Fe3O4/Ag/Bi2MoO6 Photoactivatable Nanozyme for Self-Replenishing and Sustainable Cascaded Nanocatalytic Cancer Therapy

Abstract

Catalytic cancer therapy based on nanozymes has recently attracted much interest. But the types of the current nanozymes are limited and their efficiency is usually compromised and not sustainable in the tumor microenvironment (TME). Therefore, combination therapy involving additional therapeutics is often necessary and the resulting complication may jeopardize the practical feasibility. Herein, an unprecedented “all‐in‐one” Fe3O4/Ag/Bi2MoO6 nanoparticle (FAB NP) is rationally devised to achieve synergistic chemodynamic, photodynamic, photothermal therapy with guidance by magnetic resonance, photoacoustic, and photothermal imaging. Based on its manifold nanozyme activities (mimicking peroxidase, catalase, superoxide dismutase, glutathione oxidase) and photodynamic property, cascaded nanocatalytic reactions are enabled and sustained in TME for outstanding therapeutic outcomes. The working mechanisms underlying the intraparticulate interactions, sustainability, and self‐replenishment arising from the coupling between the nanocatalytic reactions and nanozyme activities are carefully revealed, providing new insights into the design of novel nanozymes for nanocatalytic therapy with high efficiency, good specificity, and low side effects. This article is protected by copyright. All rights reserved

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ReseaRch aRticle
Fe3O4/Ag/Bi2MoO6 Photoactivatable Nanozyme for
Self-Replenishing and Sustainable Cascaded Nanocatalytic
Cancer Therapy
Changyu Cao, Hai Zou, Nan Yang, Hui Li, Yu Cai, Xuejiao Song,* Jinjun Shao,
Peng Chen,* Xiaozhou Mou,* Wenjun Wang, and Xiaochen Dong*
C. Cao, N. Yang, H. Li, X. Song, J. Shao, X. Dong
Key Laboratory of Flexible Electronics and Institute of Advanced Materials
School of Physical and Mathematical Sciences
Nanjing Tech University
Nanjing , China
E-mail: xjsong@njtech.edu.cn; iamxcdong@njtech.edu.cn
W. Wang
School of Physical Science and Information Technology
Liaocheng University
Liaocheng , China
H. Zou
Department of Oncology
Shanghai Medical College
Fudan University
Shanghai , China
DOI: 10.1002/adma.202106996
good specificity, and low side-eect.[–]
The recent advance in nanochemistry
and nanocatalysis has stimulated rapid
development of nanomaterials with
enzyme-mimicking activities.[–] These
nanozymes generally outperform natural
enzymes because of excellent stability,
high catalytic activity, multifunctionality,
and low cost. Moreover, nanozymes may
be designed to be photoactivatable for
localized treatment.[–]
But most of current nanozymes mimic
peroxidase (POD) and a few simulate
catalase (CAT) to convert HO into ·OH
for chemodynamic therapy (CDT) or into
oxygen to enhance O-dependent photo-
dynamic therapy (PDT).[–] The eec-
tiveness of these strategies is, however,
not sustainable owing to limited supply
of HO and suppression of the gener-
ated reactive oxygen species (ROS) by
the elevated antioxidants in TME.[–]
In addition, most nanozymes are not
able to catalyze multielectron reactions, such as simulating
superoxide dismutase (SOD) to reduce O to HO. Therefore,
combination therapy involving additional therapeutics is nec-
essary.[–] This however complicates fabrication, encapsula-
tion, delivery, and release processes, making it not practical
Catalytic cancer therapy based on nanozymes has recently attracted much
interest. However, the types of the current nanozymes are limited and their
eciency is usually compromised and not sustainable in the tumor micro-
environment (TME). Therefore, combination therapy involving additional ther-
apeutics is often necessary and the resulting complication may jeopardize the
practical feasibility. Herein, an unprecedented “all-in-one” Fe3O4/Ag/Bi2MoO6
nanoparticle (FAB NP) is rationally devised to achieve synergistic chemo-
dynamic, photodynamic, photothermal therapy with guidance by magnetic
resonance, photoacoustic, and photothermal imaging. Based on its manifold
nanozyme activities (mimicking peroxidase, catalase, superoxide dismutase,
glutathione oxidase) and photodynamic property, cascaded nanocatalytic
reactions are enabled and sustained in TME for outstanding therapeutic out-
comes. The working mechanisms underlying the intraparticulate interactions,
sustainability, and self-replenishment arising from the coupling between
the nanocatalytic reactions and nanozyme activities are carefully revealed,
providing new insights into the design of novel nanozymes for nanocatalytic
therapy with high eciency, good specificity, and low side eects.
1. Introduction
Catalytic cancer therapy, enabled by enzymatic reactions in
the tumor microenvironment (TME), has attracted increasing
interest owing to its potential to achieve high eectiveness,
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/./adma..
Y. Cai, X. Mou
Clinical Research Institute
Zhejiang Provincial People’s Hospital
Aliated People’s Hospital
Hangzhou Medical College
Hangzhou , China
E-mail: mouxz@zju.edu.cn
P. Chen
School of Chemical and Biomedical Engineering
Lee Kong Chian School of Medicine
Nanyang Technological University
 Nanyang Drive, Singapore , Singapore
E-mail: chenpeng@ntu.edu.sg
Adv. Mater. 2021, 33, 

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due to poor reproducibility, reduced eectiveness, high side-
eects, and high cost.
BiMoO (BMO) NP has been widely used as photocatalysts
to decompose organic pollutants.[] Its potential for photody-
namic therapy was suggested based on in vitro experiments.[]
However, the UV absorption property of BMO NP makes its
clinical use impractical because short-wavelength lights cannot
penetrate through the skin and cause phototoxicity. To tackle
the aforementioned issues, we rationally designed a FeO/Ag/
BiMoO nanoparticle (FAB NP) which simultaneously pos-
sesses high POD, CAT, SOD, glutathione oxidase (GSHOD),
and photodynamic activities. Doping of FeO and Ag NPs
endows UV-absorbing BMO NP, which with strong NIR-II
absorption, greatly enhanced photocatalytic activities, ferro-
magnetic and photothermal eects which enable magnetic
resonance (MR), photoacoustic (PA), and photothermal (PT)
imaging to guide the nanocatalytic therapy. Based on both in
vitro and in vivo experiments, we demonstrated that such an
unprecedented photoactivatable “all-in-one” nanoparticulate
system enables synergistic chemodynamic, photodynamic,
and photothermal therapy as illustrated in Figure 1. Further,
the working mechanisms underlying the intraparticulate
interactions, sustainability, and self-replenishment arising from
the coupling between the cascaded nanocatalytic reactions and
manifold nanozyme activities are carefully revealed. This study
provides new insights to design novel nanozymes for catalytic
cancer therapy with high eciency, good specificity, and low
side eects, as well as for other theranostic applications.
2. Results and Discussion
FAB NPs were fabricated by a three-step synthesis (Figure ),
involving hydrothermal synthesis of BMO NPs, photoreduc-
tion of Ag NPs, and solvothermal doping of FeO together with
surface capping with hydrophilic polyvinylpyrrolidone (PVP)
(Figure2a; and Figure S, Supporting information). As shown
by transmission electron microscopy (TEM), FAB NPs have an
aspect ratio of ≈. with an average length of ≈. ± . nm
(n= ) (Figure a, b). Such size is favorable for nanopar-
ticle retention in tumor tissues via enhanced permeability and
retention (EPR) eect. FAB NPs can well and stably disperse
in various media because of the small size and PVP coating
(Figure S, Supporting Information). The high-resolution TEM
Adv. Mater. 2021, 33, 
Figure 1. Schematic illustration for the fabrication of FAB nanozyme and mechanisms of synergistic CDT/PDT/PTT therapy.

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(HRTEM) reveals three crystalline lattice spacings of ., .,
and .nm, corresponding to (), (), and () planes of
Ag, FeO, and BMO NPs, respectively. These high-index facets
were also identified by the selected area electron diraction
(SAED) pattern (Figurea).
The elemental mapping of FAB NPs demonstrates the
homogenous distribution of Bi, Mo, O, Fe, and Ag (Figurec).
The atomic composition is also confirmed by X-ray photo-
electron spectroscopy (XPS) (Figure d; and Figure S, Sup-
porting Information). The high-resolution XPS Mo spectrum in
Figuree exhibits four major peaks derived from Mo d/ and
Mo d/, which can be deconvolved into the double peaks at
. and . eV from Mo+ and double peaks at . and
.eV from Mo+. The XPS spectrum of Fe can be fitted by
eight peaks (Figuref). Among them, the peaks at ., .,
., and . eV are assigned to Fe+, while the other four
peaks at ., ., ., and . eV are ascribed to Fe+.
Besides, as shown in Figure S (Supporting Information), in
the presence of oxidant (HO), the binding energy of FAB NP
upshifts, indicating the transition of Fe+/Mo+ to the higher
valence state (Fe+/Mo+); while in the presence of reductant
(GSH), the binding energy shifts downward, indicating the
reduction of Fe+/Mo+ to Fe+/Mo+. Taken together, the exist-
ence of Fe+/Fe+ and Mo+/Mo+ redox couples endow the nan-
oparticle with enzymatic properties.
As schematically proposed in Figure 3a, electrons are greatly
enriched in the conduction band of BMO NP because of pho-
toexcitation, migration of excited electrons from FeO NP,
Adv. Mater. 2021, 33, 
Figure 2. Characterization of FAB NPs. a) TEM, HRTEM, SAED pattern. b) Size distribution. c) Elemental mapping. d) XPS survey spectrum. e,f) High-
resolution XPS spectra of Mo d and Fe p.

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and electron injection from Ag NP with lower work function,
whereby eciently catalyzing O reduction. On one hand, O
is reduced to ·O− via one electron transfer and generated
·O− is then oxidized toO by down-transition of Fe+/Mo+
to Fe+/Mo+ in FAB NP for photodynamic therapy. On the
other hand, O is reduced to HO via a two-electron pathway
mimicking superoxide dismutase (SOD). Coupling with up-
transition of Fe+/Mo+ to Fe+/Mo+, HO is then converted
to ·OH (mimicking peroxidase – POD) for chemodynamic
therapy or O (mimicking catalase – CAT) to sustain photo-
dynamic therapy in hypoxic TME. The eciency of PDT and
CDT are maintained by catalytic depletion of antioxidant GSH
via down-transition of Fe+/Fe+ and Mo+/Mo+ redox couples,
mimicking glutathione oxidase (GSHOD). Finally, the nonradi-
ative relaxation of photoexcited electrons enables photothermal
therapy. In sum, a cascade of nanocatalytic reactions (Figure S,
Adv. Mater. 2021, 33, 
Figure 3. Photo-enhanced catalytic activities of FAB nanozymes. FAB NP concentration is  µg mL–. (a) Schematic illustration of the working
mechanisms (GSH: glutathione, GSSG: glutathione disulfide). Orange arrows represent oxidation reactions. Green arrows represent reduction reac-
tions. Arrows with frames indicate the valence transition reactions. (b) O generation curve at pH . with or without HO addition or nm
laser irradiation (L). (c) HO production curves by FAB NPs and FeO/BMO NPs at pH = . or .. (d) Degradation of MB by FAB NPs. (e) Light
adsorption of DPBF decreases due to FAB-NP inducedO generation under laser irradiation with dierent durations (-s). (f) GSH depletion by FAB
NPs with dierent concentrations (-µg mL–).

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Supporting Information) is triggered in TME to continuously
produce cytotoxic ·OH andO, which are sustained by photo-
stimulation, coupling between reactions and nanozyme activi-
ties, and cycling between Fe+/Mo+ and Fe+/Mo+.
The CAT-like activity of FAB nanozyme was evidenced by
quick increase of dissolved O upon adding them into HO at
pH . (analogous to acidic TME) (Figureb). As expected, O
generation was enhanced by exposure to NIR-II laser irradiation
( nm), testifying the light enhancement of the nanozyme
activity. To assess the SOD-like activity of FAB nanozyme under
dierent conditions, KI was used as the detection probe which
reacts with HO to generate I−. As presented in Figure c,
with nm laser irradiation, much HO ( µmol L−) was
produced at pH .. In contrast, no obvious generation of
HO was observed without laser irradiation or in the absence
of Ag, implying their critical role to enrich free electrons for
catalyzing the two-electron reduction of O. Further, the POD-
likely activity of FAB nanozyme to reduce HO into ·OH for
chemodynamic therapy (CDT) was probed by methylene blue
(MB) whose light adsorption decreases upon reaction with
·OH. As shown in Figured, FAB NP is more POD-active in
acidic environment and with laser stimulation. Production of
·OH via Fenton-like reaction was further confirmed by its char-
acteristic signals in electron spin resonance (ESR) (Figure Sa,
Supporting Information).
As evidenced by the decrease of light absorption of
,-diphenylisobenzofuran (DPBF) and the characteristic sig-
nals in ESR, FAB NPs were also able to produce abundantO
upon NIR-II irradiation (Figuree; and Figures Sb and S, Sup-
porting Information). Thus, FAB NP can serve as an eective
photosensitizer for photodynamic therapy (PDT). Noteworthy,
the eciency of the current chemodynamic and photodynamic
therapies are largely compromised by the antioxidant defense
system in tumor tissues, mainly because highly elevated GSH
molecules neutralize the generated ·OH andO. Interestingly,
FAB nanozyme can also mimic GSH oxidase (GSHOD) to
deplete GSH, thereby self-enhancing its CDT and PDT. This is
supported by the observation that the adsorption of ,′-dithiobis-
(-nitrobenzoic acid) decreases upon reaction with the oxidized
GSH in a FAB concentration-dependent manner (Figuref).
As shown in Figure S (Supporting Information), the band-
gaps of BMO, Ag/BMO, and FeO/Ag/BMO are ., .,
and . eV, respectively. Doping of Ag NP, which introduces
impurity energy level, and FeO NP, which has a higher
valence band level than that of BMO, greatly narrows the eec-
tive bandgap, and thus transforms UV-absorbing BMO NP to
a hybrid NP with strong adsorption in both NIR-I and NIR-II
regions (Figure S, Supporting Information). Ag@FeO NPs
have been previously synthesized for photothermal and chemo-
dynamic cancer therapy.[,] But, because of the wider bandgap
than FAB NP, it is not capable of NIR-II adsorption. Compared
with the commonly used nm laser in NIR-I, nm laser
in NIR-II used in this study is more desirable due to its higher
maximum permissible exposure (vs . W cm−) and deeper
tissue penetration depth. Being suitable for photothermal
therapy (PTT), FAB NP exhibits concentration-, laser power
density-, and irradiation time-dependent photothermal eect
under  nm laser irradiation, with a photothermal conver-
sion eciency of .% and outstanding stability (Figure S,
Supporting Information). Taken together, utilizing the multiple
nanozyme activities (mimicking CAT, SOD, POD, GSHOD),
photothermal eect, and ferromagnetic property from FeO
NP, FAB NP can serve as an unprecedented “all-in-one” thera-
peutic agent for synergistic CDT, PDT, and PTT guided by mul-
timodal (magnetic resonance, photoacoustic, photothermal)
imaging.
Using T murine breast cancer cells, it was found that
green fluorescence FITC-labeled FAB NPs, but not free
FITC molecules, were eectively endocytosed to enter the
nucleus (Figure S, Supporting Information) and caused a
quick increase of intracellular HO under laser irradiation
(Figure 4a) and depletion of GSH (Figureb). The intracellular
O level was reported by tris (,-diphenyl-,-phenanthroline)
ruthenium(II) dichloride (RDPP), whose fluorescence can be
quenched by O. As depicted in Figure c, addition of HO
(mimicking TME) plus laser greatly stimulated intracellular
O production by FAB nanozyme. Altogether, these in vitro
observations suggest that FAB nanozyme can eectively modu-
late TME to boost ROS generation by suppressing antioxidant
defense, producing HO, and relieving hypoxia.
FAB NP exhibited no apparent toxicity to human immor-
talized keratinocytes (HaCaTs) whereas it was cytotoxic to T
tumor cells in a dose-dependent manner (Figure d), pre-
sumably because tumor cells have higher endogenous HO
than normal cells. And the tumor-killing eect was greatly
enhanced by laser irradiation or adding HO (Figure e).
With µg mL− nanozyme, nm irradiation ( W cm−,
min), and  mM extracellular HO, essentially all T cells
were killed. Live/dead cell staining experiment (Figuref) and
flow cytometry (Figure g) further confirmed the CDT and
PDT eects of FAB NP toward tumor cells and the enhance-
ments by NIR-II irradiation and HO. Moreover, western blot-
ting analysis showed that Cas- expression was significantly
induced by FAB NP under laser irradiation, suggesting the
occurrence of Cas- dependent apoptosis. (Figure S, Sup-
porting Information). Intracellular ROS level was reported by
fluorescence increase of a cell-permeable probe (,-dichloro-
fluorescein diacetate). Consistently, with laser and external
HO, FAB NP became very potent to induce intracellular
ROS (Figureh,i).
The hemocompatibility of FAB NP was firstly confirmed
(Figure S, Supporting Information) before using T tumor-
bearing Balb/c mice to investigate the in vivo therapeutic per-
formance of FAB nanozyme. After intravenous (i.v.) injection,
the pharmacokinetic profiles of NPs were investigated and
the blood circulation half-time was determined to be . h
(Figure 5a). Endowed by FeO, FAB NP has a typical ferromag-
netic behavior with saturation magnetization of  emu g−
(Figureb) and r relaxivity of . × − − s− (Figure c),
therefore can act as a good contrast agent for MRI. After i.v.
injection of FAB NPs, the MR signal of tumor site increased
over time and reached the maximum at  h with a time con-
stant of  h (Figure d,e), indicating the dynamic accumu-
lation of NPs through the EPR eect. This is similar to the
dynamics revealed by PAI based on the photothermal eect of
FAB NP (Figuref). FAB NP accumulation in the tumor was
further confirmed by iron ion-enabled Prussian blue staining
(Figureg).
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The accumulation of FAB NPs in the heart, liver, spleen,
lung, kidney, and tumor site at dierent time points (– h)
was quantified by inductively coupled plasma-optical emis-
sion spectrometry (ICP-OES). As shown in Figureh, FAB
NPs were also retained in these major organs except heart
and reached maximum accumulation in the tumor at  h
before being metabolized. Therefore, in the following experi-
ments, laser stimulation was applied at this optimal time
point.
The tumor temperature of FAB NP injected mouse rose
to . °C in  min upon laser irradiation, indicating the
realization of photothermal therapy (Figure 6a,b). Without
lasering, the nonsustainable CDT enabled by FAB NPs sup-
pressed tumor growth to an extent. In comparison, min laser
irradiation once a day significantly inhibited tumor growth
(% reduction comparing to control) and irradiation twice a
day completely eliminated the tumor in  days, testifying the
outstanding potency of FAB NPs due to sustained and syner-
gistic combination of CDT, PDT, and PTT (Figurec–e).
Tumor tissues were harvested and stained with dihydro-
ethidium to report ROS levels. As expected, FAB NP alone
increased ROS in tumors due to chemodynamic generation
Figure 4. Intracellular catalyzes and cytotoxicity by FAB NPs. Unless otherwise stated, cells are T cells and FAB NP concentration is µg mL–.
(a) Intracellular HO generation under nm laser irradiation. (b) GSH depletion with dierent concentrations of FAB NPs ( to µg mL–).
(c) Cellular O level reflected by RDPP staining. Scar bar: µm. (d) Relative cell viability of HaCaTs and T cells after incubation with FAB NPs of
dierent concentrations. (e) Relative cell viability of T cells treated with FAB NPs of dierent concentrations, without or with HO addition and laser
irradiation. (f) Fluorescence images of T cells treated by FAB NPs and then stained by PI (red, dead cells) and Ca-AM (green, live cells). Scar bar:
µm. (g) Flow cytometry using Annexin-V-FTIC/PI assay. (h) Fluorescence images of T cells stained by DCFH-DA to indicate nanoparticle-induced
ROS generation. Scar bar: µm. Laser irradiation was applied only to the right sides of the dashed lines. (i) Corresponding quantitative analysis of
ROS generation.

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of ·OH, while additional laser irradiation caused much more
ROS generation because of additional photodynamic pro-
duction ofO and photodriven self-replenishment of the
coupled cascaded nanocatalytic reactions (Figure f). Apop-
tosis of tumor cells caused by the photoactivatable nano-
catalytic therapy was confirmed by Hematoxylin and eosin
(H&E) staining (Figure g). Moreover, inhibition of tumor
cell proliferation was evidenced by the Ki- immunohisto-
chemistry assay (Figureh; and Figure S in the Supporting
Information). Noteworthy, the mouse body weight was not sig-
nificantly aected by laser or FAB NP treatment (Figure S,
Supporting Information). Based on H&E staining, no notice-
able damage was observed in heart, liver, spleen, lung, or
kidney (Figure S, Supporting Information). Blood bio-
chemistry assay and complete blood panel analysis after the
treatments also did not show any abnormality (Figure S,
Supporting Information). Taken together, the catalytic therapy
does not exert apparent o-target toxicity.
Figure 5. Pharmacokinetic, imaging, and biodistribution studies. (a) Blood circulation curve after i.v. injection of FAB NPs ( µg mL–). (b) Field-
dependent magnetization curves at  K for Ag/BMO and FAB NPs. (c) MR images of aqueous solutions containing dierent amounts of FAB NPs
and the corresponding relative T relaxation rates. (d) MR images of T tumor on mice, at dierent time points after injection of FAB NPs. (e) Quan-
tification of MR signals. (f) PA images of the tumor at dierent time points. (g) Prussian blue staining of the tumor tissues after injection of FAB NPs.
Scar bar: µm. (h) Biodistribution of FAB NPs at , , ,  and  h.

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3. Conclusion
In summary, to tackle the current problems of catalytic cancer
therapy, including compromised and nonsustainable e-
ciency, incapability to catalyze multielectron reactions, and
complexity due to involvement of multiple therapeutic compo-
nents, we herein developed a simple unprecedented “all-in-one”
nanozyme – FeO/Ag/BiMoO nanoparticle (FAB NP).
Through essential intraparticulate coupling, the NP exhibits a
narrowed bandgap for ecient NIR-II adsorption, enhanced
photocatalytic property, replenishable catalytic activity due
to existence of Mo+/Mo+ and Fe+/Fe+ redox sites, and fer-
romagnetic property. It enables eective chemodynamic,
photo dynamic, and photothermal therapy guided by magnetic
Figure 6. In vivo nanocatalytic therapy. (a) Photothermal images of T tumor-bearing mice injected with PBS (control) or FAB NPs (µg mL–,
µL), under nm laser irradiation ( W cm–) for dierent durations. (b) Corresponding temperature change. (c-e) Changes in tumor volume,
relative tumor weight and tumor size after dierent treatments. P-values were calculated by Student’s two-sided t-test. **P<., ***P<. (n = ).
(f) DHE staining of tumors with dierent treatments to indicate ROS level. Scar bar: µm. (g, h) H&E (chromatins stained by purple-blue) and Ki
(cell proliferation indicated by brown staining) staining of tumors with dierent treatments. Scar bar: µm.

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resonance, photoacoustic, and photothermal imaging, as
evidenced by both in vitro and in vivo experiments. The out-
standing performance is attributed to synergy between the
multi-mode therapy, guidance by multimode imaging, sustain-
ability of the coupled catalytic reactions, and the simplicity of
the system. This study provides new insights to design novel
nanozymes for nanocatalytic therapy with high eciency, good
specificity, and low side-eects, as well as for other theranostic
applications.
4. Experimental Section
Preparation of BMO, Ag/BMO, and FAB NPs: First, . g
NaMoO·HO and . g Bi(NO)·HO were separately dissolved in
mL glycol under sonication, followed by mixing and addition of mL
ethanol. After stirring for . h, the mixture was hydrothermally treated
in a mL Teflon-lined autoclave at  °C for  h. The centrifugated
precipitate was washed thrice with deionized (DI) water and ethanol,
then dried in oven at  °C for  h. The resulting powder was calcined
at  °C for  h ( °C min− heating rate) to obtain BMO NPs. Ag/
BMO NPs were synthesized by the photoreduction method. Specifically,
g of BMO NPs was dissolved in  mL ethanol under sonication, and
subsequently, mL AgNO solution (mg mL−) was added. The mixture
was then irradiated with a Xe lamp ( W,  h) for photoreduction of Ag
NPs onto BMO NPs. The centrifugated precipitate was washed thrice
with ethanol to remove the unreacted AgNO. Next, the sample was
dried at  °C for  h to obtain Ag/BMO NPs. To produce FAB NPs,
.g Ag/BMO NPs,  g FeCl·HO, g PVP, and  g natrium acetate
were dissolved into mL propanediol with ultrasonication for  min,
followed by titrating pH to . using NaOH ( ). After stirring for  h
at  °C, the above solution was hydrothermally treated in a mL of
Teflon-lined autoclave at  °C for  h. The centrifugated precipitate
was dried at  °C for  h and washed thrice with DI water and ethanol
to obtain FAB NPs.
Cell Culture, Cytotoxicity Assay, and Apoptosis Assay: Human
keratinocytes cells (HaCaTs) and mouse breast carcinoma cells (T
cells) were cultured with dulbecco’s modified eagle medium (DMEM)
medium supplemented with % fetal bovine serum (FBS), streptomycin
( µg mL−), and penicillin ( units mL−) in % CO atmosphere at
 °C. Cytotoxicity of FAB NPs was evaluated by MTT (-(,-Dimethylthiazol-
-yl)-,-diphenyltetrazolium bromide) assay. Specifically, cells ( µL,
 ×  cells mL−) were seeded into -well plates and incubated
with NPs with dierent concentrations (, ., ., , , , or
 µg mL−) for  h. Then, µL MTT solution (mg mL−) was added
for another  h incubation. After rinsing with phosphate buer solution
(PBS) to remove NPs,  µL dimethyl sulfoxide (DMSO) was used to
dissolve the formazan crystals sediment in each well. The absorbance at
nm was determined using a microplate spectrophotometer (Epoch ,
Biotek, USA). To test apoptosis induced by FAB NPs, T cells (. × )
were incubated with NPs (µg mL−) for  h, then rinsed with cold PBS
and immediately dyed with Annexin V-FITC/PI kit (KeyGEN, BioTECH),
followed by detection using flow cytometry (AccuriC, Biosciences).
Animal Experiments: Female Balb/c mice (– weeks old) were
ordered from the Comparative Medicine Centre of Yangzhou University.
The procedure was approved by Nanjing Tech University. PBS containing
T cells ( µL,  ×  cells) was subcutaneously injected into the
back of Balb/c mice to induce tumor. The tumor-bearing mice were
randomly divided into five groups: ) control (i.v. injection with µL
PBS); ) NIR irradiation only (nm, . W cm−, min, once a day);
) treatment with FAB NPs (i.v. injection with µL NP solution with
a concentration of  µg mL−); ) treatment of FAB NPs and NIR
irradiation at  h after injection once a day; ) treatment of FAB NPs
with NIR irradiation twice a day. Magnetic resonance imaging (MRI)
was conducted with a Bruker BioSpec / USR MR scanner (Bruker,
Germany). Photoacoustic imaging was performed through Vevo LAZR-X
Multimodal Imaging (FUJIFILM VisualSonics). Tumor tissues and blood
samples were digested with HNO and hydrochloric acid for ICP-OES
analysis.
Supporting Information
Supporting Information is available from the Wiley Online Library or
from the author.
Acknowledgements
C,C., H.Z., and N.Y. contributed equally to this work. The work was
supported by NNSF of China (Nos. , , and
), Jiangsu Province Policy Guidance Plan (No. BZ),
Natural Science Foundation of Shandong Province (No. ZRKB),
“Taishan scholars” construction special fund of Shandong Province, and
AcRF Tier- Grant (No. MOE-T--) from Ministry of Education
of Singapore.
Conflict of Interest
The authors declare no conflict of interest.
Data Availability Statement
Research data are not shared.
Keywords
chemodynamic therapy, nanocatalytic therapy, nanozymes,
photodynamic therapy, photothermal therapy
Received: September , 
Revised: October , 
Published online: October , 
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