An Intracellular H2O2-Responsive AIEgen for the Peroxidase-Mediated Selective Imaging and Inhibition of Inflammatory Cells

Article abstract of DOI:10.1002/anie.201712803

Inflammatory cells have gained widespread attention because inflammatory diseases increase the risk for many types of cancer. Therefore, it is urgent and important to implement detection and treatment methods for inflammatory cells. Herein, we constructed

Full text of DOI:10.1002/anie.201712803

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Intracellular H2O2-responsive AIEgen with peroxidase-mediated
catalysis for inflammatory cell selective imaging and inhibition
Authors: Fan Xia, Yong Cheng, Jun Dai, Chunli Sun, Rui Liu, Tianyou
Zhai, and Xiaoding Lou
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712803
Angew. Chem. 10.1002/ange.201712803
Link to VoR: http://dx.doi.org/10.1002/anie.201712803
http://dx.doi.org/10.1002/ange.201712803

Angewandte Chemie International Edition
10.1002/anie.201712803
COMMUNICATION
Intracellular H O -responsive AIEgen with peroxidase-mediated
2
2
catalysis for inflammatory cell selective imaging and inhibition
+
+
+
Yong Cheng , Jun Dai , Chunli Sun , Rui Liu, Tianyou Zhai, Xiaoding Lou,* and Fan Xia*
4
Abstract: Inflammatory cells are caused widespread attention due
to that inflammatory diseases increase the risk of developing many
types of cancer. Therefore, it is urgent and important to implement
detection and treatment of inflammatory cells. Herein, we employed
a probe reform strategy to construct a theranostic probe with
enzymatic catalysis and aggregation-induced emission (AIE)
characteristics, in which the tetraphenylethene (TPE) was modified
detection of inflammation and cancer. In addition, the H
2
O
2
-
responsive and peroxidase-mediated treatments of disease
have been more and more attractive in clinical therapy and
aroused extensive attention. A theranostic system that can not
only sensitively detect the abnormity of H O and peroxidase
2 2
levels but also enable to effective treatment for inflammation will
be greatly desirable and still challenging.
5
2 2
with two tyrosine (Tyr) moieties. Due to the H O -based and
Recently, large numbers of innovative strategies and
enzyme-catalyzed dityrosine formation, Tyr-contained TPE (TT)
would link with each other by dityrosine linkages to induce the
2 2
technologies are being developed in peroxidase-mediated H O
detection, such as electrochemical sensing, magnetic resonance
6
hydrophobic aggregates, activating the AIE process in H
O
2 2
and
imaging, fluorescence imaging and photoacoustic imaging.
myeloperoxidase overexpression inflammatory cells. The emission
turn-on results in the conversion of TT could be used for cell
selective imaging between inflammatory cells and normal cells.
Moreover, the massive TT aggregates induced mitochondria
Among them, fluorescence imaging has aroused great interest
because of its high detection sensitivity and rapid signal
acquisition, which has been widely used in the biochemical
7
analysis. However, the conventional fluorescence imaging
damage and cell apoptosis. This study demonstrates that the H
2
O
2
-
probes are limited by the aggregation-caused quenching (ACQ)
effect. Fortunately, large numbers of fluorescence materials
based on aggregation-induced emission (AIE) characteristics
responsive AIEgen with peroxidase-mediated catalysis property
holds great promise for inflammatory cell selective imaging and
inhibition.
are applied to biomedical imaging with high selectivity and
8
strong stability. Liu and co-workers have synthesized
a
tetraphenylethene (TPE) derivative bearing four carboxyl acid
moieties and charge-generation polymers to identify H with
enhanced detection sensitivity through electrostatic interaction.
Moreover, they proposed a creative approach by integrating
substrate-selective enzymatic reactions with a TPE derivative
Inflammation plays a critical role at different stages for tumor
development, including tumorigenesis, invasion and metastasis.
Reactive oxygen species (ROS) produced by inflammatory cells
may cause mutations in neighboring cells. Hydrogen peroxide
2
O
2
1
9
(
H
2
2
O ) is one of the most crucial ROS endogenously generated
bearing four tyrosine (Tyr) moieties to perform the detection of
by cellular respiration. Particularly, an abnormal level of H
2
O
2
10
2 2 2 2
H O with high sensitivity and selectivity. However, the H O -
production has been closely associated with inflammation,
responsive and peroxidase-mediated therapeutic strategies with
AIEgens haven't been developed yet.
Herein, we synthesized a Tyr-contained TPE derivative
named TT, which comprises one TPE as an emissive core in the
middle and two tyrosine as ROS-activable units as well as
2
neurodegeneration disease, diabetes and cancer. Moreover,
the enzyme-catalyzed dityrosine formation in inflammatory cells
is related to oxidative damage to proteins in the presence of
3
H
2
O
2
and peroxidase. Therefore, the sensitive detection and
real-time imaging of intracellular H
2 2
O and peroxidase would be
emission mediators at both ends (Scheme S1). Through H
2 2
O -
of great importance in disease surveillance, especially for early
responsive and myeloperoxidase (MPO)-mediated TT in suit
[*]
Dr. Y. Cheng, Dr. R. Liu, Prof. X. Lou, Prof. F. Xia
Faculty of Materials Science and Chemistry, China University of
Geosciences
Wuhan 430074, P. R. China
E-mail: louxiaoding@hust.edu.cn; louxioading@cug.edu.cn
xiafan@hust.edu.cn; xiafan@cug.edu.cn
Dr. J. Dai
Department of Obstetrics and Gynecology, Tongji Hospital
Tongji Medical College
Huazhong University of Science and Technology
Wuhan 430074, P. R. China
Dr. Y. Cheng, Prof. T. Zhai
State Key Laboratory of Material Processing and Die & Mould
Technology
School of Materials Science and Engineering
Huazhong University of Science and Technology
Wuhan 430074, P. R. China
Dr. C. Sun, Prof. F. Xia
Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica
School of Chemistry and Chemical Engineering
Huazhong University of Science and Technology
Wuhan 430074, P. R. China
[
+]
These authors contributed equally to this work.
Scheme 1. (a) The reaction sketch of TT is to form TT oligomer based on
and peroxidase-specific catalysis. (b) Illustration of TT is used for cell
selective imaging and inhibition after incubation with co-cultured cells.
2 2
H O
Supporting information for this article is available on the WWW
under http://
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201712803
COMMUNICATION
1
1
1+
self-assembly, it could be used for inflammatory cell selective
imaging and inhibition (Scheme S2). Because of the introduction
of functional amino acids, the hydrophobic TPE had become the
hydrophilic TT with weak fluorescence in aqueous solution. TT
would link with each other by dityrosine linkages and become
901.3879 was mainly attributed to [M+Na] ion of TT (calculated,
901.3914); the strong peak at 917.3604 was attributed to
[M+K] ion of TT (calculated, 917.3654). Moreover, the cis-trans
isomers of TT were separated and confirmed (Figures S19-
S22). Importantly, the formation of TT oligomer (TT)
(TT) and T1T dimer through catalytic cycle initiated by H
MPO were validated by UHPLC-MS (Figures S23-S26).
As shown in Figure S27a, TN showed strong absorption
peaks in the range of 300-400 nm in DMSO/water mixture
(v/v=1/99). After chemical modification, the absorption peaks of
TT exhibited blue-shift and moved to 270 - 380 nm, which are
1
+
1
2
2
, (TT)
3
,
aggregate, activating the AIE process in the presence of H
and MPO (Scheme 1a). DFT calculation could partly verify
molecular orbital amplitude energy change after reaction
Scheme S3). Thus, the emission turn-on results could be used
for cell selective imaging in H and MPO overexpression cells.
Finally, the massive TT aggregates could induce mitochondria
2
O
2
4
O and
2 2
(
2
O
2
damage and cell apoptosis (Scheme 1b). To our best knowledge, associated with the more twisted conformation owing to the
this is the first report on the AIEgens for inflammatory cell
selective imaging and inhibition based on H and MPO.
The synthetic routes toward the designed TT were illustrated
in Scheme S4. Firstly, azide-functionalized TPE (TPE-(N ; TN)
linkage of Tyr moiety. Therefore, the optimal absorption peak for
both TN and TT at 320 nm was chosen as the excitation
wavelength. And TN showed strong fluorescence signal from
400 nm to 550 nm in a mixture of DMSO/ water (v/v = 1:99; pH =
7) at room temperature (Figures S27b, S28). While TT had little
fluorescence signal in the range of pH 3-8. It attributed to the
good water solubility and stability of TT.
2
O
2
3 2
)
and the alkynyl-functionalized Tyr (4) were prepared. Then, a
copper-catalyzed click reaction between one molar equivalent of
TN and two molar equivalent of compound 4 took place in the
presence of in a DMSO/water (v/v=1/1) mixture containing
CuBr/sodium ascorbate, affording TT derivative (5) at room
temperature. Finally, the protection groups of compound 5 were
hydrolyzed off to obtain TT with by-products of TPE-Tyr (T1T) in
dilute hydrochloric acid solution. Detailed preparation
procedures and characterization data including nuclear magnetic
resonance spectra (NMR), high resolution mass spectra (HRMS)
and performance liquid chromatography (HPLC) were provided
in the supporting information (SI) (Figures S1-S18). As can be
seen in Figure S13, the strong peak at 879.4088 was attributed
To investigate the response property, TT was incubated with
10 g/mL MPO and different concentrations of H
30 min. The fluorescence signal of TT was gradually enhanced
with the increasing of H from 5 M to 100 M (Figure 1a).
2 2
O at 37 °C for
2
O
2
Interestingly, the high concentrations of TT and TT oligomer
could also display fluorescence intensity (Figure S29a).
However, the PL spectrum of TT oligomer was much stronger
than TT, showing the concentration-dependent manner. Owing
1
3
to the strong photostability of AIEgens, the fluorescence
intensity of TT oligomer could maintain more than 1 hour (Figure
1
+
to [M+H] ion of TT (calculated, 879.4095); the strong peak at
2 2
S29b). To prove the selectivity for H O and MPO, TT was
further incubated with other oxygen species and different kinds
of proteins. The fluorescence signal of TT only had significant
enhancement after incubation with H O but not the nitrate,
2 2
nitrite, hypochlorite, tertbutylhydroperoxide and glutathione
Figure 1. (a) Photoluminescence (PL) spectra of 10 M TT treated with
different concentrations of H O and 10 g/mL MPO. (b) Plot of (I-I )/I versus
2 2 0 0
response of 10 M TT to various ROS species (40 M) with 10 g/mL MPO. (c)
PL spectra of 10 M TT treated with 10 g/mL different kinds of proteins
Figure 2. (a) The real-time CLSM images showing the RAW264.7 cells
incubated with 3.0 M TT from 0 min to 150 min, and 3.0 M MTG was added
from 65 min to 150 min under the standard cell culture conditions. (b) The
average fluorescence intensity of RAW264.7 cells incubated with TT and MTG
in different times; (c) The fluorescence intensity of RAW264.7 cells incubated
with TT and MTG shown in the red line after incubation for 150 min. Scale bar:
20 m.
(
bovine serum albumin (BSA), hemoglobin (HGB), aminopeptidase N (CD13),
integrin  , thrombin (TB), carcinoembryonic antigen (CEA)) and 40 M
. (d) Dynamic light scattering results of 1 mg/ mL TT with and without
incubation with 40 M H and 10 g/mL MPO, the insets are the optical
photographs under UV light (365 nm, 16W), respectively. Scale bar: 2.5 mm.
v 3

2 2
H O
2 2
O
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201712803
COMMUNICATION
(
Figure 1b). Furthermore, different kinds of proteins were
incubated with TT solution in presence of 40 M H , including
MPO, BSA, HGB,  , CD13, TB and CEA (Figure 1c). As
cells with good biocompatibility.
To further validate the selectivity of TT for H
2 2
inflammatory cells, RAW264.7 cells which could generate H O
2
O
2
2 2
O and MPO in
v

3
6d, 15
expect, only with the aid of MPO TT showed obvious
fluorescence signal. Moreover, dynamic light scattering (DLS)
and transmission electron microscope (TEM) tests were also
used for measuring the change of particle size after incubation.
The particle size was distinctly bigger than TT only (Figure S30).
To obtain bigger TT aggregates for observation by naked eyes,
and MPO were chosen for further verification.
Firstly, the
real-time CLSM images of RAW264.7 cells were incubated with
TT and MTG (Figure 2a). Especially, to avoid interference during
co-localization with commercial dyes, MTG would subsequently
add after the incubation of TT in 65 min. The blue fluorescence
signal enhanced very obvious after incubation in 35 min (Figure
2b). And the blue fluorescence signal could overlap well with the
green fluorescence signal of MTG (Figure 2c). While RAW264.7
cells had faint blue fluorescence signal with 3 M T1T incubation
under the same condition because of its poor water solubility
and inability to form long oligomer (Figure S35). Furthermore,
1
2 2
00 M H O were respectively added into 1 mg/mL TT in
aqueous solution with and without 10 g/mL MPO to incubate for
0
3
0 min at 37 C. Compared with the insoluble TN, TT could only
exhibit intense blue fluorescence and form aggregate with MPO
and H simultaneous addition (Figures 1d and S31). It clearly
indicated that TT had response property to H and MPO.
To assess the imaging capacity of TT for monitoring H
living cells, and consider the intracellular expression of H
2
O
2
2
O
2
2 2
phorbol-12-myristate-13-acetate (PMA) was used to induce H O
1
5
2
O
2
in
generation via a cellular inflammation response. RAW264.7
cells could be seen that the fluorescence intensity increased
distinctly upon stimulation with PMA from 15 M to 150 M
(Figure S36). The average blue and green fluorescence intensity
of RAW264.7 cells were all obviously enhanced as shown in
2
O
2
and
1
4
peroxidase, HeLa cells as severe cancer cell model were
chosen for cell experiment. Different concentrations of TT (1.0

M, 3.0 M and 10.0 M) were incubated with HeLa cells for 4 h
under the standard cell culture conditions (Figure S32). It
indicated that 3.0 M of TT was bright enough for cell imaging
with blue fluorescence. Moreover, the commercial dyes Mito-
tracker green (MTG) was regarded as the co-localized reagent
for TT to further illuminate its imaging effect of H O in
2 2
mitochondria. The blue fluorescence of TT was overlapped well
with the green fluorescence of MTG (Figure S33a). When HeLa
Figure S36d. It mainly due to large amounts of H
produced after the stimulation, which indicated that the probe
could image of H in inflammatory cells. Moreover, RAW264.7
cells displayed strong blue and green fluorescence signals after
4 h incubation with TT and MTG (Figure 3a). In addition, the
blue and green fluorescence signals also respectively increased
2 2
O was
2
O
2
2 2
15.3% and 36.8% after RAW264.7 cells pretreated with H O
cells were pretreated with MPO and H
2
O
2
, the blue and green
and MPO (Figures 3a, 3b and 3e). However, the normal human
lung fibroblast (HLF) cells showed the barely blue fluorescence
signals and the apparently green fluorescence signals (Figure
3c). The location of MPO is in the cytoplasm, and high level of
fluorescence signals were enhanced (Figure S33b). Especially,
there were some dying cells with strong blue fluorescence
signals after prolonging incubation time to 12 h (Figure S33c,
3
3d). The average blue fluorescence intensity of HeLa cells and
2 2
H O is in the mitochondria and cytoplasm for RAW264.7 cells
3
the pretreated HeLa cells showed a similar trend with MTG
green channel (Figure S33e). However, TN and MTG co-
incubated HeLa cells could induce strong green fluorescence
but negligible blue fluorescence in the same condition (Figure
2 2
but not in HLF cells. Particularly, the H O and MPO pretreated
HLF cells simultaneous exhibited strong blue and green
fluorescence signals that each enhanced 1450.8% and 54.5%
(Figures 3c, 3d and 3f). Compared with the variance ratio of blue
and green fluorescence intensity between RAW264.7 cells and
2 2
S34). It revealed that TT could respond well to H O in HeLa
Figure 4. (a) The experimental scheme of TT incubated with RAW264.7 &
HLF co-cultured cells to simulate tumor microenvironment; (b-d) The CLSM
images of RAW264.7 cells, HLF cells and RAW264.7 & HLF co-cultured cells
incubated with 20.0 M TT for 24 h, 3.0 M MTG and 0.2 M PI for 30 min
under the standard cell culture conditions, respectively; (e) Western blot
results of RAW264.7 cells after incubation with PBS, 20.0 M TT and 50.0 M
TT for 24 h, respectively. (f-h) Bio-TEM images of RAW264.7 cells incubated
with PBS, 20 M TT and 50 M TT for 24 h, respectively. Scale bar: 20 m.
Figure 3. (a-d) The CLSM images of RAW264.7 cells, the MPO & H
2 2
O
pretreated RAW264.7 cells, HLF cells and the MPO & H pretreated HLF
2 2
O
cells incubated with TT (3.0 M), and MTG (3.0 M) for 4 h under the standard
cell culture conditions, respectively. (e-f) The average fluorescence intensity of
RAW264.7 cells, the MPO & H
2 2
O pretreated RAW264.7 cells, HLF cells and
the MPO & H pretreated HLF cells, respectively. Scale bar: 20 m.
2 2
O
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201712803
COMMUNICATION
pretreated RAW264.7 cells, the variance ratio of blue and green Acknowledgements
fluorescence intensity between HLF cells and pretreated HLF
cells significant increased, especially for the blue fluorescence
signal. Moreover, the blue fluorescence intensity was stronger in
HeLa cells than that in RAW264.7 cells (Figure S37). It could
further demonstrate that TT could distinguish intracellular H O
2 2
and MPO levels between inflammatory cells, cancer cells and
normal cells.
This work is supported by the National Basic Research Program
of China (973 Program, 2015CB932600) ， the National Key
R&D Program of China (2017YFA0208000, 2016YFF0100800)，
the National Natural Science Foundation of China (21525523,
21722507, 21574048, 21605053), China Postdoctoral Science
Foundation funded project (2017M620309), The Fok Ying-Tong
Education Foundation, China (151011). We thank Dr. Yue'e
Peng in State Key Laboratory of Biogeology and Environmental
Geology for the UHPLC-MS analysis and Dr. Hui Xu in
Ultrastructural Pathology Laboratory of Tongji Medical College,
Huazhong University of Science and Technology for Bio-TEM
analysis.
To evaluate the possible cytotoxic effects of TT for different
cell lines, we performed cell viability experiment within HeLa
cells, RAW264.7 cells and HLF cells. The MTT tests could be
verified the distinct cytotoxicity of TT in HeLa cells and
RAW264.7 cells rather than HLF cells (Figure S38). For further
prove its inhibitory effect, RAW264.7&HLF co-cultured cells
1
6
were carried out (Figure 4a). In this model, a commercial red
fluorescence dye propidium Iodide (PI) was chosen for detecting
dead cells. The bright blue, green and red fluorescence signals
were observed which demonstrated the good inhibitory effect of
TT in RAW264.7 cells (Figure 4b). However, the HLF cells only
showed green fluorescence signal of MTG, indicating good
cellular activity (Figure 4c). In the following, RAW264.7 cells and
HLF cells were co-cultured and incubated with TT, MTG and PI.
As shown in Figure 4d, red fluorescence signals could only be
observed in the RAW 264.7 cells which exhibited features of
apoptosis. The blue and green fluorescence intensity of
RAW264.7 cells were much higher than that in HLF cells
Conflict of interest
The authors declare no conflict of interest.
Keywords: aggregation-induced emission • biocatalyst •
hydrogen peroxide • self-polymerization • cell inhibition
[1]
a) H. Guo, J. B. Callaway, J. P. Ting, Nat. Med. 2015, 21, 677-687; b) S.
I. Grivennikov, F. R. Greten, M. Karin, Cell 2010, 140, 883-899; c) A.
Mantovani, P. Allavena, A. Sica, F. Balkwill, Nature 2008, 454, 436-444.
a) G. S. Shadel, T. L. Horvath, Cell 2015, 163, 560-569; b) R. A. Cairns,
I. S. Harris, T. W. Mak, Nat. Rev. Cancer. 2011, 11, 85-95; c) N.
Houstis, E. D. Rosen, E. S. Lander, Nature 2006, 440, 944-948; d) K. J.
Barnham, C. L. Masters, A. I. Bush, Nat. Rev. Drug. Discovery 2004, 3,
[
2]
(
Figures S39 and S40). In the absence of TT, RAW264.7 cells
could just display green fluorescence signal (Figure S41a). On
the contrary, the TT aggregate could lead to inhibition of cell
growth and reveal bright red fluorescence (Figure S41b).
Moreover, western blots were conducted using a standard
protocol to testify the possible cell signaling pathway of TT in
RAW264.7 cells. Compared with the PBS incubated RAW264.7
cells, the protein expression of Bcl-2 was decreased significantly
while Casp-9 and Casp-3 were increased for TT incubated
205-214.
[3]
[4]
a) W. N. Nauseef, Cell. Microbiol. 2014, 16, 1146-1155; b) J. M. Souza,
B. I. Giasson, Q. Chen, V. M. Y. Lee, H. Ischiropoulos, J. Biol. Chem.
2000, 275, 18344-18349; c) D. A. Malencik, J. F. Sprouse, C. A.
Swanson, S. R. Anderson, Anal. Biochem. 1996, 242, 202-213; d) H. G.
Hall, Cell 1978, 15, 343-355.
1
7
R. Etzioni, N. Urban, S. Ramsey, M. McIntosh, S. Schwartz, B. Reid, J.
Radich, G. Anderson, L. Hartwell, Nat. Rev. Cancer. 2003, 3, 243-252.
a) M. Ye, Y. Han, J. Tang, Y. Piao, X. Liu, Z. Zhou, J. Gao, J. Rao, Y.
Shen, Adv. Mater. 2017, 29, 1702342; b) J. Shi, P. W. Kantoff, R.
Wooster, O. C. Farokhzad, Nat. Rev. Cancer. 2016, 17, 20-37; c) Z.
Deng, Y. Qian, Y. Yu, G. Liu, J. Hu, G. Zhang, S. Liu, J. Am. Chem.
Soc. 2016, 138, 10452-10466; d) P. T. Wong, S. K. Choi, Chem. Rev.
2015, 115, 3388-3432.
RAW264.7 cells after 24h (Figures 4e and S42). While there
was almost no difference in the protein expression between the
PBS incubated HLF cells and the TT incubated HLF cells
[5]
(
(
Figure S43). Particularly, transmission electron microscope
TEM) images of RAW264.7 cells revealed the obvious
difference about the mitochondria after incubation with PBS, 20
1
8

M and 50 M TT (Figures 4f, 4g and 4h). It directly
[6]
a) Q. Chen, C. Liang, X. Sun, J. Chen, Z. Yang, H. Zhao, L. Feng, Z.
Liu, Proc. Natl. Acad. Sci. USA 2017, 114, 5343-5348; b) G. Liu, G.
Zhang, J. Hu, X. Wang, M. Zhu, S. Liu, J. Am. Chem. Soc. 2015, 137,
corroborated the mitochondria damage induced by TT in
RAW264.7 cells.
In conclusion, aiming at the widespread problem of detecting
and monitoring inflammation cells, we have dexterously
11645-11655; c) E. Suraniti, S. B. Amor, P. Landry, M. Rigoulet, E.
Fontaine, S. Bottari, A. Devin, N. Sojic, N. Mano, S. Arbault, Angew.
Chem. Int. Ed. 2014, 53, 6655-6658; d) E. Rodrꢀguez, M. Nilges, R.
Weissleder, J. W. Chen, J. Am. Chem. Soc. 2010, 132, 168-177.
a) J. Hui, L. Bao, S. Li, Y. Zhang, Y. Feng, L. Ding, H. Ju, Angew.
Chem. Int. Ed. 2017, 56, 8139-8143; b) P. Li, L. Liu, H. Xiao, W. Zhang,
L. Wang, B. Tang, J. Am. Chem. Soc. 2016, 138, 2893-2896; c) D. Lee,
S. Khaja, J. C. Velasquez-castano, M. Dasari, C. Sun, J. Petros, W. R.
Taylor, N. Murthy, Nat. Mater. 2007, 6, 765-769.
designed and optimally synthesized
fluorescent probe TT for H -based and peroxidase-specific
cooperative catalyzed AIEgen self-polymerization in the
presence of H and MPO. It clearly confirmed the intracellular
selective imaging of H and MPO in inflammatory cells with TT.
a novel theranostic
2
O
2
[7]
2
O
2
2
O
2
Importantly, TT could be used for cell selective inhibition through
mitochondria damage route, and does no harm to normal cells.
The present study provides a fluorescent tool for inflammatory
cell selective imaging and inhibition to achieve the precise
treatment. It might be broadly applicable to inflammation
theranostics in biomedical systems.
[
8]
9]
a) Y. Cheng, F. Huang, X. Min, P. Gao, T. Zhang, X. Li, B. Liu, Y. Hong,
X. Lou, F. Xia, Anal. Chem. 2016, 88, 8913-8918; b) X. Lou, Z. Zhao, B.
Z. Tang, Small 2016, 12, 6430-6450; c) J. Mei, N. L. C. Leung, R. T. K.
Kwok, J. W. Y. Lam, B. Z. Tang, Chem. Rev. 2015, 115, 11718-11940.
C. Li, T. Wu, C. Hong, G. Zhang, S. Liu, Angew. Chem. Int. Ed. 2012,
[
51, 455-459.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201712803
COMMUNICATION
[
10] X. Wang, J. Hu, G. Zhang, S. Liu, J. Am. Chem. Soc. 2014, 136, 9890-
893.
11] a) Z. Feng, T. Zhang, H. Wang, B. Xu, Chem. Soc. Rev. 2017, 46,
470-6479; b) Z. Feng, H. Wang, R. Zhou, J. Li, B. Xu, J. Am. Chem.
9
[
6
Soc. 2017, 139, 3950-3953; c) H. Wang, Z. Feng, Y. Wang, R. Zhou, Z.
Yang, B. Xu, J. Am. Chem. Soc. 2016, 138, 16046-16055.
[
12] a) H. Q. Feng, X. Zheng, T. Han, R. T. K. Kwok, J. W. Y. Lam, X.
Huang, B. Z. Tang, J. Am. Chem. Soc. 2017, 139, 10150-10156; b) C. J.
Zhang, G. Feng, S. Xu, Z. Zhu, X. Lu, J. Wu, B. Liu, Angew. Chem. Int.
Ed. 2016, 55, 6192-6196; c) J. Liang, H. Shi, R. T. K. Kwok, M. Gao, Y.
Yuan, W. Zhang, B. Z. Tang, B. Liu, J. Mater. Chem. B 2014, 2, 4363-
4370; d) J. Wang, J. Mei, R. Hu, J. Z. Sun, A. Qin, B. Z. Tang, J. Am.
Chem. Soc. 2012, 134, 9956-9966; e) N. W. Tseng, J. Liu, J. C. Y. Ng,
J. W. Y. Lam, H. H. Y. Sung, I. D. Williams, B. Z. Tang, Chem. Sci.
2012, 3, 493-497.
[
13] a) X. Li, M. Jiang, J. W. Y. Lam, B. Z. Tang, J. Y. Qu, J. Am. Chem.
Soc. 2017, 139, 17022-17030; b) J. Liang, B. Z. Tang, B. Liu, Chem.
Soc. Rev. 2015, 44, 2798-2811; c) J. Mei, Y. Hong, J. W. Y. Lam, A.
Qin, Y. Tang, B. Z. Tang, Adv. Mater. 2014, 26, 5429-5479; d) Z. Wang,
S. Chen, J. W. Y. Lam, W. Qin, R. T. K. Kwok, N. Xie, Q. Hu, B. Z.
Tang, J. Am. Chem. Soc. 2013, 135, 8238-8245.
[
14] a) J. S. Nam, M. G. Kang, J. Kang, S. Y. Park, S. J. C. Lee, H. T. Kim, J.
K. Seo, O. H. Kwon, M. H. Lim, H. W. Rhee, T. H. Kwon, J. Am. Chem.
Soc. 2016, 138, 10968-10977; c) M. Wang, S. Sun, C. I. Neufeld, B.
Perez-Ramirez, Q. Xu, Angew. Chem. Int. Ed. 2014, 53, 13444-13448.
15] a) B. Dong, X. Song, X. Kong, C. Wang, Y. Tang, Y. Liu, W. Lin, Adv.
Mater. 2016, 28, 8755-8759; b) M. Abo, Y. Urano, K. Hanaoka, T. Terai,
T. Komatsu, T. Nagano, J. Am. Chem. Soc. 2011, 133, 10629-10637.
16] a) Y. Cheng, C. Sun, X. Ou, B. Liu, X. Lou, F. Xia, Chem. Sci. 2017, 8,
[
[
4571-4578; b) Y. Ma, Z. Wang, M. Zhang, Z. Han, D. Chen, Q. Zhu, W.
Gao, Z. Qian, Y. Gu, Angew. Chem. Int. Ed. 2016, 55, 3304-3308.
17] a) M. Kurokawa, S. Kornbluth, Cell 2009, 138, 838-854; b) R. J. Youle,
A. Strasser, Nat. Rev. Mol. Cell. Bio. 2008, 9, 47-59.
[
[
18] a) L. L. Li, S. L. Qiao, W. J. Liu, Y. Ma, Dong. Wan, J. Pan, H. Wang,
Nat. Commun. 2017, 8, 1276; b) C. Li, Y. Zhang, Z. Li, E. Mei, J. Lin, F.
Li, C. Chen, X. Qing, L. Xiong, H. Hao, Y. Yang, P. Huang, Adv. Mater.
2017, 30, 1706150.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201712803
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
For the first time, the H
2
O
2
-responsive
Yong Cheng, Jun Dai, Chunli Sun, Rui
Liu, Tianyou Zhai, Xiaoding Lou,* and
Fan Xia*
and peroxidase-mediated therapeutic
strategies with AIEgens have been
developed through intracellular self-
assembly in the presence of H
O
2 2
and
Page No. – Page No.
myeloperoxidase. The methods
described herein can provide a
fluorescent tool for inflammatory cell
selective imaging and inhibition to
achieve the precise treatment.
2 2
Intracellular H O -responsive AIEgen
with peroxidase-mediated catalysis
for inflammatory cell selective
imaging and inhibition
This article is protected by copyright. All rights reserved.