Chemiluminescence resonance energy transfer: From mechanisms to analytical applications

Journal Pre-proof Chemiluminescence resonance energy transfer: from mechanisms to analytical applications Yongcun Yan, Xin-yan Wang, Xin Hai, Weiling Song, Caifeng Ding, Jingyu Cao, Sai Bi PII:

S0165-9936(19)30564-3

DOI:

https://doi.org/10.1016/j.trac.2019.115755

Reference:

TRAC 115755

To appear in:

Trends in Analytical Chemistry

Received Date: 30 September 2019 Revised Date:

21 October 2019

Accepted Date: 22 November 2019

Please cite this article as: Y. Yan, X.-y. Wang, X. Hai, W. Song, C. Ding, J. Cao, S. Bi, Chemiluminescence resonance energy transfer: from mechanisms to analytical applications, Trends in Analytical Chemistry, https://doi.org/10.1016/j.trac.2019.115755. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

Chemiluminescence resonance energy transfer: from mechanisms to analytical applications

Yongcun Yan,a Xin-yan Wang,a Xin Hai,a Weiling Song,b Caifeng Ding,b Jingyu Cao,c Sai Bia,c,*

a

Center for Marine Observation and Communication, Research Center for Intelligent

and Wearable Technology, College of Chemistry and Chemical Engineering, Qingdao University, Qingdao 266071, PR China b

Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science,

MOE, Shandong Key Laboratory of Biochemical Analysis; Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong; College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, PR China c

Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao

University, Qingdao 266003, PR China *Corresponding author. E-mail: [email protected].

1

Abstract Chemiluminescence resonance energy transfer (CRET) is a non-radiative transfer of energy from chemiluminescence (CL) reagent to energy acceptor during the CL reaction. The reaction process does not require excitation from external source, so CRET-based assays have low background and high sensitivity. Recently, efficient energy transfer systems have been proposed and a variety of nanomaterials with different functions have been presented as acceptors. Among them, the "signal-on" type acceptors (e.g., fluorescence dye, quantum dots and semiconducting polymer) can increase the CL intensity effectively, while the "signal-off" type acceptors (e.g., gold nanoparticle and carbon nanomaterials) have highly quenching efficiency. The development of the acceptors has extended the applications of CRET ranging from biosensing and bioimaging to biomedicine and therapy. In this review, the CRET modes are divided according to the type of acceptors based on the different energy transfer mechanisms. Their recent advances and future prospect are summarized and discussed. Keywords: chemiluminescence resonance energy transfer (CRET); energy acceptor; nanomaterials; biosensing; imaging; theranostics

Abbreviations ABEI, N-(4-aminobutyl)-N-ethylisoluminol; ACQ, aggregation-caused quenching; AEAP-POSS, 3-(2-aminoethylamino)propyl]trimethoxysilane-polyhedral oligomeric silsesquioxanes; AIE, aggregation-induced emission; AuNPs, gold nanoparticles; BP QDs, black phosphorus QDs; C-CRET, cascaded chemiluminescence resonance energy transfer; CDNs, constitutional dynamic networks; CEA, carcino-embryonic antigen; CHA, catalytic hairpin assembly; CL, chemiluminescence; CNPs, carbon nanoparticles;

CNTs,

carbon

nanotube;

CPPO,

bis[3,4,6-trichloro-2-(pentyloxycarbonyl) phenyl] oxalate; CRET, chemiluminescence resonance energy transfer; CRP, C-reactive protein; Cu2+-NMOFs, Cu2+-modified metal-organic framework nanoparticles; DNA-4WJ, DNA four-way junction; Exo III, 2

exonucleases III; FA, folic acid; FAM, fluorescein amidite; FITC, fluorophore isothiocyanate; FRET, fluorescence resonance energy transfer; GO, graphene oxide; GQDs, graphene quantum dots; HCR, hybridization chain reaction; HPOX, hydroxybenzyl alcohol-incorporated copolyoxalate; HRP-anti-IgG, HRP-labeled goat antihuman human immunoglobulin G; LDHs, layered double hydroxides; m-THPC, meta-tetra(hydroxyphenyl)-chlorin;

MEH-PPV,

poly[2-methoxy-5-((2-ethylhexyl)oxy)-p-phenylenevinylene];

MGO,

magnetic

graphene oxide; MIP, molecular imprinted polymer; MOFs, metal-organic frameworks; MPs, magnetic particles; N-dots, nitrogen quantum dots; NIR, near-infrared; OA-BP QDs, oleic acid capped black phosphorus QDs; Pdots, semiconductor

polymer

nanoparticles;

PDT,

photodynamic

therapy;

PFPV,

poly[(9,9’-dioctyl-2,7-divinylene-fluorenylene)-alt-2-methoxy-5-(2-ethyl-hexyloxy)-1 ,4-phenylene];

PEG-PCL,

poly(ethyleneglycol)-co-poly(caprolactone);

PFBT,

poly[9,9′-bis(6″-N,N,N-trimethylammonium)hexyl)fluorene-co-alt-4,7-(2,1,3-benzoth iadiazole)dibromide];

PFODBT,

poly(2,7-(9,9-dioctylfluorene)-alt-4,7-bis(thiophen-2-yl)benzo-2,1,3-thiadiazole); POCL, peroxyoxalate chemiluminescence; QDs, quantum dots; RET, resonance energy transfer; RNS, reactive nitrogen species; ROS, reactive oxygen species; SDR, strand displacement reaction; SDS, sodium dodecyl sulfate; SPR, surface plasma resonance; ssDNA, single-stranded DNA; TCPO, bis(2,4,6-trichlorophenyl) oxalate; TPP, tetraphenylporphyrin.

3

1. Introduction Resonance energy transfer (RET) has great potential in analyte detection, immunoassay, enzyme activity assay, in vitro and in vivo imaging and disease diagnosis. RET is depended on the intermolecular distance and energy level, so the RET process can be controlled by adjusting the distance and the energy interval. Accordingly, the subtle changes of molecules can be characterized by RET, such as the conformation transition of proteins and the specific recognition of antigen and antibody [1]. Chemiluminescence resonance energy transfer (CRET) is a form of RET in which the energy transfer occurs between a CL donor and a suitable energy acceptor [2]. Typically, the CL substrate is stimulated by the CL reaction and generates high energy intermediate, leading to the light emission when the intermediate release energy in the form of photon. In this case, if an acceptor with suitable absorption approaches the CL substrate within 10 nm, the emission of the substrate will excite the acceptor or be quenched by the acceptor. Compared with fluorescence resonance energy transfer (FRET), CRET has demonstrated many advantages. Instead of the CL substrate, the donor of FRET is usually an excited fluorophore, which thus requires external light source to excite the process of energy transfer. Therefore, the autoluminescence can be effectively avoided during the CRET, leading to a low background [3]. Further, the specificity of many FRET-based methods is relatively low, which mainly attributes to the cross-talk between the donor and acceptor. Multiple fluorophores can be excited non-specifically due to their broad excitation spectra. By contrast, the "light source" of CRET is the CL reaction, and the effect of cross-talk can be eliminated because all the acceptor must be excited by the donor. In addition, CRET can avoid the photobleaching, making it more sensitive in sensing and imaging. Although the CRET using luminol as donor was reported early in 1967 [4], the incipient development of CRET systems was slow. From 1990s, with the exploitation of CL systems and acceptors, new CRET strategies have been presented and applied 4

for immunoassays. For example, CL substrate N-(4-aminobutyl)-N-ethylisoluminol (ABEI) was labeled on antigen and then bound fluorescein-labeled antibody specifically to form a CRET-based homogeneous immunoassay, in which the energy was transferred from ABEI to fluorescein [5]. With the update of fluorescein, fluorophore isothiocyanate (FITC) as the acceptor was used to label the antibody to improve the sensitivity of microfluidic immunoassay [6]. Although the development of organic fluorescent dyes has greatly promoted the application of CRET, there are still some inherent disadvantages, especially small Stokes shifts, which can lead to the poor separation of emission spectrum and low energy-transfer efficiency. Over the recent decades, nanomaterials have attracted great attention in the development of CRET, including graphene and graphene oxide (GO) [7], quantum dots (QDs) [8], noble metal nanoparticles [9], semiconductor polymer nanoparticles (Pdots) [10], metal-organic frameworks (MOFs) [11], upconversion nanoparticles [12] and so on. In view of their unique optical properties, most of them have been used as the CRET acceptors with high surface area and quantum size effect. For example, both graphene and GO have large specific surface area, high electrical conductivity and extraordinarily optical property [13], which have been adopted as the typical "signal-off" type acceptors because the light emission in a wide wavelength range can be quenched effectively, resulting in a low background. In addition, graphene and GO can easily absorb the single-stranded DNA (ssDNA) via π-π interaction, which facilitate their applications in bioassays. In addition, two-dimensional WS2 nanosheet has been explored as the acceptors of CRET [14]. QDs have high fluorescence quantum yield and good photostability. Besides, their surface is easy to modify and the size-depended consecutive band gap can be adjusted readily. Therefore, QDs have been used as a suitable kind of CRET acceptors [15]. AuNPs also have quenching effect to the CL emission with the characteristics of surface plasma resonance (SPR) and high molar absorptivity [16]. Pdots composed of semiconductor polymer and multiform CL substrates have functionalized surface and large Stokes shifts even to near-infrared (NIR) region. In addition, their biological stability and integration 5

performance are excellent, which have been versatilely applied in the in vivo analysis and imaging [17]. Moreover, photosensitizer can be incorporated into the Pdots for photodynamic therapy (PDT) of cancers [18]. In this review, we mainly focus on the mechanisms of CRET systems based on the different energy acceptors and their latest applications in bioanalysis, in vitro and in vivo imaging, and theranostics. To further extend the applications of CRET, the prospects and challenges of CRET are also proposed. 2. Organic fluorescent dye-based CRET Organic fluorescent dyes are a class of photoluminescent substances that can be excited by incident light and emitting fluorescence in a longer wavelength range than the exciting light [19]. Since Stokes developed fluorescence as an analytical tool, the synthesis of fluorescent dyes has developed rapidly. At present, there are many kinds of synthetic and modified dyes with certain excitation and emission wavelengths, molar absorption coefficients, and quantum yields. The dyes with high quantum yield, good biostability and photostability have been widely used as fluorescent probes in biological, environmental, and medical fields [20-23]. So far, more and more fluorescent dyes have been used in CRET reaction [24]. Utilizing fluorescent dyes as the energy acceptors of CL reaction, the energy would transfer from donor (e.g., luminol, peroxyoxalate, 1,2-dioxetane and their derivatives) to fluorescent probe and then excite the electron to excited state. During the electron returns to the ground state, the energy would radiate out in the form of fluorescence. The energy-transfer to fluorescent probe can avoid the use of external light source and amplify the signal of the reaction effectively [25]. In addition, compared with direct CL, CRET strategy extends the application range of CL. Through using fluorescein amidite (FAM) as both acceptor and enhancer of luminol-H2O2 CL system, a target-triggered CRET system was designed for microRNA (miRNA) detection based on the formation of DNA four-way junction (DNA-4WJ) by toehold-mediated DNA strand displacement reaction (Fig. 1A) [26]. Four DNA hairpins were designed cleverly. Two of them are labeled with FAM at the 6

3′-end and the other two hairpins can form the hemin/G-quadruplex HRP-mimicking DNAzyme. Once the introduction of target miR-let-7a, DNA-4WJ was formed, which accompanied by the release of target miRNA to trigger another hairpin assembly. As a result, the HRP-mimicking DNAzyme and FAM were in a close proximity, and the energy was transferred from DNAzyme-catalyzed luminol/H2O2 CL to FAM, realizing sensitive CRET detection of miR-let-7a with a detection limit of 6.9 fM. To reduce background, magnetic graphene oxide (MGO) was used to remove the unreacted hairpins and hemin via π-π interaction. To reduce the detection background more simply, a further work was carried out by the same group through labeling fluorophore FITC and quencher Dabcyl at two ends of one hairpin, respectively [27]. Hence, the unreacted hairpins do not have to be removed because the fluorescence signal was "off" by the close proximity of the fluorophore and quencher. In addition, G-quadruplex sequences were encoded in different hairpins to ensure that only the initiator can trigger the catalytic hairpin assembly (CHA) and result in the CRET, which further reduced the background. To further improve the detection sensitivity, the same group proposed a DNA self-assembly strategy based on CHA and hybridization chain reaction (HCR), in which plentiful G-quadruplex sequence and FAM were encoded in one hyperbranched DNA structure [28]. This method achieved sensitive detection of miRNA with a detection limit of 0.72 pM, which was ~10-fold lower than that obtained by direct CL detection. Recently, Cu2+-modified metal-organic framework nanoparticles (Cu2+-NMOFs) were synthesized with HRP catalytic activity, and fluorescent dyes were incorporated into the pores of Cu2+-NMOFs to construct the CRET system [29]. As shown in Fig. 1B,

the

UiO-type

NMOFs

composed

of

Zr4+

ions

bridged

by

2,2′-bipyridine-5,5′-dicarboxylic acid ligands. After modifying with Cu2+, the NMOFs demonstrated HRP-mimicking activity which can catalyze the luminol-H2O2 CL reaction. The porous structure of the Cu2+-NMOFs with 1.65 nm sizes enabled the incorporation of fluorescein and the close proximity between Cu2+ and fluorescein. During the CL measurement, the band of fluorescein at 520 nm was observed, 7

indicating the Cu2+-NMOFs-catalyzed CRET from luminol to fluorescein and the CRET efficiency was 35%. Fig. 1. Magnetic particles (MPs) are magnetically responsive, biocompatible and easy to conjugate with biomolecules on their surface, which thus are commonly used in bioanalysis [30-32]. Using MPs as carriers to reduce the detection background, various CRET biosensing platforms have been proposed [33]. For example, Bi’s group realized CRET imaging miRNA (Fig. 2A) through self-assembly of DNA networks on MPs, in which the background was greatly reduced through magnetic separation to remove the unreacted hemin. Since the acceptor FAM was also acted as the enhancer of the luminol-H2O2 CL system, the CRET signal was further amplified, achieving a high detection sensitivity at fM level [34]. In addition, CRET-based immunoassays have been developed for antigen detection [35]. As shown in Fig. 2B, by immobilizing HRP-labeled

goat

antihuman

human

immunoglobulin

G

(HRP-anti-IgG) on MPs, Zhao’s group developed a competitive immunoassay for human IgG detection based on CRET [36]. The FITC-labeled human IgG was first incubated with HRP-anti-IgG on MPs to form antibody-antigen immunocomplex. At this point, CRET was fully performed and the CL intensity at 525 nm (FITC) was maximum. Then, the addition of target human IgG competed with the FITC-IgG, leading to the increased intensity at 425 nm (luminol) and decreased intensity at 525 nm (FITC) because the CRET only occurred in the HRP-anti-IgG/FITC-IgG complex. Magnetic separation used in this method could reduce the background, resulting in a high sensitivity with the detection limit of 29 pM IgG. To further improve the detection sensitivity, gold nanoparticles (AuNPs) were introduced to CRET-based immunoassay for signal amplification [37]. In addition to single enzyme immunoassay, dual enzymes [38] and enzyme-free [39] CRET-based immunoassays have also been explored. Fig. 2. To further improve the CRET efficiency, dioxetane-based luminophores were 8

presented [40, 41]. Shabat’s group synthesized different dioxetane-fluorophore conjugates by tethering fluorescent dyes to Schaap’s dioxetane via covalent conjugation [42]. The presence of analyte would remove the trigger from a phenol and initiate the electron exchange luminescence. Subsequently, the energy transferred from the excited benzoate to dye via CRET, realizing signal amplification as well as color modulation. The CRET efficiency of dioxetane-fluorogenic dye conjugates was high, which realized the in vitro and in vivo imaging of β-galactosidase. As mentioned above, the directly covalent conjugation between CL probe and fluorescent dye could ensure the efficiency of CRET. Recently, a novel CRET system was presented in which the 3-(2-aminoethylamino)propyl]trimethoxysilane-polyhedral oligomeric silsesquioxanes (AEAP-POSS) was linked covalently with dye perylene diimide derivative (PDI) [43]. This compound could be attack by •OH because the diffusive negative contours at the exterior of the compound would absorb •OH. Then the electronically carbonyl CH3CO• was generated and the energy was transferred from CH3CO• to PDI through CRET. Using this AEAP-POSS-based CRET system, •OH in ambient particular matter (PM2.5 and PM10) was monitored directly. ONOOH/ONOO- is the important link in the pathological damage of NO, and the spontaneous CL of ONOOH/ONOO- is weak [44]. Calcein is a commonly used acceptor, however, the CRET efficiency to calcein is not high enough. To increase the CRET efficiency, Wang et al. first applied the modified kaolin to ONOOH-calcein system which has porous structure and abundant oxygen vacancies [45]. After the modification by NaOH, more pore structures and active sites were produced on the surface of kaolin. In addition, the modified kaolin would attract the calcein and ONOOH through π-bond and hydrogen-bond interaction respectively, resulting in a higher CRET efficiency. Subsequently, they arranged the calcein orderly with sodium dodecyl sulfate (SDS)-layered double hydroxides (LDHs) to improve the CRET efficiency [46]. In this method, calcein was immobilized on the surface of SDS-LDHs, and then the colloidal solution was acidified. The residual calcein@SDS composite produced a stronger light emission through CRET than pure calcein, which could 9

further distinguish ONOO- from other reactive oxygen species (ROS) owing to the energy matching between ONOOH* and calcein. 3. Quantum dot (QD)-based CRET In CRET, the excited state donors come from the oxidation of luminescent substrates, avoiding the false positive signal caused by the spontaneous fluorescence of donors and direct excitation of acceptors, leading to a low background noise [2]. In conventional CRET, organic fluorescent dyes are often selected as energy acceptors. However, due to their small Stokes shifts, the emission spectral separation of the acceptor from the donor is poor, thereby decreasing the energy transfer efficiency. Alternatively, QDs with large Stokes shifts and high luminescence efficiency have become attractive energy acceptors in CRET systems. QDs, also known as luminescent semiconductor nanocrystals, are a class of quasi-zero dimensional materials with the sizes between 2 and 10 nm. Generally, QDs are composed of inorganic atoms from groups II-VI, III-V, or IV-VI, such as CdTe QDs [47-49], ZnS QDs [50, 51], and CdSe QDs [52]. In addition, metal-free QDs have emerged and drawn great attention, including carbon QDs [53], nitrogen QDs [54] and black phosphorus QDs (BP QDs) [55]. Because the sizes of QDs are smaller than or close to the exciton Bohr radius of the material, quantum domain limiting effect is produced in QDs, which endow QDs unique photoelectric characteristics, such as wide excitation spectrum, size-controllable fluorescence emission peak, high fluorescence quantum yield, and high fluorescence stability [15, 56]. Moreover, because of the wide excitation spectrum, quantum dots with different sizes can be excited by the same CL donor to generate different emission wavelengths, thus realizing multiple analysis. Recently, QDs as energy acceptors have been successfully applied in CRET systems. Ren’s group firstly demonstrated an efficient CRET between luminol and HRP-QD conjugates, which constructed a novel CRET system utilizing the immuno-interaction between the QD-BSA and anti-BSA-HRP (Fig. 3A) [47]. Furthermore, this system was proved to be capable of multiplex analysis using 10

multiple QDs with different emission wavelengths as acceptors. The low efficiency of CRET in luminol CL system is often attributed to the high concentration of oxidant (typically H2O2), which leads to the oxidative quenching of QDs. To solve this problem, Hou’s group proposed a CRET sensor using luminol as the donor and bienzyme-QD bioconjugate as the acceptor moiety (Fig. 3B) [57]. The bienzyme-QDs can generate and consume H2O2 in situ, thus avoiding the excessive concentration of H2O2 in the system and alleviating the potential quenching of QDs by H2O2. What’s more, the nanosized QDs confined the two enzymes in a nanometric range, which thus limited the CL reaction to occur only on the surface of QDs. As a result, the CL reaction rate and CRET efficiency (as high as 30~38%) were improved, exhibiting potential in sensitive analysis of a series of oxidase substrates at nM level. In addition, Wang’s group reported a competitive immunoassay for sulfamethazine detection based on homologous CRET using hapten-functionalized core/multishell QDs to improve the CRET efficiency [58]. Fig. 3. Catalytic nucleic acids, such as DNAzymes, play a vital role in the fabrication of biosensors. The hemin/G-quadruplex HRP mimicking DNAzyme as the most extensively studied DNAzyme has been widely used in the CRET system, which acts as the catalyst for the generation of CL through the oxidation of luminol by H2O2. Willner’s group has developed a series of biosensing platforms based on hemin/G-quadruplex HRP mimicking DNAzyme catalyzed CRET [50, 52, 59-61]. For example, they designed nucleic acid subunits containing the HRP-mimicking DNAzyme fragments and aptamer domains of ATP or Hg2+ (Fig. 4A) [59]. The presence of ATP or Hg2+ revealed the catalytic activity of DNAzyme and generated CL. At the same time, the aptamer subunits were functionalized with CdSe/ZnS QDs, leading to the CRET signal. Furthermore, hairpin nucleic acids were designed with G-quadruplex sequence to functionalize QDs for DNA analysis. The presence of target DNA resulted in the generation of hemin/G-quadruplex DNAzyme and stimulated the CRET signal. This strategy achieved the detection sensitivity at nM 11

level. By attaching different hairpins to different sized QDs, multiplexed analysis of three DNA targets was realized via CRET. The metal-ion and ligand can stimulate the formation and dissociation of nucleic acid duplexes, which has been applied in the fabrication of DNA switch sensors. Willner’s group demonstrated a switchable photonic device based on CRET-induced luminescence of the QDs (Fig. 4B) [50]. The K+-ion can stimulate the formation of hemin/G-quadruplex which was linked onto the QDs. However, the addition of 18-crown-6-ether caused the dissociation of G-quadruplexes. Therefore, the reversible aggregation/deaggregation of the QDs was demonstrated by cyclically treating the QDs with K+-ions/18-crown-6-ether. What’s more, two-sized QDs achieved the dual switchable CRET-induced luminescence. Substantial recent researches have been focused on the development of chemical networks that mimic biological networks, in which the constitutional dynamic networks (CDNs) are up-regulated or down-regulated by auxiliary triggers. In 2018, Willner’s group used the adaptive re-eqilibration of CDNs to regulate the plasmonic and optical properties of size-controlled nanomaterials, such as AuNPs and semiconductor QDs (Fig. 4C) [61]. In this work, the dynamic CDNs guided the switchable aggregation of different-sized QDs cross-linked by hemin/G-quadruplex HRP-mimicking DNAzyme units, which thus controlled the CRET-induced luminescence. Fig. 4. Electron-hole annihilation of nano dots is becoming a hot topic recently within which the generated intermediate may serve as energy donors to stimulate CRET. For example, Ju’s group developed a CdTe QDs-bis(2,4,6-trichlorophenyl) oxalate-H2O2 CL system, in which the production of dioxetanedione, OH• and O2•- causing electron-hole annihilation to generate high CL intensity [49]. Due to the spectrum matching between CdTe QDs and dioxetanedione, efficient CRET occurred and the CL signal was greatly amplified. This CRET system exhibited good practicability for enzyme-free immunoassay with the detection limit of 0.3 pM CEA. 12

Traditional semiconductor QDs contain heavy metals as basic elements are highly toxic and hazardous to environment. Therefore, the metal-free QDs have attracted extensive attention, owing to their environmental friendliness, excellent biocompatibility and facile functionalization. Among them, GQDs are effective energy acceptors that can avoid the photo-bleaching problem. An immunoassay has been developed for the detection of ovarian cancer biomarker CA-125 utilizing the GQD-based CRET [62]. CA-125 antigen could serve as a cross-linking agent to connect HRP-labeled antibody and GQDs-modified capture antibody, promoting the formation of sandwich structure, which thus induced a close proximity of HRP-labeled antibody to GQDs and facilitated CRET from luminol donor to GQDs acceptor. In addition, Lin’s group synthesized nitrogen quantum dots (N-dots) containing up to 57% nitrogen, which exhibited unique optical properties and significantly enhanced the ultra-weak CL reaction of NaIO4 with H2O2 by 400-fold via CRET and electron hole injection (Fig. 5A) [54]. They speculated that the decrease in 1O2 caused by the reaction between the N-dots and •O2-, •OH, leading to improvement of CRET efficiency between N-dots and 1O2. Very recently, Lv’s group synthesized oleic acid capped black phosphorus QDs (OA-BP QDs) which were firstly observed extraordinary CL emission in the presence of NaHSO3 [55]. In the CRET mechanism (Fig. 5B), OA-BP QDs firstly catalyzed the generation of 1O2 in NaHSO3 and then acted as energy acceptors in CRET between (1O2)2* (1O2 dimeric aggregate) and OA-BP QDs. On this basis, a new CL system for directly monitoring SO32- in airborne fine particulate matter (PM2.5) was fabricated. The study opens up an attractive prospect for the application of metal-free QDs based CRET in PM2.5 chemical species monitoring. Fig. 5. The blue light emitted in CL can only be detected on the surface of lesion due to the tissue absorption and scattering. By constructing QDs-based CRET system, the blue light emitted by CL reagent can excite QDs to emit light in the NIR spectral range (generally 700-900 nm), which thus significantly improves the ability of in vivo 13

analysis. Ansaldi’s group demonstrated that luminol-generated short-wavelength light was redshift by NIR QDs through CRET, which was applied to assess myeloperoxidase activity in deep tissue and rapid screening of anti-inflammatory agents in animal models [63]. However, the long-term toxicity of QDs to animals and humans remains unknown, which limits their preclinical and clinical applications. To solve the problem, polymer shell-covered and surface-modified QDs have been developed to reduce their biological toxicity. Park’s group designed PEG coated QDs as CRET acceptors while luminol derivative-H2O2 system act as the donors, achieving the imaging of H2O2 in disease models (Fig. 6) [64]. Fig. 6. 4. Semiconducting polymer-based CRET In the last few years, semiconducting polymers have attracted significant attention because of their bright fluorescence emission, multiple emission colors and good photostability [65]. In addition, these polymers have π-conjugated structures, so the electrons can travel through the polymer backbone through overlaps in the π-electron clouds [66]. Many fluorescent semiconducting polymers have been used as fluorescent probes and energy acceptor of CRET, such as polyfluorene [67], poly(phenylene ethynylene) [68], poly(phenylene vinylene) [69] and fluorene-based copolymers [70]. Poly[2-methoxy-5-((2-ethylhexyl)oxy)-p-phenylenevinylene]

(MEH-PPV)

is

commonly used in the synthesis of Pdots with broad absorption (400~550 nm) and emission (550~700 nm). By synthesizing folic acid (FA) and HRP-bifunctionalized MEH-PPV-based Pdots, Wang et al. realized the CRET imaging and PDT of cancer cells

(Fig.

7A)

[71].

The

MEH-PPV

and

photosensitizer

meta-tetra(hydroxyphenyl)-chlorin (m-THPC) were coprecipitated with Janus dendrimer to form hydroxyl-terminated photosensitizer-doped Pdots, in which Janus dendrimer was a powerful amphiphile and could conjugate HRP and aminated FA. After the addition of luminol and H2O2, CRET was occurred between luminol and MEH-PPV, of which the maximum emission was 590 nm. C6 glioma cells, NIH 3T3 14

fibroblasts cells and MCF-7 breast cancer cells were imaged with this semiconducting P-dots. Simultaneously, the CRET and FRET to m-THPC led to the generation of 1O2, therefore realizing the PDT of cancer cells. Subsequently, an improved MEH-PPV-based Pdots for CRET imaging and PDT were presented [72]. As shown in Fig. 7B, poly(styrene-co-maleicanhydride) was used to coprecipitate with MEH-PPV to form carboxyl-terminated Pdots. Then hemoglobin as an oxygen carrier and catalyst of luminol-H2O2 CL reaction was covalently conjugated to the Pdots through a carbodiimide reaction. Finally, the hemoglobin-Pdots were encapsulated in fusogenic liposomes for cellular internalization. During the CRET process, MEH-PPV could sensitize oxygen present in hemoglobin, producing ROS to kill cancer cells. Since the H2O2 concentration in normal cell was much lower than that in cancer cells, the normal cells cannot be killed during the PDT process. Fig. 7. Poly[(9,9’-dioctyl-2,7-divinylene-fluorenylene)-alt-2-methoxy-5-(2-ethyl-hexylo xy)-1,4-phenylene] (PFPV) was a typical fluorene-based copolymer with broad absorption (300~530 nm), which was certified to be suitable energy acceptor of CRET. Ren’s group used PFPV-based Pdots to encapsulate hemin and formed a mimic-enzyme-catalyzed CRET system (Fig. 8A) [73]. After the encapsulation, hemin showed enhanced catalytic activity like HRP-mimicking DNAzyme because the situation of hemin in Pdots was almost the same to HRP-mimicking DNAzyme and HRP. Besides, one Pdot could encapsulate 20~30 hemin molecules in a hydrophobic environment, which enhanced the catalytic activity significantly. During the CL reaction, the diffusion of CL substrates (L012 and H2O2) into Pdots was very slow, resulting in a long-lasting CL imaging more than 10 h. Therefore, using this CRET-based Pdots the real-time imaging of ROS in peritoneal cavity and tissues of mice was realized. Very recently, another long-lasting CRET system was presented (Fig. 8B), in which H2O2 was bound to poly(vinylpyrrolidone) and slowly released to Tris-Co(II) complex. Combining with the sustained release of luminol, the CRET process could last ~13 h [74]. 15

Peroxyoxalate chemiluminescence (POCL) are nonenzymatic CL systems that are more stable and suitable than the CRET-based Pdots. Meanwhile, more and more CL substrates have been developed for POCL, such as hydroxybenzyl alcohol-incorporated copolyoxalate (HPOX) and TCPO. Pu et al. synthesized five Pdots by coprecipitating TCPO, amphiphilic PEG-b-PPG-b-PEG and different semiconducting polymers (Fig. 8C) [75]. During the CRET process, TCPO first reacted with H2O2 to generate high-energy dioxetanedione intermediate. According to the energy interval between the highest occupied molecular orbital of semiconducting polymers and the lowest unoccupied molecular orbital of dioxetanedione intermediate, PFPV was chosen as the most suitable polymer for CRET because the energy interval between PFPV and dioxetanedione was minimum and the CL quantum yield was accordingly highest. The PFPV-based Pdots achieved sensitive in vivo imaging of H2O2

that

was

related

to

peritonitis

Bis[3,4,6-trichloro-2-(pentyloxycarbonyl) phenyl]

and

neuroinflammation.

oxalate (CPPO)

is

also

a

commonly used substrate in POCL with high reactivity to H2O2. As shown in Fig. 8D, CPPO, photosensitizer tetraphenylporphyrin (TPP) and PFPV were co-encapsulated by

poly(ethyleneglycol)-co-poly(caprolactone)

(PEG-PCL)

and

folate-PEG-cholesterol matrix, realizing the imaging and treatment of cancers through intraparticle CRET [76]. H2O2 in the tumor microenvironment would trigger the POCL and then the energy was transferred to PFPV for CL imaging. In addition to imaging, TPP in the Pdots would be stimulated as the same time to generate 1O2 and result in the PDT of cancer cells. Fig. 8. In

addition

to

MEH-PPV

and

PFPV,

poly(2,7-(9,9-dioctylfluorene)-alt-4,7-bis(thiophen-2-yl)benzo-2,1,3-thiadiazole) (PFODBT) was a versatile semiconducting polymer with high quantum yield and could be used as the acceptor of CPPO. To real-time image the drug-induced ROS and reactive nitrogen species (RNS), Rao et al. presented CRET and FRET Pdots that contained both PFODBT and NIR dye IR775S [77]. PFODBT in Pdots served as the 16

acceptor of CRET as well as the donor of FRET, so the H2O2 can trigger both CRET and FRET simultaneously. Furthermore, RNS-responsive IR775S would decompose in the presence of ONOO- and -OCl, leading to the emission enhancement at 680 nm. After PS-g-PEG-Gal targeting the Pdots to liver, drug-induced hepatotoxicity was monitored in real time. Superoxide anion (O2•-) is one of the primary ROS and the sensitive detection of O2•-

is

imperative.

Poly[9,9′-bis(6″-N,N,N-trimethylammonium)hexyl)fluorene-co-alt-4,7-(2,1,3-benzoth iadiazole)dibromide] (PFBT) was found to be a good acceptor to the imidazopyrazinone (CLA)-O2•- CL system. Recently, a PCLA-O2•- Pdot was prepared by nanoprecipitation for in vivo imaging of O2•-, in which CLA and PFBT were linked covalently [78]. Once the O2•- was added, CLA was excited and then transferred the energy to PFBT, of which the maximum emission was at 560 nm. The interior of the Pdots was hydrophobic, which can further enhance the CL intensity and extend imaging time during the detection of O2•-. Generally, organic fluorescent dyes, QDs and Pdots are typical acceptors to construct "signal-on" CRET systems. In these systems, the absorption spectrums of acceptors are overlapped with the emission spectrums of CL substrates. After the energy transfers to these "signal-on" type acceptors, the CL emission peak would be red-shifted. In addition, most of them have higher CL intensity than normal CL substrates so the CL signals are "turned on" with high sensitivity, making the CRET as a powerful analysis tool. Novel nanomaterials with large Stokes shifts, enhanced luminescent intensity and long-lasting emission will be developed as "signal-on" type acceptors in the future to promote the in vivo analysis of CRET. 5. Carbon nanomaterial-based CRET Carbon nanomaterials, including zero-dimensional carbon nanoparticles (CNPs) [79] and graphene quantum dots (GQDs) [62], one-dimensional carbon nanotube (CNTs) [80], and two-dimensional graphene [81, 82] and GO [83], can serve as energy acceptors and super-quenchers in CRET systems due to their wide-range 17

energy transfer capability. Most of the carbon nanomaterials possess extraordinary electronic properties, large π-π conjugated structure and strong energy absorption, which contribute to the non-radiative transfer of electrons from the excited states of CL donor to the π system of carbon nanomaterials [26]. Unlike fluorophore acceptors that are excited by the CL donors via energy transfer and then emit new optical signals, carbon nanomaterial-based acceptors in CRET system are usually non-FL quencher that can directly quench the CL from the donors or fluorophore-based acceptors excited by the donors with high efficiency [2, 84]. As the energy acceptors, the absorption spectrum of carbon nanomaterials should be overlapped with the emission spectrum of the donor molecules (CL substrates). The CRET occurs when the energy transfers from CL compounds (such as luminol-H2O2 system) to carbon nanomaterials within close proximity (normally <10 nm). Graphene can be regarded as a highly efficient energy acceptor owning to the highly planar surfaces and numerous energy-accepting sites. A graphene-based CRET platform was proposed for homogeneous immunoassay of C-reactive protein (CRP) using graphene nanosheets as energy acceptor and luminol as energy donors [81]. As shown in Fig. 9A, the CL reaction of luminol-H2O2 was catalyzed by HRP labeled on anti-CRP antibody. Upon the addition of CRP, a sandwich-type immunocomplex formed between anti-CRP antibody-conjugated graphene and HRP-labeled anti-CRP antibody, which shortened the distance between luminol-H2O2 system (CL donor) and graphene (CL acceptor) and further triggered the CRET to quench the CL intensity of luminol. Thus, the CL intensity of luminol gradually decreased with the increase of CRP concentration, which achieved a detection limit of 0.93 ng mL-1 in human serum. What’s more, graphene was demonstrated as a more efficient energy acceptor for CRET than GO. To obtain the high selectivity in complex sample matrix, MPs were used in CRET to immobilize biomolecules and the anti-interference ability was greatly improved through magnetic separation [82]. Very recently, inspired by the molecular imprinted polymer (MIP) that can recognize the target analytes specifically, molecularly imprinted microspheres for chloramphenicol were polymerized on the 18

surface of magnetic graphene, which served as the recognition reagent to improve the detection selectivity and the energy acceptor to develop a CRET platform using luminol-H2O2-4-(imidazole-1-yl) phenol system as the energy donor [85]. In addition to the direct quenching of CL [86], GO can also quench the CL emission of acceptor (e.g., fluorophores) excited by the donors with high efficiency, achieving cascaded CRET (C-CRET) for sensitive detection of target DNA and proteins (Fig. 9B) [83]. To further improve the detection sensitivity, tool enzymes (e.g. exonuclease [87, 88] and nicking endonuclease [89]) assisted signal amplification strategies have been integrated with CRET for versatile analytical applications. To reduce the interference caused

by

nonspecific

adsorption,

luminol/H2O2/HRP-mimicking

based

on

the

C-CRET

DNAzyme/fluorescein/GO,

a

system

of

controllable

hot-spot-active substrate was fabricated by covalently attaching hairpin probes on magnetic GO (MGO) rather than physical adsorption [90]. Through strand displacement reaction (SDR) and magnetic separation, this C-CRET biosensing platform achieved regeneration of magnetic carriers and as low as 79 pM of miRNA can be detected with high reversibility and reproducibility. Besides graphene, other carbon nanomaterials, such as amorphous CNPs [79, 91] and GQDs [62], are also served as direct acceptors to develop CRET platforms for biomolecules detection via competitive immunoreaction. CNTs have been demonstrated as effective energy acceptors with long-range energy transfer property [80]. For example, the ABEI-labeled DNA-1 (CL donor) was adsorbed onto the surface of SWNTs (acceptor), resulting in the quenching of CL via CRET. The target DNA-2 blocked the donor-acceptor interaction, resulting in a turn-on CL signal that was further amplified by exonuclease III (Exo III)-assisted target recycling strategy, achieving a detection limit of 45 fM (Fig. 9C). Fig. 9. 6. Gold nanoparticle (AuNP)-based CRET AuNPs have been widely applied in optical assays because of their unique properties of high stability, excellent biocompatibility, extremely high extinction 19

coefficients, and so on [92]. What’s more, excellent redox catalytic property, long-range nanoscale energy transfer property and wide absorption spectra make AuNPs attractive in CRET systems. For example, Zhang’s group developed a label-free and non-derivatization CRET system based on the quenching ability of AuNPs [93]. In this system, TCPO-H2O2-fluorescein served as the donor and AuNPs as the acceptor. In the absence of 6-mercaptopurine, the CL can be quenched by the AuNPs, while in the presence of 6-mercaptopurine, as well as Cu2+ ions, the AuNPs aggregated due to the cooperative metal-ligand interactions. As a result, the maximum absorption peak of the AuNPs was redshifted and no longer overlapped with the CL spectrum. Therefore, the CL signal was restored. This AuNP-based CRET detection platform showed great potential in the determination of non-fluorescent small molecules. In CRET systems, high concentration of fluorescent dyes may cause aggregation-caused quenching (ACQ). Gold nanoclusters can sweep away the shortcomings of ACQ because of aggregation-induced emission (AIE), which thus can serve as good acceptors in CRET systems. Accordingly, an interesting method was proposed based on the bis(2,4,6-trichlorophenyl) oxalate (TCPO)-H2O2 CL reaction, in which gold nanocluster serving as the CRET acceptors (Fig. 10A) [94]. The aggregation of gold nanoclusters greatly improved the CRET efficiency, proving that the gold nanocluster AIE effect has the potential applications in analytical chemistry. So far, a variety of CRET biosensing platforms have been developed for the detection of biomolecules. For example, Cui’s group developed a label-free, homogeneous and nonenzymatic protocol without reference to any recognition elements based on CRET between lucigenin and AuNPs for the detection of histone [95]. This sensing platform selected lucigenin-H2O2 system as the energy donor and AuNPs as the energy acceptor, which led to the luminescence quenching of lucigenin through CRET. When there were histones, AuNPs would aggregate due to the electrostatic interaction between negatively charged AuNPs and positively charged histones. As a result, the CRET reaction was reduced and the CL signal was "turned 20

on". In addition, based on the CRET between ABEI and AuNPs, a "light on" CRET assay was proposed for thrombin detection via specific aptamer recognition [96]. To further improve the detection sensitivity, a bi-RET aptasensor was established (Fig. 10B), in which AuNPs were used to quench the luminescence, while the target can be recycled to trigger the restoration of CRET signal based on Exo III-assisted target recycling amplification [97]. Fig. 10. Using carbon nanomaterials and AuNPs as the "signal-off" type acceptors, the energy can be transferred efficiently in a close proximity, and the CL emission is therefore "turned off". In a typical analysis process, the concentration of analyte can be evaluated quantitatively by the quenched CL intensity. More quenchers with good stability and biocompatibility are still required in CRET, and their integration with other amplification strategies should be further explored for higher sensitivity. 7. Conclusions and Prospects CERT can effectively improve the sensitivity of CL analysis by solving the problem of low quantum efficiency and poor specificity of some CL reactions. As we discussed above, the enhancement effect of "signal-on" type energy acceptor is mainly attributed to the high energy-transfer efficiency, high quantum yield and red-shifted emission, while the "signal-off" type acceptor can also improve the sensitivity by the efficient quenching of CL emission. Each type of acceptors has unique characteristics, such as the easy modification of organic fluorescent dyes, the surface plasmon resonance of AuNPs, and so on. The versatility of the donors and acceptors greatly extends the applications of CRET in the field of biosensing, in vitro and in vivo imaging, and diagnosis and treatment of disease. The CRET systems have been innovated until now. The distance between CL substrate and acceptor is a key factor of CRET efficiency. In recent years, the G-quadruplex/hemin HRP-mimicking DNAzyme-fluorophore CRET systems have developed rapidly because the distance between DNAzyme and fluorophore can be readily adjusted by programming DNA strand. The directly covalent conjugation 21

between CL probe and fluorescent dye can also shorten the distance and improve the CRET efficiency. To further improve the detection sensitivity, magnetic carriers and fluorescence quencher can be used in CRET systems to reduce the background, and CRET systems can be cleverly integrated with signal amplification strategies. Future development of CRET may bring new red-shifted acceptors to match the existing CL systems, in which the excitation spectra have greater overlap with the emission of donors. The red-shifted CRET systems with better penetration will make up for the lack of in vivo analysis, such as the protein interactions, cells and tissue imaging, and so on. The long wavelength emission will also mitigate the problem of the decreased emission intensity caused by the low quantum yield of the acceptors. In addition, the short emission time is still a handicap in the applications of CL as well as CRET systems, which has high demands on the optical instruments. For more stable detection and imaging, slow release strategies for different CL substrates and optical systems with fast capture performance should be utilized. In addition to the exploitation of acceptors with higher quantum yield, photostability and biological stability, combining CRET with signal amplification strategies and specific recognition mechanisms can also improve the analysis sensitivity. The integrated CRET technologies will eventually result in the high-throughput and multiplex analysis with high sensitivity and selectivity. Therefore, it is believable that CRET will find wider applications in biological analysis, bioimaging and theranostics in future. Acknowledgements We gratefully appreciated the support from the National Natural Science Foundation of China (21722505, 21535002 and 21705086), the Special Funds of the Taishan Scholar Program of Shandong Province (tsqn20161028), the Natural Science Foundation of Shandong Province (ZR2017JL009), and Foundation of Key Laboratory of Sensor Analysis of Tumor Marker, Ministry of Education, Qingdao University of Science and Technology (SATM201803).

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Figures

Fig. 1. Organic fluorescent dye-based CRET systems via (A) self-assembly of DNA-4WJ and (B) Cu2+-NMOFs. Reprinted with permission from Ref. [26] and [29]. Copyright 2015, American Chemical Society and Copyright 2018, Wiley-VCH.

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Fig. 2. CRET biosensing systems using MPs to reduce detection background. (A) CRET imaging of miRNA via self-assembly of DNA networks on MPs. Reprinted with permission from Ref. [34], Copyright 2016, Royal Society of Chemistry. (B) Fabrication of CRET competitive immunosensor for the detection of human IgG. Reprinted with permission from Ref. [36]. Copyright 2012, American Chemical Society.

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Fig. 3. Enzyme-catalyzed QD-based CRET systems. (A) CRET using BSA-labeled CdTe QDs as accepters. Reproduced with permission from Ref. [47]. Copyright 2006, Wiley-VCH. (B) In situ generation and consumption of H2O2 for CRET using bienzyme-labeled CdTe QDs. Reprinted with permission from Ref. [57]. Copyright 2016, American Chemical Society.

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Fig. 4. Hemin/G-quadruplex HRP mimicking DNAzyme-catalyzed QD-based CRET systems. (A) CRET detection of ATP via self-assembly of DNAzyme on CdSe/ZnS QDs. Reprinted with permission from Ref. [59]. Copyright 2011, American Chemical Society. (B) Dual switchable CRET via DNAzyme-bridged aggregation of two-sized QDs. Reprinted with permission from Ref. [50]. Copyright 2014, American Chemical Society. (C) Orthogonal control of CRET via DNAzyme-cross-linked aggregation of QDs. Reprinted with permission from Ref. [61]. Copyright 2018, American Chemical Society.

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Fig. 5. Metal-free QD-based CRET. (A) The mechanism of CRET from NaIO4-H2O2 system to N-dots. Reprinted with permission from Ref. [54], Copyright 2017, Royal Society of Chemistry. (B) OA-BP QD-based CRET for monitoring sulfite in PM2.5. Reprinted with permission from Ref. [55]. Copyright 2019, American Chemical Society.

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Fig. 6. Schematic illustration of PEG coated QD as the diagnostic agent based on CRET and its imaging in (a) PC3 tumor-bearing mice, (b) LPS-induced inflammation mice and (c) collagen induced arthritis mice. Reprinted with permission from Ref. [64], Copyright 2016, Royal Society of Chemistry.

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Fig. 7. Multifunctional Pdots for cell imaging and PDT based on CRET. (A) Preparation of FA and HRP-bifunctionalized Pdots and 1O2 generation for PDT. Reprinted with permission from Ref. [71]. Copyright 2014, American Chemical Society. (B) O2-supplying system for PDT using hemoglobin-linked conjugated Pdots. Reproduced with permission from Ref. [72]. Copyright 2019, Wiley-VCH.

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Fig. 8. (A) Preparation of hemin-Pdots and long-lasting imaging based on CRET. Reprinted with permission from Ref. [73]. Copyright 2018, American Chemical Society. (B) Long-lasting CRET system with the slow release of H2O2 and luminol. Reprinted with permission from Ref. [74], Copyright 2019, Royal Society of Chemistry. (C) Mechanism of TCPO-based CRET in Pdots. Reprinted with permission from Ref. [75]. Copyright 2016, American Chemical Society. (D) Mechanism of CPPO-based CRET in Pdots for PDT. Reprinted with permission from Ref. [76]. Copyright 2019, Ivyspring International Publisher.

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Fig. 9. Carbon nanomaterial-based CRET. (A) graphene-based CRET platform for the detection of CRP. Reprinted with permission from Ref. [81]. Copyright 2012, American Chemical Society. (B) GO-based CRET for the detection of target DNA and thrombin. Reprinted with permission from Ref. [83], Copyright 2012, Royal Society of Chemistry. (C) SWNT-based CRET platform for DNA detection by Exo III-assisted target recycling amplification. Reprinted with permission from Ref. [80], Copyright 2012, Royal Society of Chemistry.

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Fig. 10. (A) CRET based on gold nanocluster aggregation-induced emission. Reprinted with permission from Ref. [94]. Copyright 2015, American Chemical Society. (B) Bi-RET-based aptasensor on AuNPs for protein detection. Reprinted with permission from Ref. [97], Copyright 2012, Royal Society of Chemistry.

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Highlights The mechanisms of CRET are summarized according to the type of receptors. The recent advances of CRET in analytical applications are introduced. The present challenges and future prospect of CRET are highlighted.

Conflict of Interest

The authors declare that they have no conflicts of interest to this work.