Excited-state intramolecular proton transfer (ESIPT)-based fluorescent probes for biomarker detection: design, mechanism, and application

Abstract

Biomarkers are essential in biology, physiology, and pharmacology; thus, their detection is of extensive importance. Fluorescent probes provide effective tools for detecting biomarkers exactly. Excited state intramolecular proton transfer (ESIPT), one of the significant photophysical processes that possesses specific photoisomerization between Keto and Enol forms, can effectively avoid annoying interference from the background with a large Stokes shift. Hence, ESIPT is an excellent choice for biomarker monitoring. Based on the ESIPT process, abundant probes were designed and synthesized using three major design methods. In this review, we conclude probes for 14 kinds of biomarkers based on ESIPT explored in the past five years, summarize these general design methods, and highlight their application for biomarker detection in vitro or in vivo.

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Hao Gu

Hao Gu graduated from Shenyang University of Chemical Technology (China) with BS degree in 2017. He is pursuing his doctorate degree under the guidance of Prof. Chen's group, College of Chemical Engineering at Nanjing Tech University (China). He has been mainly involved in the research of fluorescent dyes, fluorescent chemosensors and photochromic dyes.

Wenjing Wang

Wenjing Wang graduated from Taizhou University (China) with BS degree in 2020 and is a master's student under the guidance of Prof. Chen, College of Chemical Engineering at Nanjing Tech University (China). She has been mainly involved in the research of fluorescent chemosensors and photochromic dyes.

Wenyan Wu

Wenyan Wu graduated from Huainan Normal University (China) with BS degree in 2020 and is a master‘s student under the guidance of Prof. Chen, College of Chemical Engineering at Nanjing Tech University (China). She has been mainly involved in the research of polymer self-assembly and chiral induction for chiral and achiral molecules.

Maolin Wang

Maolin Wang graduated from Xi’an University of Science and Technology (China) with BS degree in 2020 and is a master's student under the guidance of Prof. Chen, College of Chemical Engineering at Nanjing Tech University (China). She has been mainly involved in the research of fluorescent dyes, fluorescent chemosensors and photo-controlled release of active substance.

Yongrong Liu

Yongrong Liu graduated from Yancheng Normal University (China) with BS degree in 2020 and is a master's student under the guidance of Prof. Chen, College of Chemical Engineering at Nanjing Tech University (China). She has been mainly involved in the research of fluorescent chemosensors and chemiluminescent molecular probes.

Yanjun Jiao

Yanjun Jiao graduated from Henan University of Science and Technology (China) with BS degree in 2020 and is a master's student under the guidance of Prof. Chen, College of Chemical Engineering at Nanjing Tech University (China). He has been mainly involved in the research of fluorescent dyes, fluorescent chemosensors and defaming agent.

Fan Wang

Fan Wang graduated from Anhui Science and Technology University (China) with his BS degree in 2019 and is a master's student under the guidance of Prof. Chen's group. He has been mainly involved in the research of developing chemiluminescent sensors.

Fang Wang

Fang Wang received her PhD from Ewha Womans University under the direction of Prof. Yoon (Korea) in 2012. She is currently a professor at Nanjing Tech University (China) and has joined Prof. Chen's group. Her research focuses on the design and synthesis of fluorescent chemosensors.

Xiaoqiang Chen

Xiaoqiang Chen received his PhD in Applied Chemistry from Dalian University of Technology (China) in 2007. He joined Prof. Yoon's group at Ewha Womans University (Korea) as a postdoctoral fellow in 2008. In March 2010, he moved to Nanjing Tech University, where he is currently a professor of College of Chemical Engineering. He visited Ewha Womans University as a visiting professor in 2015. His current research interests mainly focus on fluorescent dyes, fluorescent probes, and light-controlled release of active substance.

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1. Introduction

Biomarkers, which can objectively measure and evaluate physiological or pathological processes, have aroused widespread attention and research interest.^1–7 As shown in Table 1, we list some important biomarkers, their participating physiological processes, and related diseases. Evidently, these biomarkers are closely related to many diseases; therefore, there is an urgent need to monitor the indicators of these biomarkers to accurately reflect changes or even real-time changes in biomarkers.^8–12 Fluorescent probes are routinely utilized to monitor biomarkers because of their high sensitivity,^13–18 fast response^19–23 and structural adjustability.^24–28 Four mechanisms of fluorescent probes have been identified: PET (Photo-induced Electron Transfer),^29,30 FRET (Fluorescence Resonance Energy Transfer),^31–33 ICT (Intramolecular Charge Transfer),^34–36 and Excited-state Intramolecular Proton Transfer (ESIPT).^37–39 In this review, ESIPT is emphasized, and the relative combination of mechanisms, such as FRET-ESITP, PET-ESIPT, and ICT-ESIPT, are also involved.

Table 1 Important biomarkers, their participating physiological processes, and related diseases

Name of biomarkers	Abbreviation	Physiological processes	Related diseases
Acid and base	pH	Cell proliferation and apoptosis, ion transport, enzyme activity, and protein degradation^55,56	Cancer,^57–59 sepsis,^60 hyperkalemia,^61 and chronic kidney disease^62
Carbon monoxide	CO	Cytoprotection, anti-inflammation, improvement of organ transplantation survival, and inhibition of bacterial growth^63,64	Neurodegenerations, hypertension, heart failure, and inflammation^63,64
Sulfites	SO3^2−/HSO3^−	Regulation of vascular smooth muscle tone and lowering blood pressure^65	Lung cancer, cardiovascular diseases, and many neuro-logical disorders^66–69
Cysteine	Cys	Redox homeostasis, metabolism, protein synthesis, and signal transduction^70–72	Cardiovascular complications, neurotoxicity, Parkinson's disease, Alzheimer's disease, edema, lethargy, and liver damage^70–73
Glutathione	GSH	Redox homeostasis, growth and metabolism, oxidative stress and immune responses, and apoptosis^74–77	Parkinson's disease, liver injury, and cancer^78–81
Peroxynitrite	ONOO^−	Host defense, cell proliferation, and cell growth^82–84	Inflammation, cancer, atherosclerosis and neurodegenerative diseases^85–88
Hydrogen peroxide	H2O2	Immune responses, cellular signal transduction, regulation of oxidative stress, and stimulation of antioxidant defenses^89,90	Cancer,^91 diabetes,^92 cardiovascular diseases,^93,94 and neurodegenerative disorders^95
Hypochlorous acid	ClO^−	Neuronal aging, pathogen response, and anti-inflammatory regulation^96–101	Cardiovascular and kidney diseases, inflammatory disease, neuron degeneration, and cancer^57,58,102
Formaldehyde	HCHO	The carbon cycle metabolism process^103,104	Alzheimer's disease, cognitive impairment, neurodegenerative diseases, and atherosclerosis^105–108
β-Glucuronidase	GUS	Tumor invasion, and metastasis^109	/
β-Galactosidase	β-Gal	Gene expression and cellular senescence^110,111	Primary ovarian cancer^110,111
Phosphatase	ALP	Regulating phosphate metabolism^112,113	Diabetes, bone disease, liver dysfunction, and prostate cancer^114,115
Esterase	—	Gene expression, ester metabolism, material transport, and detoxification^116–118	Wolman disease, obesity, atherosclerosis, cancer, hyperlipidemia, and hepatic steatosis^119–124
Acetylcholinesterase	AChE	Metabolic processes^125	Salivation, convulsions, tremors, and even death^126,127
Leucine aminopeptidase	LAP	Leucine regulation^128,129	Hepatic dysfunction or liver cancer^130,131
Serum albumin	HSA	Maintaining colloid osmotic pressure, regulating free radicals, and transporting nutrients, fatty acids, and metabolites^132	Cardiovascular disease, kidney disease, hypertension, liver cirrhosis, and cancers^133

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ESIPT, as one of the most important photo-physical processes, has attracted substantial attention since its discovery by Weller in the 1950s.⁴⁰ The extraordinary structural feature of ESIPT emitters is that they always have an H-bond between the hydrogen bond donors (–OH, –NH₂, and –SH)^41–44 and hydrogen bond acceptors (=N, =S, and –C=O).^45–47 Upon irradiation, ESIPT emitters absorb the energy to achieve E* (excited state of Enol form). Then, ESIPT, a photoisomerization process, appears to form K* (excited state of Keto form) in less than 1 ps.^48,49 The decay of K* emits a much longer fluorescence than E* owing to the inner ICT effect arising from the electron-withdrawing property of ketone. Finally, the ground state of the Enol form (E) changes to its original state (ground state of the Keto form, K) called GSIPT (Ground-state Intramolecular Proton Transfer) (Fig. 1).^49,50 Benefitting from the transfer from the Enol form to the Keto form, the ESIPT emitters with two emissions could assist in obtaining ratiometric sensing, which could reduce the interference from the background.^48,50,51 Simultaneously, compared with traditional probes, such as fluorescein and rhodamine, annoying self-reabsorption and inner-filter effects are prevented in ESIPT emitters.^52–54 Consequently, ESIPT emitters are extensively used in biomarker detection.

Fig. 1 Process of excited-state intramolecular proton transfer (ESIPT).

Based on the feature of the ESIPT process, the general strategy for designing ESIPT-based probes is to influence the ESIPT process to achieve the alteration of fluorescence. The first and most common method involves replacing the hydrogen of the hydrogen bond donor to restrict the ESIPT process. Thus, the probes emit a short wavelength from the Enol form. However, the hydrogen bond is reconstructed by adding a specific biomarker that could activate the ESIPT process and emit long-wavelength fluorescence.^134–136 Another method of influencing the ESIPT process is destroying the hydrogen bond.^137–139 Strong acids are much more acidic than hydroxyl groups and can combine with hydrogen bond acceptors, preventing the ESIPT process. Considering the acidity of the hydroxyl group or amine group, it could react with the base, and the emission of the ESIPT-based probe would be blue shifted. Moreover, FRET-ESIPT, PET-ESIPT, and ICT-ESIPT processes are effective procedures to achieve the modification of fluorescence.^53,140 These combinatorial processes are instrumental in obtaining diversified fluorescence signals, so they are promising for designing multi-functional probes.

In this review, we highlight the design features of ESIPT emitters that have shown potential for detecting biomarkers. Moreover, the mechanism of the response to the biomarker is described. We focus on a method to optimize the optical properties and characteristics involved in biomarker detection. For example, some pesky problems, such as short wavelengths, inhibit the use of ESIPT-based fluorescent probes.^141–143 Thus, the Near-Infrared Red (NIR) emission is useful in biomarker detection. Finally, this review outlines the application of these probes in biomarker detection, disease treatment, clinical diagnosis, and high-accuracy imaging fields.

2. Inorganic biomarkers and detection methods

2.1 Acid and base

Acids and bases play essential roles in many physiological processes, such as cell proliferation and apoptosis, ion transport, enzyme activity, and protein degradation (Table 1). As shown in Fig. 2, ESIPT relies on photoisomerization, which can be influenced effectively by acids and bases. Feng et al. synthesized a ratiometric fluorescent sensor, Probe 1, for pH sensing based on the amino-type ESIPT process.¹⁴⁴ It is a promising sensor that responds rapidly and reversibly to pH changes after the introduction of a strong electron-withdrawing tosyl group. Probe 1 had a large Stokes shift in an acidic medium exhibiting yellow emission. In contrast, blue-shifted emission was observed in an alkaline medium owing to the deprotonation of the sulfonamide fraction, which suppressed the ESIPT process. A series of dual-factor-activated ESIPT probes are displayed in Fig. 3b, and we used Probe 2 as a typical example.¹⁴⁵Probe 2 displayed three distinct fluorescent signals, indicating that it could sort acidic, neutrophils, and basic granulocytes in the presence of naphthol-AS-D-chloroacetate esterase. Tang et al. reported a pH jump probe with a midpoint of 7.5, which is closely related to physiological pH.¹⁴⁶ The alterations in Probe 3 originated from the changes in Keto and Enol forms. Moreover, some applications, including cell imaging and pH fluctuation monitoring, are mentioned in these studies. For example, as the pH increased from 6.86 to 8.07, the fluorescence of Probe 3 increased in channel I (450–520 nm), accompanied by a decrease in channel II (520–600 nm), which demonstrated that the pH fluctuations could be monitored excellently by Probe 3 as a candidate molecule in live cells.

Fig. 2 The design strategy of ESIPT-based probes.

Fig. 3 (a) Proposed mechanisms for Probe 1 changes in acidic or basic media. (b) The mechanism of Probe 2 with NSA-DCE and different pH values. (c) The mechanism of Probe 3 to sense pH.

2.2 Carbon monoxide (CO)

CO is considered a signal molecule that regulates various physiological processes, including cytoprotection, anti-inflammation, organ transplantation survival, and bacterial growth inhibition. Furthermore, many diseases, including neurodegeneration, hypertension, heart failure, and inflammation, are associated with abnormalities in CO function (Table 1). The Tsuji-Trost reaction is a nucleophilic substitution reaction of allylation between allyl ether and CO, making it a promising choice for CO detection (Fig. 4a).^147,148 Furthermore, Probes 4 and 5 are fluorophores comprising ESIPT and ICT along with the Aggregation-Induced emission (AIE) phenomenon.¹⁴⁹Probe 4 encompasses three functional components (Fig. 4a): (a) AIE that originated from the rotators belonging to tetraarylimidazole; (b) two methoxyl groups introduced as electron donors and steric hindrance units; and (c) 2-(2′-hydroxyphenyl)-benzothiazole (HBT), a traditional fluorophore providing ESIPT property. In this review, AIE is not discussed because this phenomenon is widely observed in ESIPT materials.^150–152 Liu et al. replaced the hydroxyl groups with allyl formate and allyl ether to construct two ratiometric probes, Probes 4 and 5, respectively (Fig. 4b). In the presence of CO, Pd²⁺ is reduced to Pd⁰, which further catalyzed the cleavage of the acceptor fragment to release free hydroxyl groups. Both probes could be loaded onto a test strip to visualize CO in the air. It is noteworthy that they also exhibit great potential for observing the fluctuation of exogenous and endogenous CO induced by heme, lipopolysaccharides (LPS) and hypoxia.

Fig. 4 (a) General procedure for CO detection using the Tsuji-Trost reaction. (b) Design strategy for Probes 4 and 5 with multiple phenomena. (c) CO detection method using its reducing property.

Another method for CO detection is based on its reducing property. As shown in Fig. 4c, by reducing NO₂ to NH₂, the ESIPT is released, and this process could be seen as a kind of H-bond donor replacement method.¹⁵³Probe 6 was non-fluorescent; CORM-3 impelled the reduction of the nitro group, generating a highly fluorescent phthalimide (PTI), which emitted bright green fluorescence due to the ESIPT process. More importantly, this probe is promising for CO detection in living cells, zebrafish, and other animals.

2.3 Sulfites (SO₃²⁻/HSO₃⁻)

As a key role in regulating vascular smooth muscle tone and lowering blood pressure, Sulfur dioxide (SO₂) has attracted substantial research interest and has proven to induce many respiratory responses. It is related to serious diseases, including lung cancer, cardiovascular diseases, and neurological disorders (Table 1). Because of the high reactivity between SO₂ and the double bond, FRET-ESIPT and ICT-ESIPT are widely considered in detecting SO₂ (Fig. 5a and b). Peng's group constructed a new ratiometric Probe 7 based on the ESIPT-FRET platform.¹⁵⁴ 3-Hydroxyflavone (an ESIPT dye) was used as an energy donor, and a 2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran (TCF) fluorophore was used as a “two-in-one” ptor, which is an energy acceptor and SO₂ derivatives acceptor (Fig. 5c). More importantly, high resolution of the two emission peaks could be achieved because of the effective FRET before reacting with SO₂ and quenching FRET after the reaction. A similar procedure could be performed using probes with an ICT-ESIPT mechanism. Probes 8 and 9 with NIR emission at 716 nm and 686 nm, respectively, displayed good water-solubility, attributed to the hydrophilicity and electron-withdrawing property of thiazole salt moiety.¹⁵⁵ Then, with the addition of SO₂, the double bond between HBT or HBO and thiazole salt moiety disappeared, leading to the fluorescent changes in Probe 9. These probes were also successfully applied to visualize SO₂ levels in cells under oxidative stress.

Fig. 5 (a) General procedure for SO₂ detection based on FRET-ESIPT. (b) General procedure for SO₂ detection based on ICT-ESIPT. (c) Probe 7 and its detection procedure based on FRET-ESIPT. (d) Detection procedure for Probes 8 and 9 based on FRET-ESIPT.

Another method for monitoring SO₂ is introducing the 4-Oxopentanoic ester to replace the hydroxyl group. Lin's group developed a novel ratiometric probe, Probe 10, to monitor SO₂ using a unique fluorescent signal in mammalian cells, mouse embryonic fibroblasts, and zebrafish via ESIPT and AIE.¹⁵⁶ This probe was based on the novel AIE + ESIPT platform Probe 10-O with the sensing site levulinate moiety as the receptor and fluorescence quencher. When the hydroxyl group is substituted by levulinate, the inefficient ESIPT process forbids the long wavelength of Probe 10-O. Thus, Probe 10 would show blue fluorescence arising from the enol form. After treating with SO₂, the ESIPT was released with the deprotection of levulinate in Probe 10 exhibiting a yellow aggregation fluorescence signal. Therefore, the AIE + ESIPT dye in Probe 10 is promising for monitoring SO₂ (Fig. 6).

Fig. 6 (a) General procedure for SO₂ detection: introducing the 4-Oxopentanoic ester to replace the hydroxyl group. (b) Probe 10 and its detection procedure.

2.4 Peroxynitrite (ONOO⁻)

ONOO⁻, which is closely related to various significant physiological processes, such as host defense, cell proliferation, and cell growth, is a significant biomarker for detecting Alzheimer's disease, one of the neurodegenerative diseases (Table 1). Because peroxide has strong oxidability, borate esters are widely selected as substituents owing to their excellent reducibility. Simultaneously, the borate ester substance could block the ESIPT process; thus, the probes emitted weak fluorescence corresponding to the Keto form. Upon reacting with ONOO⁻, the benzyl borate group is shed, activating the ESIPT process and releasing long-wavelength fluorescence (Fig. 7a). Fig. 7b shows a series of probes for ONOO⁻ detection containing benzyl borate, which are reported by James group.^{135,136,157–159} They reported a ratiometric fluorescent, Probe 11.¹⁵⁷ The detection limit for ONOO⁻ was 21.4 nm, resulting in excellent detection efficiency at extremely low concentrations in few seconds. Additionally, Probe 11 could perform proportional imaging of endogenous and exogenous ONOO⁻ in HeLa cells. Prominently, the probe had excellent selectivity for the endoplasmic reticulum. Comparing the co-staining in HeLa cells with Probe 11 and commercial dyes, such as ER-, Lyso-, and Mito-Tracker Red, Pearson's correlation coefficient with ER-Tracker Red was 0.93. Then, they synthesized a boronate-based ESIPT fluorescent (Probe 12) that can bind amyloid-β aggregates to construct a ratiometric probe for ONOO⁻.¹³⁵ The probe blocked the ESIPT process by protecting the group with benzylborate, which could be particularly evacuated by ONOO⁻, leading to an “On” fluorescent probe suitable for detecting ONOO⁻. Furthermore, the probe exhibited excellent selectivity for ONOO⁻ compared with other reactive oxygen species (ROS). They performed fluorescence imaging of AD-transgenic mouse brains to investigate the potential of the probes for practical applications. They observed that brain slices of Aβ42 aggregates exhibit N-state fluorescence with Probe 12. After ONOO⁻ treatment, probes bound to the peptide aggregates in the brain slice and changed the fluorescence emission to the T* (the photo tautomeric form) state. Fluorescent Probe 13 with two-photon excitation was developed to detect ONOO⁻.¹⁵⁸Probe 13 was non-fluorescent. However, the phenol fraction was released when ONOO⁻ was added. Furthermore, Probe 13 exhibited high photo-stability under two-photon illumination at 750 nm, enabling the observation of endogenous ONOO⁻ in HeLa cells and exogenous ONOO⁻ in rat hippocampal slices at a depth of 110 μm. Moreover, two-photon ONOO⁻ex vivo and in vitro imaging was performed using an ESIPT-based benzimidazole fluorescence platform.¹³⁶ Each platform enabled the rapid detection of micromolar concentrations of ONOO⁻. Importantly, Probe 14 was used for the ratio detection of endogenous ONOO⁻ in RAW264.7 macrophages and rat hippocampus tissue.

Fig. 7 (a) General procedure for detecting ONOO⁻ based on ESIPT-based probes. (b) Probes for ONOO⁻ detection. (c) Multifunctional Probe 15 and its “AND” logic detecting processes for ONOO⁻ and GSH.

Probe 15 was highlighted as the special double function with “AND” logic (Fig. 7c).¹⁵⁹ The ESIPT process of Probe 15 with benzyl borate was blocked, which acted as a reaction unit of ONOO⁻. Probe 15 was functionalized as an amino group to recognize thioalcohol, which assisted in fluorescence quenching through the PET process. The fluorescence intensity rapidly recovered in the presence of biothiols. Therefore, the probe yielded an efficient PET + ESIPT with “AND” logic. Additionally, the probe exhibited high sensitivity and selectivity for biological thiols and ONOO⁻, and it visualized exogenous ONOO⁻ and GSH in living cells.

2.5 Hydrogen peroxide (H₂O₂)

Hydrogen peroxide (H₂O₂), which is a typical member of reactive oxygen species (ROS), plays an essential role in immune responses, cellular signal transduction, oxidative stress regulation, and antioxidant stimulation in high-oxygen-stressed tissues. Similar to other ROS, abnormal levels of H₂O₂ in the body can lead to cancer and neurodegenerative diseases. In addition, H₂O₂ is closely related to other diseases, such as diabetes and cardiovascular diseases (Table 1). Considering that H₂O₂ has similar oxidative properties with ONOO⁻, benzyl borate substituent is used as the recognition group for H₂O₂ owing to the high oxidative activity of H₂O₂ (Fig. 8a). Zeng et al. designed and synthesized a HBT-based fluorescent Probe 16.¹⁶⁰ Boronesterification of phenol could interrupt the intramolecular hydrogen bond, leading to the blockage of the ESIPT process and inactivating the AIE effect (Fig. 8b). H₂O₂ and Probe 16 underwent phenylboronic oxidation and 1,6-elimination to regenerate p-BHBT and recover ESIPT-AIE fluorescence. Probe 16 could selectively and sensitively monitor H₂O₂ in an aqueous solution or living cells with the assistance of AIE + ESIPT, so it is a promising contender for H₂O₂ detection accurately and highly efficient. Liu et al. explored an H₂O₂ fluorescent probe based on the ESIPT dye, 1,3-bis(bispyridin-2-irimo) isoindole-4-ol, by choosing an aromatic boronic ester group as the responsive moiety (Fig. 8b).¹⁶¹ The introduced functional unit masked the hydroxyl group to block the proton transfer process and quench its fluorescence. In the occurrence of H₂O₂, the responsive moiety is cleaved in Probe 17, followed by fluorescence recovery. Significantly, Probe 17 exhibited outstanding performance in detecting intracellular H₂O₂ in living cells. Tang et al. reported a new ratiometric H₂O₂ fluorescent probe, Probe 18 (Fig. 8b), by utilizing phenylboronate as the recognizing group and an ESIPT blocking moiety.¹⁶² In the occurrence of H₂O₂, oxidation and 1,6-elimination reactions were conducted to release the phenolic hydroxyl group and then regain the long-wavelength emission belonging to the Enol form. It is noteworthy that Probe 18 had been used to image the exogenous and endogenous H₂O₂ in A549 cells. Chen et al. proposed a water-soluble ESIPT ratiometric fluorescent probe, Probe 19, with NIR emission, which specifically reacts with H₂O₂ through oxidation and 1,6-elimination with the release of Probe 19 appearing as NIR emission (Fig. 8b).¹⁶³ Moreover, Probe 19 was applied to detect intracellular H₂O₂ in live cells and zebrafish. When the zebrafish were treated with Probe 19 alone, green fluorescence corresponding to the Enol form was observed. Exogenous H₂O₂ injection into zebrafish would provoke the crack of phenylboronate and a visual red fluorescence could be clearly witnessed. Compared with Probe 19 alone, the red channel fluorescence signal was significantly increased after stimulation with PMA (phorbol ester), indicating an increase in endogenous H₂O₂ (Fig. 8c). Subsequently, by treating with the inhibitor NAC (acetylcysteine), the red fluorescence in zebrafish was reduced, along with the enhancement of green fluorescence, demonstrating that NAC could effectively eliminate the increase in endogenous H₂O₂ arisen from PMA. These studies confirmed that Probe 19 is a promising tool for assessing and inspecting exo-/endogenous H₂O₂ in living zebrafish.

Fig. 8 (a) General procedure for detecting H₂O₂ with ESIPT-based probes. (b) Probes for H₂O₂ detection. (c) Confocal fluorescence images for H₂O₂ in zebrafish. Control group: untreated zebrafish; Probe 19 (HBQ-B) group: zebrafish treated with Probe 19 (10 μM); H₂O₂ group: zebrafish treated with H₂O₂ (40 μM) and Probe 19 (10 μM); PMA group: treated with PMA (3 μg mL⁻¹) and Probe 19 (10 μM); PMA + NAC group: zebrafish treated with PMA (3 μg mL⁻¹), NAC (1 mM), and Probe 19 (10 μM). (left) Confocal fluorescence images of H₂O₂ in various developmental stages of zebrafish. Zebrafish at 2, 6, 12, 24, 36, 48, and 72 hpf. (right) (d) The proposed reaction mechanism of Probe 20 with the ICT-ESIPT process. (c) Reprinted (adapted) from ref. 163 with permission from Elsevier, copyright 2022.

He et al. developed the ESIPT-based Probe 20, a novel mitochondria-targeting fluorescent probe, with distinctive ICT changes in contact with H₂O₂.¹⁶⁴ Phenylboronate substituted the quinoline moiety, forming a quinoline salt with considerable electron-withdrawing property, which prolonged the emission to achieve the NIR/red fluorescence of Probe 20. In the presence of H₂O₂, double step reactions occurred containing borate oxidation and 1,6-elimination reactions, resulting in the appearance of HK with fluorescence at 594 nm (Fig. 8d). Remarkably, laser scanning confocal microscopy was employed to observe exogenous and endogenous H₂O₂ in live HeLa cells after treating Probe 20. The excellent results demonstrate that Probe 20 possesses outstanding prospects in biological applications.

2.6 Hypochlorous acid (HClO)

Hypochlorous acid (HClO) is a vital member of ROS, which is linked to the risk of cardiovascular, inflammatory, kidney diseases, and neuron degeneration (Table 1). N,N-Dimethylamino-thiomethyl ester is an excellent substrate for recognizing HClO, with the assistance of a hydrolyzing reaction (Fig. 9a). Wu et al. constructed an ESIPT-based Probe 21 with excellent HClO/ClO⁻ responsiveness.¹⁶⁵ On adding HClO, the protecting group was removed, and a strong emission could be observed. With great sensitivity and selectivity, the probe was applied to the endogenous and exogenous detection of HClO/ClO⁻ in HeLa cells. Moreover, considering that HClO has relative acidity, a novel on–off Probe 22 was reported by Young et al., which could selectively monitor HClO with high solubility in 100% aqueous solution (Fig. 9c).¹⁶⁶ With the appearance of HClO, the ESIPT process was forbidden, exhibiting shorter wavelength emission than the Keto form. Probe 22 possessed a low limit level of 8.2 × 10⁻⁹ M over a wide pH range of 5–11. Moreover, Probe 22 was successfully applied to the physiological system.

Fig. 9 (a) General procedure for detecting HClO with ESIPT-based probes. (b) The proposed reaction mechanism of Probe 21. (c) The proposed reaction mechanism of Probe 22.

2.7 Formaldehyde (HCHO)

Excess HCHO in the human body can cause many diseases, including Alzheimer's disease, cognitive impairment, neurodegenerative diseases, and atherosclerosis (Table 1). HCHO with exceptional reactivity can be monitored using the ICT-ESIPT and PET-ESIPT methods. As shown in Fig. 10a, Zhou et al. designed a new ratio of fluorescence Probe 23 for detecting HCHO in air and water based on the aza-Cope reaction.¹⁶⁷ Before reacting with HCHO, the weak ICT endowed probes with short-wavelength emission at 462 nm owing to the electron-donating moiety weakening ICT. After adding HCHO, the aldehyde group as an electron-withdrawing group strengthened the ICT, and emission at 525 nm appeared. Additionally, the probe could be applied for the visual detection of gas FA and its fluorescence ratio in calf serum. Moreover, Probe 24 with PET-ESIPT was designed by Zeng et al. (Fig. 10b).¹⁶⁸ Secondary ammonia has a strong nucleophilic attacking ability, which promoted the formation of β-hydroxy tertiary ammonia. Next, the formative hydroxyl group attacked the five-membered ring, linked to nitrogen (an electronic donor in the PET process), forming a six-membered azalactone. After the rearrangement of 2-aza-Cope in an aqueous solution, the C-N bond was broken owing to chemical structural instability. This structural change was followed by PET removal, leading to turn-on emission. Then, Probe 24 was used in imaging for FA in live AD mouse brain tissues.

Fig. 10 (a) Reaction between probe Probe 23 and FA (formaldehyde) with weakened ICT-ESIPT and strengthened ICT-ESIPT. (b) The proposed reaction mechanism of Probe 24 with the PET-ESIPT process.

3. Organic biomarkers and detection methods

3.1 Cysteine (Cys)

Cys is an amino acid that participates in physiological processes, such as redox homeostasis, metabolism, protein synthesis, and signal transduction. Abnormal levels of Cys can trigger many diseases, including cardiovascular disease, neurotoxicity, Parkinson's disease, Alzheimer's disease, edema, lethargy, and liver damage (Table 1). As shown in Fig. 11a, β-aminothiol can react with acrylic esters in two steps containing Michael addition and nucleophilic addition reactions under ambient conditions. With the sloughing of the acrylic ester moiety, the exposed hydroxyl group ensures the ESIPT process, and the probe emits strong fluorescence.^169,170 Based on the method, many probes have been synthesized in the past few years. In Fig. 11b, we list some of them that could release red or NIR emissions after reacting with Cys.^171–176 NIR probes are outstanding in expanding tissue penetration depth, and one of the promising routes to obtaining NIR probes is introducing an electron-withdrawing moiety, such as pyranonitrile and pyridine salt. As shown in Fig. 11, this method was successfully utilized in in vitro and in vivo experiments, as discussed below. Probe 25 is an HBT-based (benzothiazole-based) fluorescent probe with a large Stokes shift (263 nm) emitting NIR fluorescence at 673 nm.¹⁷¹ It was successfully applied in Cys detection with high selectivity and sensitivity, and its detection limit was as low as 6.51 × 10⁻⁶ M. By introducing a strong electronic acceptor group dicyanoisophorone to the HBT fluorophore, Probe 26 emitted NIR fluorescence and was sensitive to Cys with a detection limit of 0.20 μM at pH 8.0 and 0.98 μM at pH 7.4.¹⁷² When Probe 26 reacted with Cys, a kinetically advantageous seven-membered ring was formed rapidly. In contrast, an eight-membered ring was formed slowly when in contact with homocysteine (Hcy), and the reaction with glutathione (GSH) or H₂S could not be observed, so ESIPT-based Probe 26 was an excellent choice for the selective detection of Cys. Chen et al. designed a novel biflavone derivative, Probe 27, that could be located in the mitochondria without targeted groups, which exhibited ESIPT and showed visible monitoring of Cys with a large Stokes shift (approximately 260 nm).¹⁷³Probe 28 was synthesized and grafted HBT in SCM-based ICT scaffolds by converting electron-withdrawing members from DCM to SCM and detected Cys with short-wave infrared (SWIR, 900–1700 nm).¹⁷⁴ In collaboration with the ICT and ESIPT processes, SH-OH exhibited a NIR maximum absorption, SWIR emission, large Stokes shift, and excellent photostability. Long et al. designed an NIR two-photon fluorescence Probe 29 using an HBT derivative as fluorophore and implanting a butadienyl-N-methylpyridinium moiety.¹⁷⁵ The selective detection of the photoluminescence mechanism of Cys by Probe 29 was considered ESIPT and ICT. It had a superior NIR fluorescence emission enhancement (713 nm), a significant Stokes shift (302 nm) and a two-photon absorption cross-section (213.5 GM at 820 nm). Successful application in Cys imaging was conducted by one/two photon imaging in live cells, zebrafish, live mouse brains or abdominal cavities. Zhao et al. reported a novel ESIPT-ICT-based NIR fluorescent Probe 30, with acrylate as the recognition group for the detection of Cys.¹⁷⁶ The positively charged methylquinoline group of Probe 30 provided ICT and increased the emission wavelength. When Probe 30 reacted with Cys, the product further underwent intramolecular cyclisation, thus releasing Probe 30 with the advantages of long-wavelength emission at 740 nm and a large Stokes shift of 310 nm. Probe 30 could recognize Cys with high selectivity and sensitivity at pH = 5.5–8.0, and it has been successfully used to specifically recognize Cys in A549 cells. Moreover, we chose Probe 28 as a typical example for cell and living mouse imaging, owing to the near 950 nm emission (SWIR region) of Probe 28 (Fig. 11c–e). As shown in Fig. 11c, the SWIR signal was obviously obtained when treated with Probe 28. Moreover, they evaluated the in vivo performance of Probe 28 as a cis-activated SWIR probe using PerkinElmer IVIS spectroscopy. Then, real-time in vivo monitoring of Cys in mouse tumours was implemented. The SWIR emission was immediately displayed after injecting with Probe 28 in nude mice, indicating that Probe 28 is a sensitive probe for endogenous Cys.

Fig. 11 (a) General procedure for Cys detection by replacing the hydrogen of the hydrogen donor with ESIPT-based probes. (b) Probes for Cys detection. (c) Confocal laser scanning microscope (CLSM) images of HeLa cells incubated with different compounds (100 μmol L⁻¹), such as SCM-OH, probe SOC, exogenous Cys and SOC, NEM, and SOC, for 1 h. Note: the NIR fluorescence intensity monitored channel was obtained in the range of 740 nm to 760 nm, λ_ex = 605 nm. (d) Plate fluorescence imaging of SH-OH (10 μmol L⁻¹), Probe 28 (SHC) (10 μmol L⁻¹) and Probe 28 (10 μmol L⁻¹) incubated with Cys (100 μmol L⁻¹), yellow-red scale. (e) In vivo SWIR fluorescence imaging (rainbow scale) of mice with HeLa xenograft after in situ injections of Probe 28 at various times (1 min, e1; 5 min, e2; 25 min, e3; 60 min, e4). Note: λ_ex = 600 nm, SWIR fluorescence signal monitored at 950 nm. (c–e) Reprinted (adapted) from ref. 173 with permission from Elsevier, copyright 2022.

Despite the method mentioned above, PET is a tool to lock the emission before reacting with Cys and release the fluorescence after reacting with Cys. Maleimide is a useful recognition functional group that provides lone-pair electrons to occupy the empty orbit after excitation, and it can react with Cys, which is attributed to the reducibility of Cys (Fig. 12a). Feng et al. reported a fluorescent Probe 31 that could successfully distinguish Cys from other biothiols (GSH and Hcy) having a similar structure and reactivity to Cys, with high sensitivity (the ultralow detection limit at 9.4 nM) (Fig. 12b).¹⁷⁷ Strong fluorescence emission at 503 nm occurred by yielding amino-adducts when Probe 31 reacted with Cys. In the case of GSH, the thermodynamic hindrance of a 10-membered cyclic transition state was created, and the adjacent amino group was interrupted by the glutamyl group, preventing visual observation. Although the cyclic transition state of Hcy was thermodynamically allowed, the increased carbon chain led to a slower cascade reaction, reducing the number of amino adducts produced at the same reaction time with only weak fluorescence. Moreover, they successfully applied Probe 31 to detect Cys in test papers and to the imaging of Cys in A549 live cells. This method is significant in Cys detection, especially for multi-functional applications, owing to the rich functionalizing possibilities of free hydroxyl groups. Thus, detailed examples are mentioned again in the next section.

Fig. 12 (a) General procedure for Cys detection based on PET-ESIPT-based probes. (b) Probe 31 and its mechanism for distinguishing Cys, GSH, and Hcy.

3.2 Glutathione (GSH)

When discussing intracellular redox homeostasis, growth and metabolism, oxidative stress, immune responses, and apoptosis, GSH is always considered to play a significant role in these biological processes. Simultaneously, abnormal concentrations of GSH are important transmission signals for many diseases, including Parkinson's disease, liver injury, and cancer (Table 1). GSH can be monitored by introducing an acrylic ester moiety, which is similar to the detection method of Cys (Fig. 13a). Zhang et al. reported an HBT-based fluorescent, Probe 32, that has specific double functions, which could emit infrared fluorescence (684 nm) reacting with GSH and blue fluorescence (469 nm) reacting with Arg (Arginine).¹⁷⁸ The detection of GSH, which depends on the Michael addition reaction and ester lysis, exhibited NIR emission owing to the ESIPT process. However, ESIPT was inhibited in the presence of Arg attributed to the suitable basicity and acidity of benzothiazole and Arg, respectively. Hence, this strategy provides an outstanding method for preparing multi-functional probes using various procedures, including chemical reactions and weak intermolecular interactions.

Fig. 13 (a) General procedure for GSH detection based on the ESIPT process. (b) Proposed mechanisms of Probe 32 for GSH and Arg detection.

Considering the acidity of GSH, it could influence the ESIPT process with a dominant blue shift (Fig. 2, Method 2). Ren et al. reported a series of fluorescent Probes 33, 34, and 35 based on HBT derivatives for detecting GSH (Fig. 14).¹⁷⁹Probe 33 could respond to GSH reversibly and rapidly compared with Probes 34 and 35. The proton transfer from OH to C=N in the excited state contributed to Probe 33 emitting double emission (Enol and Keto forms). Conversely, the presence of GSH prevented the formation of the hydrogen bond between “C=N” and “COOH”, which blocked ESIPT and stabilized the conformation of the probe-GSH adduct. Consequently, this process assisted in emitting the blue-shifted emission arising from the ICT process.

Fig. 14 Proposed mechanisms of Probes 34, 33, and 35 with GSH.

3.3 β-Glucuronidase (GUS)/β-galactosidase (β-gal)

GUS, a matrix degradation enzyme, is involved in tumor invasion and metastasis, and it acts as an important biomarker for Escherichia coli (E. coli) (Table 1). β-Gal is generally considered a reporter for monitoring gene expression and a significant biomarker for primary ovarian cancer and cellular senescence (Table 1). Galactoside is an efficient substrate for the recognition of β-glucuronidase and β-galactosidase because of its enzyme specificity (Fig. 15a). Wu and his colleagues introduced a GUS activation unit into a water-insoluble fluorophore HBT with ESIPT and AIE effects (Fig. 15b).¹⁸⁰ The probe had high selectivity, low toxicity, and good cell permeability and sensitivity. Probe 36 emitted strong fluorescence at 519 nm via UV excitation. Hu and colleagues reported a novel fluorescent Probe 37 for the detection of β-gal activity (Fig. 15b).¹⁸¹ The probe was based on a hydroxyphenylquinazolinone (HPQ) chromophore with AIE and ESIPT effects. The β-galactopyranoside group bond of Probe 37 quenched the fluorescence owing to breaking the intramolecular hydrogen bond and preventing the ESIPT process. After adding β-gal, an efficient enzymatic hydrolysis occurred, releasing the green chromophore. HPQ exhibited enhanced fluorescence because of ESIPT between the phenolic hydroxyl group and the imine moiety. Owing to its high sensitivity, good selectivity, and large Stokes shift, this probe can well image intracellular β-gal activity.

Fig. 15 (a) General procedure for detecting GUS/β-gal with ESIPT-based probes. (b) Probes for GUS detection. (c) The strains grown for 18 h at 37 °C in the air were observed under visible light (left), and 375 nm UV flashlight excitation (right), dying by Probe 36. (c) Reprinted (adapted) from ref. 180 with permission from Elsevier, copyright 2022.

Because β-gal is involved in the significant process in coli, we focus on coli imaging, which is an important application for fluorescent probes (Fig. 15c). Probe 36 was designed as a new type of chromogenic fluorescent medium (C–F E. coli agar) by observing the activity of β-gal in Escherichia coli (E. coli O157:H7) and non-O157:H7 E. coli for effective monitoring and separation. The chromogenic substrates 5-bromo-6-chloro-3-indolyl-β-D-galactoside (Magenta-Gal) and 5-bromo-4-chloro-3-indolyl-β-D-glucoside (X-Glu) were added to C–F E. coli agar. Then, E. coli O157:H7 ATCC 35150, E. coli ATCC 25922, Enterobacter sakazakii ATCC 29544, and Salmonella typhimurium ATCC 14028 were inoculated at the upper right, upper left, lower left and lower right of the C–F E. coli agar plates, respectively. As shown in Fig. 15c, these species were distinguished by excitation with visible light and 375 nm UV light.

3.4 Phosphatase (ALP)

Alkaline Phosphatase (ALP) is a widespread hydrolase in living organisms that can regulate phosphate metabolism. Abnormal fluctuations in ALP serum levels are important for diagnosing diseases, including diabetes, bone disease, liver dysfunction, and prostate cancer (Table 1). By replacing the phenol with phosphate, the probes could effectively respond to ALP through a simple enzymatic reaction (Fig. 16a). Zhang et al. reported a new fluorescent Probe 38 for the detection of ALP activity in aqueous buffers and various cell lines.¹⁸² ALP selectively reacted with the phosphate group, and then the hydroxyl group was released to form a fluorescent compound SA (salicylaldazine), which had the characteristics of AIE + ESIPT. Probe 38 selectively exhibited a fast and 240-fold turn-on ratio in response to ALP. It presents the ability to identify and visualize endogenous ALP activity in various cell lineages, including human osteoblasts, mouse melanoma cells, and macrophages. Yang et al. employed the ESIPT fluorophore N-(3-(benzo[d]thiazol-2-yl)-4-hydroxyphenyl) benzylamide to design a ratiometric Probe 39 for ALP detection.¹⁸³ By enzymatic dephosphorylation, Probe 39 exhibited a large red shift (120 nm) and high sensitivity for ALP sensing at 0.004 mU mL⁻¹. Enzymatic dephosphorylation converted the probe to fluorophore, followed by conspicuous fluorescence changes. Thus, the probe exhibited high sensitivity to ALP, with an extremely low detection limit (0.004 mU mL⁻¹). Then, this probe was applied to monitor endogenous ALP in living cells (HeLa cells) and exhibited excellent biocompatibility. By regulating the protection and deprotection of hydroxyl groups, Ding et al. announced a novel mitochondrial-targeted ratiometric fluorescent Probe 40 with ESIPT characteristics for ALP recognition and visualization.¹⁸⁴ The probe was highly soluble in water and emitted green fluorescence in aqueous buffers by blocking ESIPT. As the ALP increased, the fluorescence changed from green to red (650 nm), along with ESIPT recovery. The probe could quantify ALP activity from 0 to 60 mU mL⁻¹ with a minimum LOD of 0.072 mU mL⁻¹. It could also be used to detect ALP in serum samples, HeLa and A549 cell lines, and tumor-bearing BALB/c nude mice.

Fig. 16 (a) General procedure for detecting ALP with ESIPT-based probes. (b) Probes for ALP detection.

3.5 Esterase

Esterase catalyzes the esterification reaction, which plays an important role in human physiological processes, such as gene expression, ester metabolism, material transport, and detoxification. As an important biological enzyme, its deletion or abnormal expression is directly related to many diseases, such as Wollman's disease, obesity, atherosclerosis, cancer, hyperlipidemia, and fatty liver. (Table 1). Normally, an ester bond is introduced to block the ESPIT process. Once reacted with specific esterase, the ester group is cleaved by turning on the ESIPT process (Fig. 17a). Tian et al. developed a fluorescent Probe 41 that distinguished living and dead cells in two-color mode by esterification of 3-hydroxyflavones (Fig. 17b).¹⁸⁵ They proved that the probe could be degraded to 3-hydroxyflavonoid by active esterase, and the ESIPT process was restored, with an orange fluorescence peak at 570 nm in living cells. In dead cells, the esterase was inactivated with blue emission peaks at 440 nm, preventing the ESIPT process. Thus, this probe is promising for distinguishing between living and dead cells because it can provide accurate information in biological applications. Chen et al. designed and synthesized three fluorescent probes based on HBT derivatives (Probes 42, 43 and 44) to detect esterase (Fig. 17b).¹⁸⁶ Based on the ESIPT effect, acetoxymethyl (AM) ether was introduced on HBT as the recognition group. Under esterase catalysis, the recognition group was converted to a hydroxyl group, which led to the release of the fluorescence signal. Moreover, dipstick experiments showed that the probes recognized esterase accompanied by significant color changes. Importantly, this kind of probe is more suitable for detecting and visualizing endogenous esterases in biological environments.

Fig. 17 (a) General procedure for detecting esterase with ESIPT-based probes. (b) Probes for esterase detection.

AChE, a special esterase and the target enzyme for nerve agents, is a biological enzyme involved in the metabolic processes of the human body (Table 1). Once bound to the nerve agent, it inhibits the hydrolysis of the neurotransmitter acetylcholine, leading to neurological problems, such as salivation, convulsions, tremors, and even death. In general, butyrylcholinesterase was selected as the recognition group, which was bound by esterification to fluorophores, turning off the fluorescence (Fig. 18a). Meng et al. reported the fluorescence sensor Probe 45, which can selectively detect the activity of real nerve agents and AChE (Fig. 18b).¹⁸⁷ Given that this probe had a dual recognition of nerve agents and AChE, Probe 45 changed from no fluorescence to blue fluorescence when exposed to nerve agent and produced orange fluorescence when exposed to AChE under excitation at 365 nm. Benefiting from the excellent properties of the probe, it was used to monitor the concentration of nerve agent and AChE activity conditions of Probe 45 in living cells. They also used Probe 45 to diagnose neurotoxin intoxication by identifying the AChE activity in the entire blood.

Fig. 18 (a) General procedure for detecting AChE with ESIPT-based probes. (b) Probe 45 for AChE and nerve agent detection based on ESIPT.

3.6 Leucine aminopeptidase (LAP)

As a catalytic enzyme, LAP is involved in many important physiological processes in the human body, and disorders of catalytic function are accompanied by diseases, such as hepatic dysfunction or liver cancer (Table 1). Based on the specificity of the enzymatic reaction, leucine is an ideal substrate for the recognition of LAP (Fig. 19a). Zeng et al. developed the first tetraarylimidazole-based AIE fluorophore by substituting different aryl groups at the 4,5 positions (Fig. 19b).¹⁸⁸ Leucine was elaborately introduced to replace the hydrogen bond donor and prohibited ESIPT. Therefore, only short-wavelength emission belonging to the Enol form was perceived. In the presence of LAP, the blocking moiety Leucine was cleaved from the fluorophore along with the release of fluorescence attributed to the AIE and ESIPT. The HBT backbone enabled the fluorophore to exhibit AIE-assisted ESIPT emission at 554 nm, and the obtained Probe 46 was the first probe to combine the AIE with the ESIPT mechanism for precise LAP ratio tracking. Probe 46 possessed a promising ability for sensitive and selective LAP detection in hepatoma cells and zebrafish liver lesions with a large Stokes shift and considerable biocompatibility.

Fig. 19 (a) General procedure for LAP detection with ESIPT-based probes. (b) Probe 46 and its detection of LAP.

3.7 Serum albumin (HAS)

Serum albumin (HSA), which is particularly abundant in the human circulatory system, is closely related to various physiological processes, including the maintenance of colloidal osmotic pressure, the regulation of free radicals, and the transport of nutrients, fatty acids, and metabolites. Additionally, abnormal HSA levels in humans can exhibit various symptoms of the disease, including cardiovascular disease, kidney disease, hypertension, liver cirrhosis, and even cancers (Table 1). Owing to the Lewis acidity from hydrogen and Lewis basicity from the carbonyl group of amide, serum albumin could be sensed by method 2, as depicted in Fig. 2. Huang et al. designed a new fluorescent Probe 47 (Fig. 20).¹⁸⁹ The hydroxyl substituent at the specific site in the probe could change the binding site from DS1 (drug site 1) to DS2 (drug site 2) and then restore the ESIPT process of the probe, thus showing a unique dual emission response to HSA. The binding mode of Probe 47 to HSA was confirmed by site-specific competition experiments and molecular docking techniques, and the specific binding of flavonoids to DS2 was confirmed for the first time.

Fig. 20 Structural description of fluorescent Probe 47 and reaction mechanism with arginine.

4. Conclusions and future work

In this review, we investigated the function of some significant biomarkers, possible diseases closely related to them, and the corresponding probes for biomarker detection. Considering some features, including high efficiency, low background interference, and good structural adjustability, ESIPT probes explored in the past five years are emphasized. To functionally monitor specific biomarkers, three major design strategies for ESIPT probes are generally utilized: (1) replacing hydrogen of hydrogen bond donor, (2) destroying hydrogen bond by acid or base, and 3) combining with other electron transfer or energy transfer processes, such as FRET-ESIPT, PET-ESIPT, and ICT-ESIPT. From this perspective, we carefully summarize and classify a series of ESIPT-based probes using deserve strategies. Simultaneously, attributed to the limitation of organizational penetration, NIR ESIPT probes, and their design strategies, such as introducing electron-withdrawing groups, are all highlighted. Moreover, in addition to in vitro experiments, some biological applications are mentioned, including cells, bacteria, and animal experiments.

Through this feature article, we have emphasized recent progress made in the development of ESIPT-based fluorescent probes. Despite these successes, exploring NIR probes with a high quantum yield is still of vital significance to increase the depth of tissue penetration. Additionally, ESIPT probes with a long lifetime might be another rising field, including ESIPT-based chemiluminescence and Thermal Activation Delayed Fluorescence (TADF) probes, showing advantages in observing long-term biological processes.^190–193 It is definite that the ESIPT-based fluorescent probes for biomarker detection will still be a challenging and flourishing area with developing measurement techniques and pluralistic biomarker probes, assisted by improved targeting properties, efficient recognizing groups, and excellent photophysical properties. We hope this feature article will inspire researchers to construct more novel, powerful and not-yet-involved probes.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Key R & D Program of China (2021YFC2103600), the National Natural Science Foundation of China (22278224, 21978131, and 21878156), the Natural Science Foundation of Jiangsu Province (BK20200691), the Project of Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and the State Key Laboratory of Materials-Oriented Chemical Engineering (KL21-08).

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Footnote

† These authors contributed equally to this work.

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