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Nanocatalytic Tumor Therapy www.advancedscience.com

Nanocatalytic Tumor Therapy by Biomimetic Dual

Inorganic Nanozyme-Catalyzed Cascade Reaction
Shanshan Gao, Han Lin, Haixian Zhang, Heliang Yao, Yu Chen,* and Jianlin Shi*

Tumor microenvironment (TME) is gen-

Emerging nanocatalytic tumor therapies based on nontoxic but catalyti- erally known to feature abundant unique
cally active inorganic nanoparticles (NPs) for intratumoral production of characteristics such as acidity,[1] hypoxia,[2]
high-toxic reactive oxygen species have inspired great research interest in inflammation,[3] and overproduced hydrogen
peroxide.[4] Based on the unique tumor
the scientific community. Nanozymes exhibiting natural enzyme-mimicking
physiological microenvironment and
catalytic activities have been extensively explored in biomedicine, mostly in the rising nanotechnology, a number of
biomolecular detection, yet much fewer researches are available on specific promising nanotheranostic strategies of
nanocatalytic tumor therapy. This study reports on the construction of an designing TME-specific/responsive nano-
efficient biomimetic dual inorganic nanozyme-based nanoplatform, which platforms for efficient tumor therapy and
triggers cascade catalytic reactions for tumor microenvironment responsive precise bioimaging diagnosis have been
extensively explored and developed.[5]
nanocatalytic tumor therapy based on ultrasmall Au and Fe3O4 NPs coloaded
Tumor cells produce large amounts of
dendritic mesoporous silica NPs. Au NPs as the unique glucose oxidase- hydrogen peroxide (H2O2) by the over-
mimic nanozyme specifically catalyze β-D-glucose oxidation into gluconic expressed superoxide dismutase (SOD)
acid and H2O2, while the as produced H2O2 is subsequently catalyzed by through a catalytic process by superoxide
the peroxidase-mimic Fe3O4 NPs to liberate high-toxic hydroxyl radicals for ions as generated from mitochondria.[6]
As a typical feature of TME, the overex-
inducing tumor-cell death by the typical Fenton-based catalytic reaction.
pressed H2O2 has thus been exploited for
Extensive in vitro and in vivo evaluations have demonstrated high nanocat- triggering responsive drug-releasing in
alytic-therapeutic efficacy with a desirable tumor-suppression rate (69.08%) chemotherapy or producing endogenous
based on these biocompatible composite nanocatalysts. Therefore, this work O2 for oxygen-favored cancer therapy such
paves a way for nanocatalytic tumor therapy by rationally designing inorganic as photodynamic therapy,[7] sonodynamic
nanozymes with multienzymatic activities for achieving high therapeutic therapy,[8] or radiotherapy.[9]
As an emerging efficient cancer-
efficacy and excellent biosafety simultaneously.
therapeutic modality, the proof-of-concept
nanocatalytic tumor therapy as first pro-
posed by our group[10] utilizes intratu-
S. Gao, H. Lin, H. Yao, Prof. Y. Chen, Prof. J. Shi
moral in situ catalytic chemical reactions to produce oxidative
State Key Laboratory of High Performance Ceramics and Superfine stress for inducing cancer-cell death by damaging intracellular
Microstructure biomolecule substances such as proteins, lipids, and DNA.[11]
Shanghai Institute of Ceramics A typical strategy of the proposed nanocatalytic tumor therapy
Chinese Academy of Sciences is the representative chemodynamic therapy,[12] which converts
Shanghai 200050, P. R. China
E-mail: [email protected]; [email protected] less reactive endogenous H2O2 into the most harmful reactive
S. Gao, H. Lin oxygen species (ROS), hydroxyl radicals (·OH) under mildly
University of Chinese Academy of Sciences acidic TME via an intratumoral Fenton or Fenton-like reac-
Beijing 100049, P. R. China tion by metal ions.[13] Such an endogenous but direct chemical
Dr. H. Zhang energy conversion strategy uses no external energy input such
Department of Ultrasound as laser, ultrasound, or magnetic field, thus avoiding the limi-
Fudan University Shanghai Cancer Center
Department of Oncology
tations of low tissue-penetration depth and nonspecificity of
Shanghai Medical College these external triggers on inducing cancer-cell death.
Fudan University Based on the fact that the intratumoral H2O2 concentra-
Shanghai 200032, P. R. China tion, generally believed to be 50–100 × 10−6 m,[4b] is too low to
The ORCID identification number(s) for the author(s) of this article produce desirable and sufficient amount of hydroxyl radicals
can be found under https://doi.org/10.1002/advs.201801733. for inducing satisfactory nanocatalytic-therapeutic efficacy via
© 2018 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Fenton or Fenton-like reactions, natural glucose oxidase (GOx)
Weinheim. This is an open access article under the terms of the Creative was introduced to elevate the intratumoral H2O2 concentration
Commons Attribution License, which permits use, distribution and re-
production in any medium, provided the original work is properly cited. through natural catalytic oxidation of intratumoral glucose to
H2O2 and gluconic acid.[14] However, natural GOx possesses
DOI: 10.1002/advs.201801733 several intrinsic drawbacks such as high cost in preparation

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and purification, and relatively low operational stability, which number of reports on peroxidase (POD)-mimic nanozymes
will undoubtedly hamper its practical biomedical application have been reported, while other kinds of enzyme-mimic NPs,
under complicated and harsh physiological environments.[15] such as GOx-mimic nanozymes, glutathione peroxidase-mimic
Therefore, exploring and developing natural GOx alternatives nanozymes, or SOD-mimic nanozymes, have been rarely
with much-enhanced stability and lowered cost is highly desir- explored. Fortunately, Rossi and co-workers discovered that
able and necessary. Au NPs could catalyze the oxidation of glucose to H2O2 and
Recently, the merging of biology with nanotechnology has glucono delta-lactone (GDL) under the presence of dissolved
motivated extensive research fever for designing functional oxygen, which was very similar to the reaction as catalyzed
nanoplatforms that exhibit unique natural enzyme-mimic cata- by GOx, suggesting that Au NPs could serve as a mimic for
lytic activities for a broad range of biomedical applications.[16] GOx.[27] Since then, owing to the unique GOx-mimic activity,
As the promising alternatives for natural enzymes, catalyti- Au NPs have been explored for diverse applications, most of
cally active nanomaterials, known as the so-called “artificial which involve biomolecule (DNA, glucose, etc.) detection, while
enzymes” or “nanozymes,” have demonstrated numbers of leaving many hidden applications to be discovered.
merits over natural enzymes, such as facile fabrication, low Bearing the unique GOx-mimicking catalytic activity of Au
cost, and robust stability against severe conditions.[17] So far, a NPs and POD-mimicking catalytic performance of Fe3O4 NPs,
variety of nanomaterials, such as carbon-based nanoparticles we herein report, for the first time, on a biomimetic dual inor-
(NPs),[18] metal NPs,[19] and metal oxides NPs[16a,20] have been ganic nanozyme-triggered TME-responsive cascade catalytic
discovered to possess unique enzyme-mimic catalytic activi- reaction for efficient nanocatalytic tumor therapy based on an
ties, which are extensively used in numerous fields, including “all-inorganic biocompatible nanosystem”, without employing
biomolecular detection,[21] biosensor,[22] antibacterial applica- any toxic chemical drug (Scheme 1). Ultrasmall and highly
tions,[23] immunoassays,[24] cancer diagnostics and therapy,[25] dispersed Au NPs and Fe3O4 NPs were successively integrated
and environmental monitoring.[26] Till now, an exceedingly large into the large pore channels of dendritic mesoporous silica NPs

Scheme 1. Schematic illustration of “toxic-drug-free” nanocatalytic tumor therapy by biomimetic inorganic nanomedicine-triggered cascade catalytic
reaction. The composite nanoplatform with dual inorganic nanozyme activity was fabricated by the sequential loading of Au NPs as GOx-mimic
nanozyme and Fe3O4 NPs as POD-mimic nanozyme into the large mesopores of DMSN NPs followed by PEGylation. The therapeutic process by
cascade catalytic chemical reaction includes the initial GOx-mimicking Au nanozyme-mediated catalytic oxidation reaction of glucose into H2O2, which
is further utilized as the reactant for the POD-mimicking Fe3O4 nanozyme-based catalytic Fenton reaction to produce highly toxic ·OH and subsequently
induce tumor-cell apoptosis.

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(DMSN NPs) to construct the composite nanoplatform, i.e., from the robust biomimetic nanozymes. It is noted that such
DMSN-Au-Fe3O4 NPs. After further modification with poly- a cascade reaction with TME acidity-responsiveness would
ethylene glycol (PEG) molecules for improved biocompatibility not be triggered under the neutral condition in normal tissue
and physiological stability, DMSN-Au-Fe3O4 NPs could accu- microenvironment, guaranteeing the high tumor-specificity
mulate into tumor tissue via the typical enhanced permeability and therapeutic biosafety.
and retention (EPR) effect, triggering the intratumoral TME- DMSN NPs with unique central-radial pore structures,
responsive cascade catalytic reaction. serving as the robust nanosupports for small NPs, were syn-
Acquiring an unusual anaerobic glycolytic behavior to sup- thesized by an anion-assisted approach based on the Stöber
port their metabolism and proliferation, tumor cells demand mechanism and sol–gel chemistry.[29] A high density of highly
nutrients, essentially glucose, in a hysterical manner.[28] There- dispersed and ultrasmall particle-sized Au NPs was confined
fore, in TME, masses of glucose molecules are transported into the large mesopores of DMSN NPs via an in situ reduc-
and accumulated, which provides the possibility of initiating tion reaction of HAuCl4 to produce DMSN-Au NPs, followed
catalytic reaction by utilizing glucose molecules. The intra- by the collection and integration of ultrasmall Fe3O4 NPs
tumoral cascade catalytic reaction is initially triggered by Au into the large mesopores of DMSN NPs to fabricate the final
NPs, the GOx mimic inorganic nanozyme which catalyzes the composite nanoplatform DMSN-Au-Fe3O4 NPs (Figure 1a).
intratumoral glucose oxidation, generating large amounts of Transmission electron microscopic (TEM) images show that
H2O2 molecules to serve as the substrate for the subsequent DMSN NPs exhibit the unique topology of central-radial den-
catalytic reaction where H2O2 is disproportionated by the dritic structure with a uniform diameter of about 140 nm
coloaded ultrasmall Fe3O4 NPs via the typical Fenton catalytic (Figure 1b and inset; Figure S1, Supporting Information). Scan-
reaction, liberating high-toxic hydroxyl radicals to effectively ning electron microscopic (SEM) images exhibit the obvious
induce tumor-cell death. DMSN-Au-Fe3O4 NPs as the potent wrinkle structure of DMSN NPs, and their corresponding
nanoplatforms are capable of realizing the endogenous cascade chemical composition was further confirmed by element map-
reaction for TME-specific and effective nanocatalytic tumor ping of Si and O elements (Figure S2, Supporting Informa-
therapy, in a noninvasive and “toxic-drug-free” way, benefiting tion). The Brunauer–Emmett–Teller surface area and the total

Figure 1. Structural and compositional characterizations of DMSN NPs, DMSN-Au NPs, and DMSN-Au-Fe3O4 NPs. a) Schematic diagram for the
fabrication of DMSN-Au-Fe3O4 NPs. TEM image of b) DMSN NPs, c,d) DMSN-Au NPs at varied magnifications, e,f) DMSN-Au-Fe3O4 NPs at different
magnifications. g) HADDF image, h) SEM image, and i) corresponding element mappings (for Si, O, Au, and Fe) of DMSN-Au-Fe3O4 NPs.

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pore volume of DMSN NPs were measured to be 197.5 m2 g−1 of silanol groups on surface, and the introduction of sur-
and 0.9 cm3 g−1, respectively, with an average pore diameter face amine groups by APTES treatment turned the negative
of 23.3 nm according to the nitrogen adsorption–desorption (−15.6 mV) zeta potential into positive (+17.4 mV). The highly
isotherm and corresponding pore-size distribution (Figure S3, negative zeta potential (−20.8 mV) of DMSN-Au-Fe3O4 NPs
Supporting Information). Such a unique branched structure ensures their excellent colloidal stability. The ultraviolet–visible
with large pore size and highly accessible surface area of DMSN (UV–vis) spectra confirm the successful synthesis of DMSN-Au
NPs is highly in favor of the subsequent growth of ultrasmall NPs and DMSN-Au-Fe3O4 NPs, featuring a typical absorption
Au NPs and deposition of Fe3O4 NPs. After functionalized peak at 505 nm attributed to the plasma resonance effect of
with amine groups by aminopropyltriethoxysilane (APTES) to Au NPs (Figure S9, Supporting Information). The atomic ratio
provide anchoring sites for Au NPs, the mesopores’ surface of among Si, Au, and Fe was calculated to be 1:0.67:0.40 by induc-
DMSN NPs was grown with Au NPs via an in situ reduction of tively coupled plasma-optical emission spectrometry (ICP-OES)
auric ions by NaBH4. TEM and SEM images reveal that ultras- measurements.
mall Au NPs of ≈1.5 nm in diameter have been well dispersed In tumor regions, owing to the unique GOx-mimic property
and immobilized within the mesopores channels of DMSN of Au nanozyme immobilized within the mesopores of DMSN
NPs (Figure 1c,d; Figure S4, Supporting Information), and the NPs, DMSN-Au-Fe3O4 NPs initially catalyze glucose oxidation
elemental mappings of Si, O, and Au elements for DMSN-Au in the presence of oxygen into gluconic acid and H2O2, which
NPs demonstrate the uniform distribution of Au NPs within was further catalyzed into highly toxic hydroxyl radicals (·OH)
DMSN’s matrix. by the coloaded POD-mimic Fe3O4 nanozyme via Fenton reac-
Subsequently, uniform and 1.5 nm sized Fe3O4 NPs were tion. In order to evaluate the function of Fe3O4 nanozyme in
initially synthesized by a pyrolysis methodology (Figure S5, Sup- producing ·OH, the catalytic performance of DMSN-Fe3O4 NPs
porting Information) and then firmly confined into DMSN-Au and the cascade catalytic performance of the biomimetic dual
NPs by soaking them in DMSN-Au NPs-dispersed dimethyl inorganic nanozyme DMSN-Au-Fe3O4 NPs were investigated in
sulfoxide (DMSO) solution for 24 h to obtain the DMSN-Au- detail.
Fe3O4 NPs. After the integration with Au and Fe3O4 NPs, the A typical colorimetric method based on 3,3′,5,5′-tetrameth-
unique morphology and dendritic structure of DMSN NPs were ylbenzidine (TMB) was introduced as a substrate to test the
well preserved without significant deformation (Figure 1e). POD-like catalytic activity of DMSN-Fe3O4 NPs. In the presence
High resolution TEM image (Figure 1f) clearly demonstrates of H2O2, DMSN-Fe3O4 NPs catalyzed the oxidation of TMB to
that the small Au and Fe3O4 NPs, both less than 2 nm in diam- form the oxidized and therefore blue-colored TMB (oxTMB) fea-
eters, have been uniformly decorated within the mesopore turing characteristic absorbances at 370 and 652 nm (Figure 2a).
structure of DMSN NPs. The relatively bright area with strong The possible reaction mechanism involves two steps where the
signal intensity in the high angle annular dark-field scanning OO bond in H2O2 molecule was broken into ·OH followed
TEM image (Figure 1g) indicates the presence and homoge- by TMB oxidation by ·OH to form oxTMB. UV–vis absorption
neous distributions of high-Z Au and Fe3O4 NPs. SEM image spectroscopy was used to monitor the production of the colori-
(Figure 1h) and corresponding elemental mappings (Figure 1i) metric product oxTMB. Negligible absorbance can be observed
of Si, O, Au, Fe elements also demonstrate the homogeneous in the absence of DMSN-Fe3O4 NPs (Figure 2b), suggesting
distributions of Au and Fe3O4 NPs into DMSN NPs. Similarly, that no oxidation reaction has occurred in the mixture of TMB
DMSN-Fe3O4 NPs were synthesized for the following experi- and H2O2. However, an apparently blue-colored solution can
ments at in vitro solution and intracellular levels. SEM and be obtained after the addition of DMSN-Fe3O4 NPs into TMB-
TEM images, and the corresponding elemental mappings of H2O2 mixture solution (pH 6.5) for 10 min with two major
Si, O, Fe elements also confirm the uniform distribution of absorbance peaks at 370 and 652 nm attributable to oxTMB,
Fe3O4 NPs into the DMSN’s mesopores in DMSN-Fe3O4 NPs which confirms the production of ·OH by DMSN-Fe3O4 NPs
(Figure S6, Supporting Information). and H2O2.
X-ray diffraction (XRD) patterns further verify the formation To further evaluate the catalytic activity of DMSN-Fe3O4
of Fe3O4 NPs and metallic Au NPs anchored on DMSN NPs nanomedicine, the steady-state catalytic kinetics was inves-
(Figure S7, Supporting Information). The diffraction peaks of tigated at room temperature in a reaction system containing
Fe3O4 NPs at 2θ of 18.9°, 29.7°, 35.4°, and 63.1° were respec- DMSN-Fe3O4 NPs, TMB, and H2O2 of varied concentrations
tively indexed to the (111), (220), (311), and (440) lattice planes (5, 10, 20, 30, 40, and 50 × 10−3 m) in Na2HPO4-citric acid
of Fe3O4 NPs (JCPDS No.26-1136). The diffraction peaks of buffer solution (pH 6.5). The time-dependent absorbance
DMSN-Au NPs at 2θ angle of 38.1°, 44.4°, 64.5°, and 77.5° variation of the reaction solution was monitored in time-scan
appeared, respectively, indexed to the (111), (200), (220), and mode at 652 nm using a microplate reader (Figure 2c). At each
(311) lattice planes of Au NPs (JCPDS No.04-0784). The XRD H2O2 concentration, the concentration-changing rate (v) of
patterns of DMSN-Fe3O4 and DMSN-Au-Fe3O4 NPs indicated oxTMB was calculated from the absorbance-changing rate via
that the diffraction peaks of Fe3O4 NPs and Au NPs decreased the Beer–Lambert law, A = εlc (A is the absorbance, ε is the
significantly after encapsulated into the DMSN NPs. molar absorbance coefficient, l is the path length, and c is the
The zeta-potential variations among DMSN, aminated molar concentration) with l = 10 mm and ε of 39 000 m−1 cm−1
DMSN (DMSN-NH2), DMSN-Au, and DMSN-Au-Fe3O4 NPs for oxTMB. Furthermore, the concentration change rates of
indicate the desirable synthesis in each step (Figure S8, Sup- TMB were plotted against corresponding H2O2 concentrations,
porting Information). Typically, the original DMSN NPs were which follows the Michaelis–Menten equation (Figure 2d),
negatively charged due to the presence of large amounts known as

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Figure 2. In vitro characterizations of the catalytic performances of DMSN-Fe3O4 nanozyme with H2O2. a) Schematic illustration of the POD-mimic
catalytic process of DMSN-Fe3O4 nanozyme. b) UV–vis absorption spectra and visual color changes of the catalyzed oxidation of TMB (oxTMB) as
catalyzed by control (black line), H2O2 (yellow line), and DMSN-Fe3O4 + H2O2 (red line) in the reaction buffer (pH 6.5). Insets show the corresponding
digital photos of each group. c) Time-dependent absorbance changes at 652 nm as a result of the catalyzed oxidation of TMB at different H2O2 concen-
trations (5, 10, 20, 30, 40, 50 × 10−3 m). d) Michaelis–Menten kinetic analysis and e) Lineweaver–Burk plotting for DMSN-Fe3O4 with H2O2 as substrate.
The steady-state catalytic rate (v) was calculated from the initial slopes of absorbance versus time plots in panel (c).

v 0 = Vmax [S ] / (K M + [S ]) (1) investigated. As a GOx mimic, Au NPs catalyze the oxidation

 of glucose in the presence of oxygen, producing gluconic acid
where v0 is the initial velocity of the reaction, Vmax is the max- and H2O2 (Figure 3a). Therefore, the production of H2O2 and
imal velocity of reaction, [S] is the substrate concentration, and gluconic acid, and the consumption of O2 were assessed.
KM is the Michaelis–Menten constant. The Michaelis–Menten First, the reaction product H2O2 generated from glucose
equation describes the relationship between the rate of sub- catalyzed by Au NPs was qualitatively detected based on the
strate conversion and the concentration of the substrate. Gener- H2O2-mediated size-enlargement of Au NPs in the presence of
ally, the maximal velocity of reaction Vmax reveals the catalytic HAuCl4.[30] DMSN-Au NPs first catalyze the glucose oxidation
activity of enzyme. Through an easy deformation, the original reaction, and the in situ generated H2O2 reduces HAuCl4 to
Michaelis–Menten equation could be converted to be Au0 following the equation

1 KM 1 1 AuCl 4 − + 3/2 H2O2 → Au 0 + 4Cl − + 3H+ + 3/2O2 (3)

= × + (2) 
v 0 Vmax [S ] Vmax

The resulting Au species can further deposit on the sur-
According to the above equation, KM and Vmax of the catalytic face of the initial Au NPs as seeds, causing the enlarged size
reaction by DMSN-Fe3O4 NPs were determined by Lineweaver– of initially deposited Au NPs and correspondingly enhanced
Burk plot (Figure 2e). The KM and Vmax values were calculated UV–vis absorbance intensity. According to the UV–vis results,
to be 10.10 × 10−3 m and 1.996 × 10−8 m s−1 for DMSN-Fe3O4 in the presence of glucose and HAuCl4, the absorption of Au
NPs with H2O2 being the substrate, respectively. NPs at 505 nm increased over time (Figure 3b) and the absorp-
After confirming the catalytic activity of POD-mimic tion peak slightly red-shifted from 505 to 515 nm in 1 h of
Fe3O4 nanozyme in generating highly toxic ·OH from reaction (Figure 3c), suggesting the size-enlargement of Au
H2O2 molecules, the catalytic activity of Au NPs as the GOx- NPs. TEM images clearly demonstrate the almost unchanged
mimic nanozyme and the cascade catalytic performance were sizes of Au NPs without glucose addition (Figure 3d) while the

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Figure 3. In vitro characterization of the catalytic performances of DMSN-Au-Fe3O4 nanoplatform with glucose. a) Schematic illustration
of DMSN-Au-Fe3O4 nanoplatform-catalyzed glucose oxidation reaction. b) Time-dependent absorbance changes of DMSN-Au NPs in the presence or
absence of glucose. c) UV–vis absorption spectra of DMSN-Au NPs in the presence or absence of glucose. TEM images of the enlarged Au NPs in the
pore channels of DMSN-Au NPs under the presence of HAuCl4 d) without or e) with the addition of glucose. f) UV–vis absorption spectra of DMSN-Au
NPs after incubation with glucose at varied concentrations (0, 100, 200, 300, 400, 500 × 10−3 m) for 3 h. DMSN-Au NPs-catalyzed oxidation of glucose
to gluconic acid, producing a red complex (505 nm) after mixing with hydroxylamine and FeCl3. g) Dissolved oxygen level of DMSN-Au solution after
incubation with glucose at varied concentrations (0, 100, 200, 300, 400, 500 × 10−3 m). h) UV–vis absorption spectra of TMB as catalyzed by control
(yellow line), glucose (blue line), and DMSN-Au-Fe3O4 NPs + glucose (red line) in the reaction buffer (pH 6.5).

significant size enlargement of Au NPs in the presence of glu- the addition of hydroxylamine and Fe3+, the resulting solution
cose (Figure 3e), which can be well-contributed to the produced turns into red with the major absorbance peak of the reac-
H2O2 via the catalytic glucose oxidation by DMSN-Au NPs. tion solution being at 505 nm and increases with the elevated
The other product of glucose oxidation reaction, gluconic concentrations of glucose (Figure 3f), which confirms the
acid, was detected using a gluconic acid-specific colorimetric production of gluconic acid in this Au NPs-catalyzed reaction
assay based on the reaction between gluconic acid, hydroxy- and implies the catalytic activity of DMSN-Au NPs on glucose
lamine, and FeCl3, which leads to the formation of a red com- oxidation.
pound hydroxamate-Fe3+ with a typical absorbance peak at In order to monitor the level of dissolved oxygen in the reac-
505 nm.[31] Specifically, DMSN-Au NPs were incubated with tion system, a dissolved oxygen meter was used. After adding
glucose of different concentrations at pH 6.5 for 30 min. After DMSN-Au NPs into the buffer solution of glucose of different

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concentrations, the oxygen level in reaction solution declined DMSN-Au-Fe3O4 NPs, the cell viabilities exhibit a marked
rapidly owing to the consumption of dissolved oxygen for the decline in a dose-dependent manner with an inhibition rate on
glucose oxidation as catalyzed by the loaded Au NPs (Figure 3g). 4T1 tumor cell viability being higher than 75% at 200 µg mL−1
Based on TMB colorimetric assay (Figure 3a), it has been (Figure 4c). This result indicates that the cytotoxicity of DMSN-
verified that the self-organized enzymatic cascade reaction can Au-Fe3O4 NPs should be attributed to the cascade catalytic reac-
be achieved by DMSN-Au-Fe3O4 NPs without the aid of any nat- tions by Au and Fe3O4 NPs, both of which are indispensable
ural enzyme. In detail, DMSN-Au-Fe3O4 NPs and glucose solu- to trigger the generation of sufficiently high amount of toxic
tion were mixed and incubated in a TMB solution for 1 h. The ·OH to induce the apoptosis of 4T1 tumor cells. In detail on
reaction solution then turned blue with the absorbance peak at the related therapeutic mechanism, H2O2, as produced by the
370 and 652 nm, indicating the production of ·OH originating reaction between glucose and oxygen under the catalysis by
from the cascade catalysis of Au and Fe3O4 NPs (Figure 3h). GOx mimic-Au NPs in cell culture medium, is further cata-
To be specific, the Au NPs immobilized within the mesopores lyzed by Fe3O4-based Fenton nanocatalysts to disproportionate,
of DMSN NPs initially catalyze the oxidation of glucose into producing ·OH for killing the cancer cells.
H2O2, which is further utilized as the reactant for Fe3O4 NPs- Furthermore, the intracellular uptake of fluorescein iso-
based catalytic Fenton reaction to produce hydroxyl radicals. thiocyanate (FITC)-labeled DMSN-Au-Fe3O4 NPs was investi-
Finally, the generated hydroxyl radicals oxidize the colorless gated by flow cytometry and confocal laser scanning micros-
TMB into the blue-colored oxTMB. Therefore, DMSN-Au-Fe3O4 copy (CLSM). The flow cytometric results reveal a substan-
NP is indeed a robust composite nanozyme with dual enzy- tial enhancement of fluorescence intensity of FITC-labeled
matic functionalities capable of catalyzing the cascade reaction DMSN-Au-Fe3O4 NPs at the prolonged incubation duration
without the assistance of any natural enzyme, i.e., initially cata- (Figure S15, Supporting Information). CLSM images of 4T1
lyzing glucose oxidation to yield gluconic acid and H2O2, and tumor cells clearly exhibit the green fluorescence originated
then catalyzing H2O2 into high-toxic ·OH. Especially, the cata- from FITC-labeled DMSN-Au-Fe3O4 NPs after coincubation for
lytic performances of DMSN-Au-Fe3O4 NPs in buffer solutions 2 h, indicating the efficient intracellular uptake of DMSN-Au-
at pH 5.0, 6.5, 7.4, and 8.0 were conducted to investigate the Fe3O4 NPs (Figure S16, Supporting Information) and guaran-
influence of pH. It has been found that the catalytic activity of teeing the following efficient intracellular cascade nanocatalytic
DMSN-Au-Fe3O4 NPs is pH-dependent, exhibiting better cata- reactions for killing the cancer cells.
lytic activity in acid condition than in neutral or alkaline condi- To evaluate the intracellular ·OH generation, a ROS fluo-
tion (Figure S10, Supporting Information). rescence probe 2′,7′-dichlorofluorescin diacetate (DCFH-DA),
Before assessing the in vitro nanocatalytic therapeutic effi- which turns into 2′,7′-dichlorofluorescein (DCF) with strong
ciency, the surface of DMSN-Au-Fe3O4 NPs was modified with green fluorescence in the presence of ROS, was introduced to
methoxy PEG-thiol (mPEG-SH) molecules for improved sta- stain cancer cells in order to reveal the intracellular ROS pro-
bility in physiological microenvironment. The Fourier trans- duction. At pH 6.5, 4T1 cancer cells exhibit negligible fluores-
form infrared spectroscopy (FTIR) was conducted for the cence when coincubated only with high doses of glucose in
characterization of PEGylation. The FTIR spectrum of DMSN- DMEM or with DMSN-Au-Fe3O4 NPs in glucose-free DMEM
Au-Fe3O4-PEG NPs shows the stretch of the COC band at for 1 h. Comparatively, strong green fluorescence of 4T1 cancer
1060, 1110, 1150, 1250, and 1280 cm−1, as well as the stretch cells can be observed after coincubation with DMSN-Au-Fe3O4
band of CH2 and CH3 at 2890 and 2740 cm−1, respectively, NPs in the presence of glucose (Figure 4d), implying the mas-
indicating the successful modification of mPEG-SH molecules sive intracellular ROS production by DMSN-Au-Fe3O4 NPs and
(Figure S11, Supporting Information). Attributing to the PEG glucose under weakly acidic condition. Furthermore, it has
modification, the DMSN-Au-Fe3O4-PEG NPs could be well been found that the DCF fluorescence intensity is dependent
dispersed in water, phosphate buffer solution, simulated body on the pH value of cell culture medium and incubation dura-
buffer, saline, dulbecco’s modified eagle medium (DMEM), and tion. As the incubation duration is prolonged from 15 min to
fetal bovine serum, indicating their excellent stability (Figure 1 h, the DCF fluorescence intensity of cells increases accord-
S12, Supporting Information). ingly when incubated with DMSN-Au-Fe3O4 NPs and glu-
Initially, the cytotoxicities of DMSN-Au-Fe3O4 NPs were cose under the weakly acidic condition (pH 6.5). However, in
tested on murine breast cancer 4T1 cells, as well as two normal the neutral condition (pH 7.4), much weaker DCF fluores-
cell lines, namely brain capillary endothelial cells and human cence intensity is observed even after prolonged incubation
umbilical vein endothelial cells by the standard cell-counting (Figure 4e). The DCF fluorescence can be further monitored by
kit 8 assay. The results show that the DMSN-Au-Fe3O4 NPs flow cytometry (Figure 4f), which demonstrates that the DCF
exhibit negligible effects on the proliferation of the two kinds fluorescence increases by prolonging the incubation duration
of normal cells, at the elevated concentration up to 200 µg mL−1 of DMSN-Au-Fe3O4 NPs. The CLSM and flow cytometry results
within 12 and 24 h, indicating their high biosafety and biocom- demonstrate that the intracellular ROS production as catalyzed
patibility for further in vitro and in vivo therapeutic applications by DMSN-Au-Fe3O4 NPs has been substantially promoted in
(Figure S13, Supporting Information). In addition, it has been the mildly acidic environment as compared to that in the neu-
found that DMSN-Au NPs and DMSN-Fe3O4 NPs exhibit no tral condition.
significant inhibition on 4T1 cancer cells proliferation even at Especially, the intracellular nanocatalytic therapeutic mecha-
the elevated concentration up to 200 µg mL−1 after incubation nism of DMSN-Au-Fe3O4 nanoplatform was investigated by
for 12 and 24 h, at pH 6.5 (Figure 4a,b) and 7.4 (Figure S14, the typical flow cytometric apoptosis assay after stained with
Supporting Information). Importantly, when incubated with FITC-labeled Annexin V and propidium iodide (PI). According

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Figure 4. In vitro assessments of the nanocatalytic tumor therapeutic efficacy by DMSN-Au-Fe3O4 nanoplatform. Relative viabilities of 4T1 cells after
being incubated with a) DMSN-Au NPs and b) DMSN-Fe3O4 NPs at varied concentrations (0, 6.25, 12.5, 25, 50, 100, and 200 µg mL−1) for 12 and 24 h

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to the fluorescence intensity, cell populations are assigned therapeutic efficiency of DMSN-Au-Fe3O4 NPs was evaluated
into four quadrants including live, early apoptotic, late apop- against the 4T1 breast tumor xenograft on nude mice. Eighteen
totic, and necrotic cells (Figure 4g). 4T1 cells were incubated 4T1 tumor-bearing mice (tumor volume ≈ 50 mm3) were ran-
in different conditions including Control (Glucose), DMSN-Au domly separated into three groups (n = 6 per group). Saline
+ Glucose, H2O2, DMSN-Fe3O4 + H2O2, DMSN-Au-Fe3O4, and (control) and DMSN-Au-Fe3O4 NPs at different doses (10 and
DMSN-Au-Fe3O4 + Glucose at pH 7.4 or pH 6.5. The quantita- 20 mg kg−1) were i.v. administrated to investigate the thera-
tive analysis on the cell populations in four quadrants in each peutic performance and related in vivo mechanism. During
group was also conducted (Figure 4h). At pH 7.4, compared a 15 day therapeutic period, the body weights of mice in two
to the control group, cells incubated with H2O2 group exhibit therapeutic groups show no significant difference from those
apparent apoptosis owing to the cytotoxicity of the moderate- of mice in the control group (Figure 5c). The tumor volumes
toxic ROS, H2O2. The cells treated with DMSN-Fe3O4 + H2O2 of mice in each group were recorded using a digital caliper,
show a significantly promoted apoptosis, indicating the extra and the digital photos of mice were taken every 2 days after
production of highly toxic ROS, hydroxyl radicals. In compar- the i.v. injection(Figure S19, Supporting Information). It has
ison, cells in group of DMSN-Au + Glucose, DMSN-Au-Fe3O4, been found that the i.v. administration of DMSN-Au-Fe3O4 NPs
and DMSN-Au-Fe3O4 + Glucose display negligible apoptosis shows a dose-dependent tumor-growth inhibition effect during
at pH 7.4, indicating that neither DMSN-Au NPs nor DMSN- the therapeutic period (Figure 5d,e), with the inhibition rates of
Au-Fe3O4 NPs contribute to the ROS production and cell apop- 45.96% and 69.08% at the doses of 10 and 20 mg kg−1, respec-
tosis in the netural environment. However, at pH 6.5, cells in tively. This substantial tumor inhibition effect is attributed to
group of DMSN-Fe3O4 + H2O2 show enhanced late apoptosis the high-toxic hydroxyl radicals as produced by the endogenous
compared to those at pH 7.4, which demonstrate that the acid- cascade reaction triggered by the biomimetic Au and Fe3O4
ity-benefited Fenton reaction catalyzed by Fe3O4 nanozyme coloaded nanoplatforms under the mildly acidic TME, effec-
has produced high-toxic hydroxyl radicals for inducing the tively inducing tumor cell death. It should be noted that the
cell apoptosis. More importantly, cells in group of DMSN-Au- constructed nanocomposites are highly biocompatible without
Fe3O4 + Glucose exhibit the mostly enhanced cell apoptosis any toxic substance used, and the toxic effect can only be trig-
rate up to about 90% at pH 6.5 while only a slight early apop- gered under the mildly acidic TME, which means that this
tosis rate at pH 7.4 is detectable, suggesting the massive ROS DMSN-Au-Fe3O4-based nanocatalytic tumor therapy features
production and cell apoptosis as contributed by the cascade high tumor specificity and excellent therapeutic biosafety. The
catalytic reaction of Au NPs and Fe3O4 NPs under the mildly neutral condition of normal tissue will not trigger such a cas-
acidic condition (Figure 4i). The flow cytometric results indi- cade catalytic reaction, therefore no toxic effect will be induced
cate the much enhanced efficiency of ROS production and cell to cause noticeable damages to normal cells/tissues.
apoptosis of nanocatalytic therapy as triggered by biomimetic In order to reveal the detailed therapeutic mechanism by
DMSN-Au-Fe3O4 nanomedicine via cascade catalytic reactions. tumor-pathological analysis, hematoxylin and eosin (H&E),
The in vivo toxicity assessment of DMSN-Au-Fe3O4 com- terminal deoxynucleotidyl transferase mediated dUTP nick-
posite nanocatalysts has demonstrated the high biosafety and end labeling (TUNEL) and Ki-67 antibody staining of dissected
biocompatibility of DMSN-Au-Fe3O4 NPs for further in vivo tumor tissues from each group were conducted. H&E and
therapeutic application on combating cancer (Figures S17 and TUNEL staining results exhibit severe damage and necrosis
S18 and Discussion S1, Supporting Information). Furthermore, of tumor cells in two therapeutic groups in comparison to the
the blood circulation and biodistribution of DMSN-Au-Fe3O4 control group (Figure 5f). Ki-67 antibody staining results reveal
NPs were comprehensively investigated. The circulation half- the suppressed proliferative activities of tumors cells in two
life of DMSN-Au-Fe3O4 NPs in the bloodstream was calculated therapeutic groups while there is almost no significant adverse
to be 1.38 h based on a two-compartment pharmacokinetic effect on cell proliferation in the control group. Furthermore,
model (Figure 5a).[31] Importantly, after i.v. administration, H&E staining of the major organs (heart, liver, spleen, lung,
DMSN-Au-Fe3O4 NPs efficiently accumulated into the tumor and kidney) conducted after the therapeutic period shows no
tissue with the passive accumulation efficacy of 3.49% ID g−1 noticeable pathological side effects on major organs of mice in
in 2 h and 1.80% ID g−1 in 12 h (Figure 5b) based on the typical therapeutic groups (Figure S20, Supporting Information), indi-
EPR effect for tumor-passive targeting and accumulation.[32] cating the high biocompatibility and therapeutic biosafety of
Encouraged by the high efficiency of in vitro nanocatalytic DMSN-Au-Fe3O4 NPs as nanocatalytic agents.
therapy for killing cancer cells, the prolonged blood circulation, Additionally, the rapid clearance of therapeutic nanomaterials
and potent tumor accumulation effect, the in vivo nanocatalytic is highly favorable for the clinical translation, which can avoid

at pH 6.5. c) Relative viabilities of 4T1 cells after being incubated with DMSN-Au-Fe3O4 NPs at varied concentrations (0, 6.25, 12.5, 25, 50, 100,
and 200 µg mL−1) for 24 h at pH 7.4 and pH 6.5 (P values: ***P < 0.001). d) Confocal fluorescence imaging of DCFH-DA stained 4T1 cells after various
treatments (Control, Glucose, DMSN-Au-Fe3O4, DMSN-Au-Fe3O4 + Glucose) for 1 h at pH 6.5. Scale bar: 50 µm. e) Confocal fluorescence imaging
of DCFH-DA stained 4T1 cells after incubated with DMSN-Au-Fe3O4 NPs at pH 7.4 and 6.5 for 15 min and 1 h. Scale bar: 50 µm. f) Flow cytometric
analysis of intracellular ROS levels in 4T1 cells incubated with DMSN-Au-Fe3O4 NPs for different durations of 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h,
and 12 h. g) Flow cytometric apoptosis analysis of Annexin V-FITC/PI stained 4T1 cells after different treatments at pH 7.4 and 6.5 for 4 h: Control
(Glucose), DMSN-Au + Glucose, H2O2, DMSN-Fe3O4 + H2O2, DMSN-Au-Fe3O4, DMSN-Au-Fe3O4 + Glucose. h) Quantification analysis of the percent-
ages of live, early apoptotic, late apoptotic and necrotic cells after different treatments in panel (g). i) Quantification analysis of the percentages of
apoptotic cells at pH 7.4 and pH 6.5 after different treatments.

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Figure 5. In vivo pharmacokinetic analysis and nanocatalytic tumor therapy. a) Blood-circulation curve of intravenously injected DMSN-Au-Fe3O4 NPs
after i.v. injection (n = 3). The half-life (T1/2) was calculated to be ≈1.38 h. b) Biodistribution of Si element after i.v. injection of DMSN-Au-Fe3O4 NPs
(dose: 20 mg kg−1) in 4T1 tumor-bearing mice measured at different time points as determined by ICP-OES. c) Time-dependent body-weight curves of
4T1 tumor-bearing nude mice after i.v. injection with saline (control) and DMSN-Au-Fe3O4 NPs (10 and 20 mg kg−1). d) Time-dependent tumor growth
curves (n = 6, mean ± s.d.) of mice from each group (P values: **P < 0.01, ***P < 0.001). e) Digital photos of 4T1 tumor-bearing mice and dissected
tumors from each group on the 15th day. f) H&E staining, TUNEL staining for pathological changes, and Ki-67 immunohistochemical staining for
cellular proliferation in tumor tissues from each group after a 15-day therapeutic period. Scale bar: 100 µm. g) Accumulated Fe (in urine and feces)
excretion out of the mice body (n = 3) after i.v. injection of DMSN-Au-Fe3O4 NPs (dose: 20 mg kg−1) for different durations (2, 4, 6, 12, 30, and 48 h).

long-term body retention and potential toxicity. To investigate In summary, this work reports on the effective TME-respon-
the metabolism process, 4T1-tumor-bearing mice were intrave- sive catalytic cascade reactions for nanocatalytic tumor-specific
nously injected with DMSN-Au-Fe3O4 NPs (20 mg kg−1, n = 3) therapy with marked therapeutic efficacy and biosafety based on
and their urine and feces were collected at predetermined time an inorganic biomimetic DMSN-Au-Fe3O4 composite nanoplat-
points (2, 4, 6, 12, 30, and 48 h) after the injections. The Fe ele- forms. The in situ grown Au NPs within the large mesopores
ment levels in urine and feces were quantitatively determined of DMSN NPs as a GOx-mimic nanozyme specifically cata-
by ICP-OES. The excretion pathways including urine and feces lyze β-D-glucose oxidation into gluconic acid and H2O2 under
reveal the gradual excretion of DMSN-Au-Fe3O4 NPs out of the aerobic conditions, while the produced H2O2 can subsequently
body with nearly 70% of Fe being excreted out of mice bodies be catalyzed by the coloaded Fe3O4-based Fenton nanocatalysts
in 48 h post i.v. injection (Figure 5g). The desirable excretion to produce high-toxic hydroxyl radicals which substantially
behavior of DMSN-Au-Fe3O4 NPs indicates their potential bio- induce tumor-cell death afterward. Both the comprehensive in
compatibility and biosafety as nanocatalytic agents for further vitro cell-level and in vivo tumor-bearing mice xenograft evalu-
clinical translation. ations have demonstrated the efficient nanocatalytic tumor

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