumulate in lysosomes. Based on its excellent photostability and speciﬁcity for lysosomes, the AIE probe can be used to visualize the autophagy induced lysosomal number and morphology changes with superior resolution and contrast (Figure 17A).132 Because the autophagy process is also related with activation of ATG4B enzyme, Wang et al. reported an in situ intracellular self-assembly of AIEgen strategy for monitoring autophagy by detection of ATG4B enzyme activity. The probe is composed with a bulky dendrimer as a carrier, an AIEgen of bis(pyrene) derivative (BP) as signal molecule, and a peptide linker (GKGSFGFTG) as the responsive unit to ATG4B enzyme. The peptide linker can be speciﬁcally cleaved upon activation of ATG4B enzyme, resulting in self-aggregation of BP residues and a 30-fold enhanced ﬂuorescence (Figure 17B). This in situ intracellular self-assembly strategy provides a rapid, real-time, and quantitative method for monitoring autophagy in living cells.133 Mitophagy is a process that removes damaged mitochondria to maintain cell health in a lysosome-dependent manner.134 However, the mitophagy process is diﬃcult to be long-term monitored by commercial dye of MitoTracker Red due to its poor photostability.

Figure 16. (A) Schematic illustration of the detection for DNA synthesis with AIEgens through EdU assay. (B) Quantitative analysis of DNA synthesis in HeLa cells with increasing incubation time of EdU. Inset: ﬂuorescence images of nuclei stained by EdU/TPE−Py− N3. Reprinted with permission from ref 130. Copyright 2015 Royal Society of Chemistry.

Recently, Tang and Zheng et al. reported a TPE-Py-NCS probe for real time monitoring of the mitophagy process.135 TPE-Py-NCS can speciﬁcally stain mitochondria in live cells with superior photostability and long-term retaining ability. The combination with commercial probe LysoTracker Red in HeLa cells can in situ monitor the mitophagy process in which mitochondria are digested by autophagosome (Figure 17C). Importantly, the tracking ability of TPE-Py-NCS will not be aﬀected by microenvironmental changes, including pH variation and decreasing membrane potential. Apoptosis is the programmed cell death, and the real-time monitoring of cell apoptosis will provide valuable insights into evaluation of therapy eﬃciency.136 In addition to elevated activity of caspase enzymes,112 apoptosis is also featured with cell membrane structural changes with negatively charged phosphatidylserine (PS) exposure on the surface of early apoptotic cells.137 Liu et al. reported an AIE-active probe AIEZnDPA to detect cell apoptosis based on the electrostatic interaction between ZnDPA group and the negatively charged cell membrane induced by early apoptosis. Moreover, AIEZnDPA can stain the nuclei of late stage apoptotic cells due to the disruption of cell membrane (Figure 18).138 Compared with the commercial dye Annexin V for indicating early apoptosis, AIE-ZnDPA has the additional advantage to diﬀerentiate early and late stage apoptosis.

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PATHOGENS The sensitive detection of pathogenic bacteria, especially drugresistant bacteria, is critical in food safety inspection and clinical infection diagnosis.139 Current methods for bacteria detection, J

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light-up imaging of bacteria, bacterial susceptibility evaluation, and photodynamic killing.140,141 However, these AIEgens cannot diﬀerentiate Gram-positive and -negative bacteria. Recently, Liu et al. developed a red emissive probe AIE-2Van through conjugation of TPE-based AIEgen with dual vancomycin (Van) as ligands for selective recognition of Gram-positive bacteria, including both nonresistant B. subtilis and vancomycin-resistant Enterococcus strains (Figure 19A).142

Figure 17. (A) Visualization of increasing lysosomes during cellular autophagy by AIE-active AIE-LysoY. Reprinted with permission from ref 132. Copyright 2016 Wiley-VCH. (B) Real-time monitoring autophagy by light-up detection of autophagy-speciﬁc enzyme of ATG4B. Reprinted with permission from ref 133. Copyright 2017 American Chemical Society. (C) Chemical structure of TPE-Py-NCS and ﬂuorescence monitoring of the mitophagy process of HeLa cells by costaining with TPE-Py-NCS (yellow) and LysoTracker Red (red). Reprinted with permission from ref 135. Copyright 2015 Royal Society of Chemistry.

Figure 19. (A) Chemical structure of AIE-2Van and confocal images of B. subtilis, E. coli, Van A, and Van B incubated with AIE-2Van (0.5 μM). Inset: photographs of bacteria suspension treated with AIE-2Van (20 μM) and GO (1.6 μg) under UV irradiation. Reprinted with permission from ref 142. Copyright 2015 Royal Society of Chemistry. (B) Schematic illustration of the turn-on sensing of E. coli by TPEMan-Grafted ﬁbers. Reprinted with permission from ref 143. Copyright 2015 American Chemical Society. (C) Schematic illustration of the ﬂuorescence array consisting of ﬁve AIE molecules for identiﬁcation of eight types of bacteria. Reprinted with permission from ref 144. Copyright 2014 Wiley-VCH.

AIE-2Van shows almost no emission in dilute aqueous solution due to its good water solubility, but emits intensively upon interaction with Gram-positive bacteria, while no emission is observed for Gram-negative bacteria (E. coli). The naked-eye identiﬁcation of Gram-positive bacteria in solution can be achieved based on a high concentration of AIE-2Van (20 μM) to enhance the binding ﬂuorescence signal and a small dose of graphene oxide (1.6 μg) to eliminate the background noise.

Figure 18. (A) Chemical structure of AIE-ZnDPA. (B) Confocal images of early and late apoptotic HeLa cells stained with AIE-ZnDPA and PI. Reprinted with permission from ref 138. Copyright 2015 American Chemical Society.

such as plating and culturing and gene microarray, suﬀer from long-time operation, expensive apparatus, and complicated procedures. Tang et al. reported several AIEgens for wash-free K

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L

Biological macromolecules

Stimulus Response

Microenvironment

CN− HSO3− Citrate ion

0.17 × 10−9 M Kd = 4.36 μM N.A. 0.5 ng/mL

β-Amyloid fibrils

Prostate-specific antigen (PSA)

22 nM

linear range of 0−28 μM

N.A.

N.A.

N.A. N.A.

N.A.

N.A.

2.78 × 10−7 M for cysteine; 1.89 × 10−7 M for glutathione 200 nM for GSH

ssDNA α-Synuclein fibrils

Heparin

Dispersion of inorganic fillers Porous size of silica NPs Gelation process Micelle transition process Mechanoluminescence Photoactivation

Thiols

8.4 ppm for NH3 vapor 12.8 nM 5 μg/L for xylene 10−9 M Linear range of 0−100 μM

100 × 10−6 M

0.1 μM 8.9 × 10−8 M 1.8 × 10−7 M

Pb2+ SDBS

Peroxynitrite (ONOO−) Amines H2S VOCs H2O2 Creatinine

0.25 μM 0.3 ppb 1 × 10−7 M 5 μM 0.051 μM

Ag+ Hg2+

detection limit 1.1 × 10−7 M

Zn2+

analyte (s)

Small molecules

Anions

Metal ions

Table 1. Recent Examples of AIE-Based Sensorsa comments

MnO2 nanosheets coated SiO2 NPs can be reduced by GSH to expose the positively charged surface of SiO2NPs and form emissive aggregates with negatively charged BSPOTPE The AIE-active probe TPE-DTAB can show the macrodispersion of montmorillonite in PVC polymer matrix via 3D fluorescence imaging Metal ions smaller than the porous size of silica NPs can induce the aggregation of inner thiolate-M(I) complex to light-up fluorescence The gelation process of TPE-labeled chitosan can be in situ monitored by light-up fluorescence The micelle-transition processes (spherical, rodlike, and wormlike micelles) can be in situ monitored based on the AIE-active surfactant TPE-SDS Based on the strong solid emission of AIEgens, mechanical stimuli can induce fluorescence, delayed fluorescence, and fluorescence− phosphorescence dual emission Photoactivatable AIE probes have been developed for mitochondria and lipid droplets-targeted imaging based on photooxidative dehydrogenation reaction Light-up detection based on multiple electrostatic interactions-induced aggregation between discrete organoplatinum(II) metallacycles and heparin Light-up detection based on electrostatic interactions-induced aggregation and synergistic displacement of the fluorescence quencher iodide ion Hybridization with target ssDNA will detach the AIE-active probes from the surface of GO to recover fluorescence Compared with the commercial ThT probe, the AIE-active probe TPE-TPP exhibits a higher sensitivity and faster response to αsynuclein fibrils β-Amyloid fibrils can be selectively detected in a light-up manner based on the aggregation of AIE probe decorated with a short peptide (RGKLVFFGR) PSA aptamer coated on SiO2 NPs can be removed by binding with PSA and then the negatively charged AIEgen of BSPOTPE can aggregate on the surface of positively charged SiO2 NPs to emit strong fluorescence

Recovery of intramolecular hydrogen bond via aminolysis reaction to activate the ESIPT process and light-up fluorescence Thiolysis of dinitrophenyl ether to remove the fluorescence quenching group Dissolving of the TPE moieties in the organic pollutants to quench the fluorescence via activation of the intramolecular motion Greatly enhanced NIR emission via the “nanophotonic energy relay” strategy Light-up detection of creatinine via formation of aggregates between AIE-active probe IDATPE and creatinine to restrict intramolecular motion Destruction of the Pt(II) metallacage to yield emissive aggregates of the TPE-based precursor

Formation of chelating complex with the probe AIE-L to disrupt the intramolecular PET process and further self-assembly into highly emissive aggregates Chelating with the naphthyridine moiety in TPE-naphthyridine to restrict intramolecular motion and light-up fluorescence Ratiometric sensing based on dark through-bond energy transfer (DTBET) strategy Hg2+-catalyzed thioacetal deprotection and subsequent keto−enol isomerization reaction to turn-on fluorescence Pb2+-induced aggregation of GSH-Au nanoclusters via coordination interaction to light-up fluorescence Formation of HBT-C18/SDBS catanionic aggregates to light-up fluorescence by restriction of intramolecular motion and protection of the intramolecular hydrogen bond from aqueous environment’s disruption Disruption of the intramolecular charge transfer (ICT) effect via addition reaction to achieve ratiometric fluorescence sensing The addition of HSO3− to the pyrene−benzthiazolium conjugate would lead to a large blue shift and turn-on emission Complexation between DPP-Py derivatives and citrate ion to restrict intramolecular motion and further self-assembly into highly emissive nanoaggregates Reaction with ONOO− to remove the phenylboronate group and recover the intramolecular hydrogen bond to light-up fluorescence

ref.

105

104

99 101

98

97

90, 91

87−89

80 81

79

78

73

72

61 63 65 68 70

54

49 50 52

34 36 37 41 46

32

ACS Sensors Review

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M

a

Mitophagy Apoptosis Gram-positive bacteria Gram-negative bacteria Bacteria

N.A.

Autophagy

N.A.

102 CFU/mL for E. coli

N.A. N.A. N.A.

N.A.

N.A. N.A.

DNA synthesis

0.33 U mL−1 N.A.

Telomerase

N.A. indicates not available.

Pathogens

Cellular processes

N.A. 0.014 U mL−1

N.A.

TPE-mannose conjugated electrospun PSMA fibers with highly porous structure and large contact surface can be used for selective recognition of Gram-negative E. coli A multifluorescence array consisting of five TPE-derived molecules can efficiently differentiate eight kinds of bacteria

Self-indicating detection through cleavage of the peptide linker to simultaneously activate the green and red fluorescence signals from Cou and TPETP The cascade activation of apoptosis initiator caspase-8 and effector caspase-3 can be detected based on the cleavage of corresponding peptide substrates and sequentially light-up two AIEgens with distinct green and red emission colors The sequential formation of TPE-Dimer and nanoaggregates could efficiently improve the signal-to-noise ratio with ″dual AIE″ effect The β-galactoside group was cleaved to restore intramolecular hydrogen bond and further form highly emissive aggregates involving ESIPT process The β-galactose group was cleaved to turn-on fluorescence of TPE-Py by decreasing the water solubility and formation of aggregates The parallel detection of dual fluorescence signals of Cy5 and Silole-R labeled on the TS primer and the elongated DNA strand could efficiently decrease the standard deviation The combination of Silole-R and a quencher (DABCYL acid) could increase the light-up ratio to 1424% The DNA synthesis during S-phase can be quantitatively monitored based on the AIE probes with advantages of wider working concentration range, higher brightness, and much stronger photostability The lysosome-specific AIE probe LysoY can visualize the autophagy induced lysosomal number and morphology changes with superior resolution and contrast The activation of ATG4B enzyme during autophagy can cleave the peptide linker (GKGSFGFTG) and induce aggregation of the AIEactive bis(pyrene) residues The TPE-Py-NCS probe can specifically stain mitochondria in live cells and monitor the mitophagy process in real time The probe AIE-ZnDPA can differentiate early and late stage apoptosis TPE-based AIEgen with dual vancomycin as ligands can be used for selective recognition of Gram-positive bacteria

N.A.

comments The phosphate groups decorated on the TPE core can be cleaved by ALPs to reduce solubility and yield highly emissive aggregates A phosphorylated chalcone derivative was used for ratiometric detection of ALP activity in both solution and living cells

detection limit 0.2 mU/mL 0.15 mU/mL

Caspase-8 and caspase-3 Furin β-Galactosidase

Alkaline phosphatases (ALPs) Caspase-3

analyte (s)

Table 1. continued ref.

144

143

135 138 142

133

132

126 130

118 125

116 117

114

113

107, 108 109

ACS Sensors Review

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ACS Sensors Notes

AIE-2Van also shows a high photodynamic activity and can eﬃciently destroy the bacterial wall of Gram-positive bacteria under white light irradiation. To selectively detect Gramnegative bacteria, Li et al. reported TPE-mannose conjugated electrospun PSMA ﬁbers with highly porous structure and large contact surface for selective recognition of Gram-negative E. coli. When exposed to bacteria, the speciﬁc binding between TPE-Mannose conjugated on ﬁbers and FimH proteins of E. coli would lead to a remarkable turn-on ﬂuorescence due to the restriction of intramolecular motion of TPE, providing a rapid detection tool for detection of E. coli bacteria with a visual sensitivity and a low detection limit of 102 CFU/mL (Figure 19B).143 Zhang et al. developed a multiﬂuorescence array (F-array) for bacteria identiﬁcation with the assistance of statistical methods of principal component analysis (PCA) and quadratic discriminant analysis (QDA) (Figure 19C).144 This F-array consisting of ﬁve TPE-derived molecules with various electronic properties can diﬀerentially recognize bacteria with diﬀerent surface electronic properties. The collective ﬂuorescent signals from labeled bacteria can be eﬀectively identiﬁed based on automatic mathematical analysis methods. This study demonstrates that eight kinds of bacteria can be eﬃciently diﬀerentiated, including both normal bacteria (E. coli, K. pneumonia, S. choleraesuis, S. aureus, S. epidermidis, B. subtilis) and multidrug-resistant bacteria (MDR E. coli and methicillinresistant S. aureus). The eﬃcient bacterial identiﬁcation method can provide important and rapid information on clinical diagnosis of bacterial types for infected patients.

The authors declare no competing ﬁnancial interest.

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ACKNOWLEDGMENTS This work was ﬁnancially supported by the Science and Technology Planning Project of Guangzhou (Project No. 201607020015); the Key Project of the Ministry of Science and Technology of China (2013CB834702); International Science & Technology Cooperation Program of Guangzhou (Project No. 20170403069); National Science Foundation of China (51620105009 and 21602063); Natural Science Foundation of Guangdong Province (2016A030313852 and 2016A030312002); the Fundamental Research Funds for the Central Universities (2015ZY013 and 2015ZZ104); the Innovation and Technology Commission of Hong Kong (ITC−CNERC14SC01); Guangdong Innovative Research Team Program (201101C0105067115).

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ABBREVIATIONS CBT, 2-cyanobenzothiazole; BODIPY, DABCYL acid, 4-(4(dimethylamino)phenylazo)benzoic acid; GO, graphene oxide; MOF, metal−organic framework; FR, far-red; FRET, ﬂuorescence resonance energy transfer; NIR, near-infrared; LDs, lipid droplets; LOD, limitation of detection; PDHA, 9,10bis(diphenylmethylene)-9,10-dihydroanthracene; USEPA, United State Environmental Protection Agency; SD, standard deviation; SDBS, dodecylbenzenesulfonate; STORM, stochastic optical reconstruction microscopy; TICT, twisted intramolecular charge transfer; TPE, tetraphenylethene; BODIPY, borondipyrromethene; DPA-CN-PPV, diphenylamine- and cyanosubstituted poly(p-phenylenevinylene)

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CONCLUSIONS AND PERSPECTIVES The concept of AIE has emerged as a powerful and versatile strategy for the design of new sensing systems. This review has summarized the latest advances of this promising ﬁeld with representative examples for diﬀerent analytes (refer to Table 1 for a summary). Through simple modulation of their structures, the AIEgens can be easily tuned to satisfy certain sensing purposes with advantages of excellent signal-to-noise ratio, strong photostability, large Stokes’ shift, and high portability. However, many eﬀorts are still needed to tackle the following challenges in biological and environmental sensing applications: (i) development of FR/NIR-emissive and multiphoton excited AIEgens for in vivo sensing of biological processes; (ii) speciﬁc detection of biomarkers in complex biological ﬂuids for in vitro diagnosis of diseases; (iii) incorporation of AIEgens into lowcost and portable diagnostic platforms, such as ﬂuorescence sensor arrays and microﬂuidics, for on-site environmental monitoring and clinical diagnosis. In conclusion, the AIE sensors are anticipated to serve as a powerful and practical platforms for wide-ranging sensing applications, and we hope that this review will inspire interest and fresh ideas into this emerging research ﬁeld.

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Vocabulary

Aggregation-induced emission, a photophysical phenomenon exhibited by luminogens that are nonemissive in dissolved state but become highly emissive in the aggregated state; Stimuli response, the luminescence changes in response to physical stimulus, including mechanical force, light, heating, cooling, and vapor fuming; Biological macromolecules, biogenic molecules with high molecular weight, including polysaccharides, DNAs, proteins, and enzymes; Cellular processes, the intracellular processes of cell growth, diﬀerentiation, apoptosis, and autophagy; Microenvironment sensing, the luminescence behavior changes with varied microenvironmental parameters, including pH, temperature, viscosity, hydrophobic eﬀect, and phase transformation

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Meng Gao: 0000-0001-8071-8079 Ben Zhong Tang: 0000-0002-0293-964X Author Contributions

The manuscript was written through contributions of all authors. N

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Review

ACS Sensors

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DOI: 10.1021/acssensors.7b00551 ACS Sens. XXXX, XXX, XXX−XXX

Review

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DOI: 10.1021/acssensors.7b00551 ACS Sens. XXXX, XXX, XXX−XXX

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