Metal–Organic Frameworks for Biomedical Applications

Abstract

Metal–organic frameworks (MOFs) are an interesting and useful class of coordination polymers, constructed from metal ion/cluster nodes and functional organic ligands through coordination bonds, and have attracted extensive research interest during the past decades. Due to the unique features of diverse compositions, facile synthesis, easy surface functionalization, high surface areas, adjustable porosity, and tunable biocompatibility, MOFs have been widely used in hydrogen/methane storage, catalysis, biological imaging and sensing, drug delivery, desalination, gas separation, magnetic and electronic devices, nonlinear optics, water vapor capture, etc. Notably, with the rapid development of synthetic methods and surface functionalization strategies, smart MOF‐based nanocomposites with advanced bio‐related properties have been designed and fabricated to meet the growing demands of MOF materials for biomedical applications. This work outlines the synthesis and functionalization and the recent advances of MOFs in biomedical fields, including cargo (drugs, nucleic acids, proteins, and dyes) delivery for cancer therapy, bioimaging, antimicrobial, biosensing, and biocatalysis. The prospects and challenges in the field of MOF‐based biomedical materials are also discussed.

Full text

1906846 (1 of 24) © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
Review
Metal–Organic Frameworks for Biomedical Applications
Jie Yang and Ying-Wei Yang*
J. Yang, Prof. Y.-W. Yang
State Key Laboratory of Inorganic Synthesis and Preparative Chemistry
International Joint Research Laboratory of Nano-Micro Architecture
Chemistry (NMAC)
College of Chemistry
Jilin University
2699 Qianjin Street, Changchun 130012, P. R. China
E-mail: ywyang@jlu.edu.cn
Prof. Y.-W. Yang
The State Key Laboratory of Refractories and Metallurgy
School of Chemistry and Chemical Engineering
Wuhan University of Science and Technology
Wuhan 430081, P. R. China
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/smll.201906846.
DOI: 10.1002/smll.201906846
tunable surface affinities exhibit a huge
impact on the properties of the MOFs.[2]
Meanwhile, the particle morphology, size
distribution, and chemical properties also
play important roles in the applications
of MOFs. Due to the prominent phys-
icochemical features including easy syn-
thesis and functionalization, tailorable
pore sizes, variable structures, high sur-
face areas and loading capacities, good
biocompatibility and biodegradability,
MOF-based systems have been applied
in many fields,[3] including catalysis,
gas adsorption/separation/storage, non-
linear optics, sensing and detection, and
biomedical applications (Figure 1) in
particular.
In recent years, the application of
MOFs, especially nanoscale MOFs
(NMOFs), in biomedicine has become a
rapidly developing hot research topic.[4]
Compared to traditional MOFs, NMOFs
possess similar highly ordered porosity
and inherent pore size and have larger
specific surface area, rendering them
enhanced biological activity and chemical/colloidal stability,
more effective surface modification, and improved biological
distribution.[2a,5] Compared with the traditional nanomaterials
for biomedical applications, MOFs including NMOFs demon-
strate the following advantages: 1) thousands of MOFs provide
a library of versatile porous materials for various bio-related
applications, 2) the stable but degradable structures guarantee
the reuse and on-demand degradation,[6] 3) the high specific
surface areas and porosities facilitate the efficient encapsu-
lation/loading of cargos, ranging from small molecules to
biomacromolecules. Particularly, the good dispersibility and
biocompatibility of NMOFs ensure the biosecurity for in vivo
applications.[7]
In this review article, we will summarize the recent devel-
opments of MOF-based composite materials including the
synthesis and functionalization[8–15] and their biomedical appli-
cations in the delivery of cargos including drugs, nucleic acids,
proteins, and dyes (Table 1),[19,21–23,25–29,31b,d,34–41] bioimaging
(Table 2),[43–45,47–54] antimicrobial (Table 3),[57,60–67] biosensing
(Table 4),[69–73,75–86] and biocatalysis (Table 5).[91–95] Moreover,
the potential of MOFs for biomedical applications has been
clarified through the analysis of recent examples reported in
literature. Finally, the developing prospects and challenges of
MOFs for biomedical applications will be discussed in depth.
In comparison to other excellent reviews related to the appli-
cations of MOFs in biomedicine, this review article will not
only focus on the selected outstanding researches of MOFs in
Metal–organic frameworks (MOFs) are an interesting and useful class
of coordination polymers, constructed from metal ion/cluster nodes and
functional organic ligands through coordination bonds, and have attracted
extensive research interest during the past decades. Due to the unique fea-
tures of diverse compositions, facile synthesis, easy surface functionalization,
high surface areas, adjustable porosity, and tunable biocompatibility, MOFs
have been widely used in hydrogen/methane storage, catalysis, biological
imaging and sensing, drug delivery, desalination, gas separation, magnetic
and electronic devices, nonlinear optics, water vapor capture, etc. Notably,
with the rapid development of synthetic methods and surface functionaliza-
tion strategies, smart MOF-based nanocomposites with advanced bio-related
properties have been designed and fabricated to meet the growing demands
of MOF materials for biomedical applications. This work outlines the syn-
thesis and functionalization and the recent advances of MOFs in biomedical
fields, including cargo (drugs, nucleic acids, proteins, and dyes) delivery for
cancer therapy, bioimaging, antimicrobial, biosensing, and biocatalysis. The
prospects and challenges in the field of MOF-based biomedical materials are
also discussed.
1. Introduction
Metal–organic frameworks (MOFs), an emerging and rap-
idly developing class of organic–inorganic hybrid materials,
are composed of organic ligands as struts and their coordi-
nated metal ions/ion clusters as nodes, which have gained
significantly increasing attention in the last decade.[1] MOFs
with various features can be easily obtained by adjusting
the almost infinite combination of metal nodes and organic
ligands, and their various pore sizes ranging from micropores
to mesopores or macropores, rigid/flexible skeletons, and
Small 2020, 16, 1906846

1906846 (2 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
the abovementioned five aspects in recent few years, but also
discuss the development prospects and challenges of MOF
in biomedical applications from different angles, and help
researchers learn the current status and promising break-
throughs of MOFs in this field comprehensively.
2. Synthesis and Functionalization of MOFs
With the development of synthetic methods and the advent of
new technologies, MOFs with controllable particle diameters
and increased pore sizes have been designed and fabricated.
Up to now, the synthetic methods of MOFs mainly include
hydro/solvothermal synthesis, microwave and ultrasonic-
assisted synthesis, microemulsion synthesis, mechanochem-
istry synthesis, continuous flow synthesis, electrochemical
synthesis, diffusion synthesis, spray-drying synthesis, and
solvent evaporation and ionothermal synthesis, showing
advantages and disadvantages in terms of synthesis effi-
ciency, scale-up production, physicochemical properties,
etc.[8] For example, hydro/solvothermal synthesis is a typical
method to prepare MOFs using high temperature and high
pressure in polar solvents, which impart the material with
advantages of easy preparation of crystals, simple and con-
venient synthetic approach. However, it usually takes a long
reaction time, and requires organic solvents and harsh con-
ditions like high temperature and high pressure, rendering
it unfavorable to scale-up production.[9] Microwave-assisted
synthesis is beneficial for the preparation of MOFs with
homogeneous size distribution in a short reaction time due
to rapid nucleation process. Continuous flow synthesis has
the advantage of highly efficient continuous preparation
of monodisperse MOFs with desired size and structures.[10]
Overall, considering the effects of size, morphology, and sur-
face functionalization on the chemical properties of MOFs,
the optimal synthetic method needs to be explored to meet
the special needs of biomedical applications.
The critical challenges of MOFs in biomedical applications
are not only the precise control of particle size and porosity, but
also the effect of surface affinity on their metabolic behaviors
in vivo. Significantly, diversified surface functionalization strat-
egies provide operational approaches to improve the physiolog-
ical/colloidal stability, to introduce special entities for controlled
cargo release and specific targeted recognition, to enhance the
catalytic reactivity, and to extend the circulation time.[11] In gen-
eral, the pendant entities used for surface functionalization can
be conjugated to the groups of organic ligands (such as –NH2,
–COOH, –N3) and the metal nodes on the surface of MOFs
through covalent bonding or strong coordination.[12] Pendant
polymers, such as polyethylene glycol (PEG) and liposomes, are
commonly used to improve the physiological/colloidal stability
and reduce immune response of MOFs.[13] Biomacromolecules,
such as nucleic acids, proteins, and peptides, bind to the sur-
face of MOFs through coordination bonds, giving MOFs the
abilities of target recognition, bioimaging, analytical detection,
and drug delivery.[14] Importantly, supramolecular macrocycles
are immobilized on the surface of MOFs through supramo-
lecular interactions to regulate the drug release and reduce the
side effects during drug delivery.[15]
3. Biomedical Applications of MOFs
3.1. MOF-Based Cargo Delivery Systems for Cancer Therapy
The undesired side effects and poor selectivity of chemotherapy
during traditional tumor treatment process have prompted the
emergence of drug delivery systems (DDSs). In the past few
decades, inorganic carriers such as mesoporous silica nano-
particles, carbon structures, oxides and nitrides, and organic
vehicles including polymers, liposomes, and dendrimers have
been developed for anticancer drug delivery to improve drug
bioavailability and therapeutic effects,[16] but the biodistribu-
tion, metabolic mechanisms, and immunogenicity of inorganic
systems are still in urgent need to be further systematically
studied. However, on the other hand, organic materials as drug
carriers often suffer from low drug loading and premature
drug leakage.[17] Compared with the abovementioned materials,
MOFs have become one of the most promising candidates that
can overcome most of the challenges of cargo delivery due to
the following unique features: 1) the wide variety of metal ions/
clusters and organic linker structures endows MOFs with mul-
tiple morphologies, different compositions, tunable sizes, and
unique chemistry properties, making them easier to accom-
modate a wide range of cargo molecules with different phys-
icochemical properties; 2) the high surface areas and large pore
Jie Yang received her B.Sc.
(2014) and M.Sc. (2017)
degrees in the College of Life
Science at Jilin University. In
2017, she started her Ph.D.
study under the supervision
of Professor Ying-Wei Yang in
the College of Chemistry at Jilin
University. Her research focuses
on the design and synthesis of
multifunctional drug delivery
systems for cancer therapy.
Ying-Wei Yang received
his degrees (B.Sc. in 2000,
Ph.D. in 2005) from Nankai
University under the supervi-
sion of Professor Yu Liu and
gained postdoctoral training
at Arizona State University
(with John C. Chaput);
University of California, Los
Angeles (with Sir Fraser
Stoddart); and University
of California, Irvine (with
Zhibin Guan) from 2005 to 2010. He became an associate
professor of Chemistry at Jilin University in 2011 and was
promoted to full professor in 2014. His research interests
focus on synthetic chemistry, organic supramolecular
chemistry, multifunctional hybrid materials, and stimuli-
responsive polymers.
Small 2020, 16, 1906846

1906846 (3 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
sizes of MOFs enable high loading capacity of small molecules
and biomacromolecules including enzymes and nucleic acids;
3) the flexible types of substituent groups on organic ligands
build a strong foundation for postsynthetic covalent modifica-
tion of MOFs; 4) the controllable drug release behaviors ensure
the safety of drug delivery; 5) weak coordination bonds ensure
good biodegradability of MOFs.[3b,18] Since the first report by
Férey and co-workers on two kinds of rigid Cr-based MOFs
(denoted as Materials of Institut Lavoisier (MIL)-100 and MIL-
101) for the delivery of model drug ibuprofen in 2006,[19] over
a decade’s fast development of drug carrier design based on
MOFs—from normal MOFs through stimuli-responsive MOFs
to multifunctional MOFs—has offered MOF materials many
possibilities in anticancer drug delivery and cancer theranostics.
3.1.1. Normal MOFs as Carriers
Typical MOF-based DDSs are formed by encapsulating drug
molecules in the nanocages of MOFs to achieve drug delivery
and sustained release in the tumor microenvironment (TME).
To date, numerous research results using this strategy have
been reported.[20] For instance, Sun et al. introduced a pair
of chiral non-interpenetrated nanoporous MOFs (1a-L, 1b-D,
Figure 2a) named [(CH3)2NH2]2[Zn(TATAT)2/3]·3DMF·H2O,
consisting of hexadentate ligand 5,5′5″-(1,3,5-triazine-2,4,6-
triyl)tris(azanediyl)triisophthalate (TATAT) and Zn2+, for the
delivery of anticancer drug 5-fluorouracil (5-Fu).[21] The as-
prepared MOFs possess a high loading capacity of 0.5 g g−1
and exhibited a sustained release of 5-Fu (1 week for complete
release in phosphate buffered saline buffer, pH 7.4), which was
attributed to the high porosity and the presence of two different
sizes of nanocages in the MOFs (Figure 2b). Interestingly, Lin
and co-workers reported a University of Oslo (UiO) NMOF plat-
form, namely siRNA/UiO-Cis, for the co-delivery of cisplatin
and small interfering RNAs (siRNAs) to treat cisplatin-resistant
ovarian cancer (Figure 2c).[22] Cisplatin prodrugs was loaded
into the UiO pores and siRNA was integrated on the surface
of NMOFs, respectively, taking advantage of the high porosity
and the Zr4+ metal ion coordination of UiO NMOFs. Such a
co-delivery strategy effectively protected siRNAs from nuclease
degradation, and promoted siRNA’s escape from endosomes to
silence multiple drug-resistant genes, resulting in an enhanced
chemotherapeutic effect of cisplatin.
Small 2020, 16, 1906846
Figure 1. Schematic representation of the synthesis and functionalization of MOFs for biomedical applications, including cargo delivery (i.e., drugs,
nucleic acids, proteins, and dyes), bioimaging, antimicrobial, biosensing, and biocatalysis.

1906846 (4 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
In 2018, Zhou and co-workers reported a highly efficient tyrosi-
nase (TYR)-MOF nanoreactor, that is, TYR@NPCN-333(Al), for
cancer treatment by activating a nontoxic prodrug paracetamol
in tumor cells in a long-lasting manner.[23] NPCN-333(Al), pos-
sessing three types of pores with diameters of 1.5, 4.2, and
5.5 nm, respectively, was synthesized from trimeric-oxo clusters
and a planar triangular ligands, 4,4′,4″-s-triazine-2,4,6-triyl-
tribenzoic acid (TATB), in N,N-dimethylformamide (DMF)
under solvothermal condition, and was selected as the carrier for
efficient encapsulation of TYR (Figure 2d,e). The experimental
results showed that TYR was loaded in the 5.5 nm cavity of
NPCN-333(Al) with a high loading capacity of 1.08 g g−1 due to
Small 2020, 16, 1906846
Table 2 . Examples of MOF-based nanocomposites for bioimaging.
MOFs MOFs skeleton components Imaging agent Imaging strategy Application References
ZIF-90 Zn2+, imidazole-2-carboxyaldehyde RhB FL AT P [43]
TP-MOF 1/2 Zr4+, TPDC derivative dicarboxylic
acid
Alkynyl-BR-NH2/alkynyl-DL FL H2S, Zn2+[44]
Bi-NU-901 Bi3+, H4TBAPy Bi-NU-901 CT – [45]
MIL-USPIO-cit Fe3+, BTC
γ
-Fe2O3@MIL-100 MRI Mice abdomen [47]
Fe3O4@UiO-66@WP6 Zr4+, NH2-BDC Fe3O4MRI HeLa cells [48]
89Zr-UiO-66/Py-PGA-PEG-F3 Zr4+, BDC 89Zr-UiO-66 PET MDA-MB-231 tumor-bearing mice [49]
UMP-FA Fe3+, NH2-BDC UCNPs&Fe-MIL-101-NH2FL&MRI KB tumor-bearing mice [50]
Fe2+-adsorbed ZIF-8 Zn2+, 2-H-MeIM ZnO, Fe3O4FL&MRI U87 xenograft tumor mice [51]
Au@MIL-88(Fe) Fe3+, fumaric acid Au nanorods, MIL-88(Fe) CT&MRI&PAI U87 MG-orthotopic tumor-bearing mice [52]
MOF@HA@ICG Fe3+, BTC ICG, MIL-100(Fe) FL&PAI&MRI MCF-7 cells/xenograft tumors [53]
Gd/Yb-MOFs-Glu Gd/Yb, BBDC DOX, Gd/Yb-MOFs FL&CT&MRI HeLa tumor-bearing mice [54]
Table 1. Examples of MOF-based carriers for cancer treatment.
MOFs MOFs skeleton components Cargo/drug Stimuli type Synergistic strategy Cell lines References
MIL-100/101(Cr) Cr3+, 1,3,5-BTC/1,4-BDC Ibuprofen – – – [19]
Chiral NMOFs Zn2+, TATAT 5-Fu – – – [21]
siRNA/UiO-Cis Zr4+, amino-TPDC Cisplatin, siRNA – – SKOV-3, A2780, PC-3,
MCF-7, H460, A2780/
CDDP
[22]
TYR@NPCN-333(Al) Al3+, TAT B Tyrosinase – – SKOV3-TR, H1299,
HeLaa)
[23]
CP5-capped UMCM-1-NH2Zn2+, NH2-BDC Rh6G/DOX pH, competitive agent – HEK293 [25]
CP5-capped UiO-66-NH-Q Zr4+, NH2-BDC 5-Fu Zn2+, thermo – HEK293 [26]
CP5-capped UiO-66-NH-A Zr4+, NH2-BDC 5-Fu Ca2+, pH, thermo – HEK293 [27]
PEG-RGD-
β
-CD-SS-MIL-101 Fe3+, NH2-BDC DOX pH, GSH – HeLa, COS7, H22a) [28]
β
-CD-capped UiO-68-azo Zr4+, 2′-ptolyldiazenyl-1,1′:4,4′-
terphenyl-4,4″-dicarboxylic acid
RhB Amantadine, UV light – – [29]
PPy@UiO-66@WP6@
PEI−Fa
Zr4+, NH2-BDC 5-Fu pH, thermo PTT L02, HeLaa) [31b]
DBP−UiO Hf4+, H2DBP – – PDT SQ20Ba) [34]
DBC–UiO Hf4+, Me2DBP – – PDT CT26a), HT29a) [35]
Pda-Pt@PCN-FA Zr4+, H2TCPP – – PDT COS7, CT26a) [36]
BQ-MIL@cat-fMIL Fe3+, NH2-BDC Catalase – PTT, PDT HeLaa) [37]
Cy5.5-PCN-224 QDs Zr4+, TCPP – – PDT HeLaa) [38]
Mn-ZrMOF
NCs
Zr4+, H2BDC – – MDT, MTT HepG2, H22a) [39]
TGZ@eM Zn2+, 2-H-MeIM GOx, TPZ Hypoxia Starvation RAW264.7, CT26a) [40]
Hf-DBB-Ru Hf4+, DBB-Ru – – RT, RDT CT26, MC38a) [31d]
Dox@MOF-Au-PEG Zr4+, H2TCPP DOX Phosphate RT U87MGa) [41]
a)Cell lines used for antitumor experiments in vivo.

1906846 (5 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
the matching of MOF cavity and TYR size, which could effec-
tively protect the encapsulated TYR from hydrolyzation and
inactivation in the TME conditions for up to 3 days. Nontoxic
prodrug paracetamol could be activated by TYR@NPCN-333(Al)
to produce a cytotoxic compound, inducing the apoptosis/
necrosis by promoting oxidative stress. Such an enzyme-MOF
nanoreactor platform provides a new strategy for expanding the
intrinsic diversities of MOF-based delivery systems in structure
and functionality.
3.1.2. Stimuli-Responsive MOFs as Carriers
Apart from these conventional DDSs based on normal MOFs,
smart MOFs with good responsiveness to various stimuli, such
as pH, redox, light, magnetic field, temperature, ions, and
ultrasound, have attracted tremendous attention to achieve on-
demand release in controlled drug delivery and cancer therapy.[24]
In 2015, a dual-stimuli-responsive DDS based on University
of Michigan Crystalline Material (UMCM)-1-NH-Py capped
Small 2020, 16, 1906846
Table 3. MOF-based antibacterial nanomaterials.
MOFs MOFs skeleton components Antibacterial composition Pathogenic bacteria References
Ag3(1) Ag+, 3-phosphonobenzoic acid Ag+Staphylococcus aureus strains (RN4220, Newman, and
MRSA), Escherichia coli strain (MG1655), Pseudomonas
aeruginosa strains (PA130709, PA240709)
[60]
HKUST-1 Cu2+, TMA Cu2+Saccharomyces cerevisiae, Geotrichum candidum [61]
ZIF-8 Zn2+, 2-H-MeIM ROS, H2O2Escherichia coli [62]
MOF-53(Fe)/Van Fe3+, terephthalic acid Vancomycin Staphylococcus aureus [63]
D-AzAla@MIL-100(Fe) Fe3+, TMA 1O2MRSA [64]
Ceftazidime@ZIF-8 Zn2+, 2-H-MeIM Ceftazidime E. coli [57]
PCN-224-Ag-HA Zr4+, TCPP Ag+, ROS S. aureus, MRSA [65]
GS5-CL-Ag@CD-MOF K+,
γ
-CDs Ag+E. coli, S. aureus [66]
ZIF-8-PAA-MB@AgNPs@Van-PEG Zn2+, 2-H-MeIM Ag NPs, vancomycin, ROS E. coli, S. aureus, MRSA [67]
Table 4. Examples of MOF-based biosensors.
MOFs MOFs skeleton components Targeting Detection range Limit of detection References
AuNPs@MIL-101@GOx/LOx Cr2+, H2BDC Glucose, lactate – – [69]
Fe-MOF-GOx Fe3+, NH2-BDC Glucose 1–500 µM 0.487 µM[70]
R-UiO Hf4+, DBP-Pt, QPDC O2Hypoxia, normoxia, and aerated
conditions in cells
– [71]
PAC Al3+, H6LH2S Living cells imaging – [72]
Eu3+/Ag+@UiO-66-(COOH)2Zr4+, NH2-BDC H2S0–312.5 µM 23.53 µM[73]
493-MOF-BA Zr4+, H3TATB Lysozyme proteins – 3.6 pg mL−1[75]
S1-AuNPs@Cu-MOFs Cu2+, NH2-BDC miRNA-155 1 fM to 10 nM 0.35 fM [76]
Ru-MOF-sDNA Zn2+, [Ru(dcbpy)3]2+miRNA-141 1 fM to 10 pM 0.3 fM [77]
MOF@AuNP@GO Zr4+, H2TCPP p53 gene, PSA – 0.005 nM, 0.01 ng mL−1[78]
Bacteriophage-NH-MIL-53(Fe) Fe3+, NH2-BDC Staphylococcus aureus 40–4 × 108 CFU mL−131 CFU mL−1[79a]
Ab/NH2-MIL-53 Fe3+, NH2-BDC S. aureus 400–4 × 108 CFU mL−185 CFU mL−1[79b]
HKUST-1/PANI Cu2+, H3BTC Escherichia coli O157:H7 21–2.1 × 107 CFU mL−12 CFU mL−1[80]
CdS@ZIF-8@PEI-Ab Zn2+, 2-H-MeIM E. coli O157:H7 10–108 CFU mL−13 CFU mL−1[81]
Cu-ZrMOF@aptamer@DNA Zr4+, 2,2′-bipyridine-5,5′-
dicarboxylic acid
Pseudomonas aeruginosa 10–106 CFU mL−12 CFU mL−1[82]
GSPs@ZIF-8 Zn2+, 2-H-MeIM 4-Ethylbenzaldehyde
biomarker
– 10 ppb [83]
Eu3+@MOF-253 Al3+, 2,2′-bipyridine-5,5′-
dicarboxylic acid
1-Naphthol – 7 µg mL−1[84]
PCN-224-Pt/HRP/dual-aptamer/
GQH
Zr4+, TCPP MCF-7 cells 20–107 cells mL−16 cells mL−1[85]
2-Picolinic acid-modified
UiO-66-NH2
Zr4+, NH2-BDC Uric acid 0.01–400 µM2.3 nM [86]

1906846 (6 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
Small 2020, 16, 1906846
Figure 2. a) Side view [–111 direction] of left-handed and right-handed double-stranded 31 helical chains in 1a-L and 1b-D, respectively. Grey, red, blue,
and green represent C, O, N, and Zn, respectively. b) The two sizes and trigonal and hexagonal prism-shaped nanocages in 1a-L. Reproduced with
permission.[21] Copyright 2011, Wiley-VCH. c) Schematic diagram of the preparation of siRNA/UiO-Cis for co-delivery of cisplatin and siRNA. Repro-
duced with permission.[22] Copyright 2014, American Chemical Society. d) The secondary building block of NPCN-333(Al). e) Two types of mesoporous
cavities in NPCN-333(Al) and the size of TYR. Reproduced with permission.[23] Copyright 2018, Wiley-VCH.
Table 5. Examples of MOF-based biocatalysis.
MOFs Pore size [nm] Enzyme Enzyme size [nm3] Improved function (compared to
free enzyme)
References
SC@FNPCN-333 1.1, 4.2, 5.5 SOD
CAT
2.8 × 3.5 × 4.2
4.9 × 4.4 × 5.6
Stability (low pH, protease) [91]
LDH@NU-1005
LDH@NU-1006
LDH@NU-1007
1.7 × 1.9, 3, 6
1.8 × 2, 3.1, 6.2
2.2 × 2.4, 3.3, 6.7
LDH ≈4.4 × 4.4 × 5.6 (two parts) Catalytic activity (1.5–3 times) [92]
MP8@NMIL-101 2.9, 3.4 MP8 3.3 × 1.1 × 1.7 Stability (low pH), repeatability,
selectivity
[93]
Protease@MIL-101(Al)-NH22.9, 3.4 (windows: 1.2, 1.6) Aspergillus saitoi protease ≈1.2 Broad pH (1–12), hyperpyrexia, catalytic
activity, repeatability
[94]
Enzyme-loaded ZIF-L – GOx, HRP, trypsin, DQ-OVA – Stability (UV, heat/cold),
stimuli-responsiveness
[95]

1906846 (7 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
with pillararene-based supramolecular switches as nanovalves
was reported for the first time by our group, in collaboration
with Wang and co-workers.[25] Owing to the variable host–
guest interactions between the positively charged pyridinium
(Py) stalks on the surface of MOF and the carboxylatopillar[5]
arene (CP5) rings, this system exhibited pH-responsive
and/or competitive binding-responsive drug release behavior
with negligible premature release (Figure 3a). A series of exper-
imental results proved that the functionalized DDS has large
drug encapsulation efficiency, low toxicity, and good biodegra-
dability and biocompatibility. In the same year, another DDS
based on positively charged quaternary ammonium salt stalk
Small 2020, 16, 1906846
Figure 3. a) Schematic diagram of the synthesis process and drug release behavior of DDS based on CP5-capped UMCM-1-NH-Py. Reproduced with
permission.[25] Copyright 2015, Royal Society of Chemistry. b) Schematic diagram for the preparation of the DDS based on Fe-MIL-101 and its applica-
tion in tumor therapy and the legends of the representative components in this system. c) The DOX release curves of the DDS based on Fe-MIL-101
under redox stimulation. Reproduced with permission.[28] Copyright 2015, Royal Society of Chemistry. d) Schematic diagram of the preparation process
of DDS based on
β
-CD-capped UiO-68-azo. Reproduced with permission.[29] Copyright 2016, American Association for the Advancement of Science.

1906846 (8 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
(Q) modified Zr-MOF and CP5 supramolecular gatekeepers was
prepared by us for on-demand delivery of 5-Fu.[26] UiO-66-NH2
with high stability and surface area, built by Zr6O4(OH)4 clus-
ters and 2-amino-1,4-benzenedicarboxylate (NH2-BDC) ligand,
ensured the efficient loading of 5-Fu. In pathological environ-
ment with high Zn2+ concentration, the coordination between
CP5 and Zn2+ weakened the binding affinity of CP5 and Q,
resulting in the separation of CP5 from Q stalk and the drug
release. Similarly, external heating can also reduce the asso-
ciation constant between CP5 and Q to achieve temperature-
responsive drug release. Considering the high Ca2+ content in
bone tumor cells and combining with our previous studies, we
further constructed a triple-stimuli-responsive system based on
Zr-MOF capped with CP5 to form pseudo[2]rotaxanes for the
treatment of bone tumors.[27] The drug release results indicated
that the supramolecular interactions between CP5 and the
stalks on the surface of MOF could be weakened by pH, high
concentration of Ca2+ as well as hyperthermia, enabling control-
lable drug release of 5-Fu. Importantly, this DDS can not only
transport the anticancer drugs to the target sites and reduce the
side effects, but also regulate the pH and Ca2+ concentration in
a pathological environment. Meanwhile, the high drug encap-
sulation capacity is twice of the similar system we reported pre-
viously.[26] Furthermore, this unique system demonstrated low
cytotoxicity, good biocompatibility, and outstanding potential
applications in regenerative medicine and treatment of bone
tumors, paving a new way for the sustainable release of anti-
tumor drugs at lesion sites.
For another instance, Zhang and co-workers reported a bio-
compatible multifunctional MOF-based DDS with pH and GSH
dual-responsiveness and good degradability for the delivery of
anticancer drug doxorubicin (DOX) by a “green” one-pot post-
synthetic surface modification strategy (Figure 3b).[28] After
surface functionalization with azide followed by DOX loading,
the Fe-MIL-101 system was further coated with a bicyclononyne-
functionalized
β
-cyclodextrin (
β
-CD) derivative, that is,
β
-CD-
SS-BCN, and a targeted peptide functionalized polymer, that
is, Lys(adamantane)-Arg-Gly-Asp-Ser-bi-poly(ethylene glycol)
(PEG) 1900 (bi refers to benzoic imine bond, K(ad)RGDS-
PEG1900), by strain-promoted [3+2] azide–alkyne cycloaddition
and host–guest inclusion complexation of
β
-CD and adaman-
tane, respectively. The presence of benzoic imine bonds and
disulfide bonds contributed to the DDS pH-responsiveness
and redox-responsiveness (Figure 3c). Moreover, after surface
modification of this DDS, the cytotoxicity of the loaded DOX on
normal cells was significantly reduced as demonstrated by in
vitro cell experiments. Importantly, such DDS showed excellent
chemotherapeutic effect and minimal side effects in hepatoma
H22 tumor-bearing mice model.
At present, owing to the noninvasiveness and spatiotem-
poral accuracy of light, light-stimuli-responsive MOF-based
DDSs have shown significant advantages in achieving effec-
tive therapy in tumor sites. Wang and co-workers reported a
water-stable Zr-MOF DDS with photo-stimuli-responsiveness,
namely UiO-68-azo, which consists of Zr4+ and a new ligand
2′-p-tolyldiazenyl-1,1′:4,4′-terphenyl-4,4″-dicarboxylic acid.[29]
After cargo loading,
β
-CD was further capped to the azoben-
zene stalks on the surface of UiO-68-azo carrier to form supra-
molecular complex for regulating the cargo release (Figure 3d).
Before UV irradiation,
β
-CD was firmly capped to the trans-
azobenzene stalks, and the cargo was held within the nanop-
ores of UiO-68-azo. On the contrary, under UV light irradiation,
the isomerization of azobenzene stalks from trans-to-cis could
drive the
β
-CD away from the stalks, resulting in cargo release.
Besides, amantadine, a drug used to treat Parkinson’s disease,
could be used as a competitive agent to promote the dissocia-
tion of
β
-CD from azobenzene stalk and cause cargo release,
which was attributed to its stronger binding affinity with
β
-CD.
3.1.3. Multifunctional MOFs as Carriers
Although the stimuli-responsive MOFs have been rapidly devel-
oped to achieve the on-demand drug delivery requirements and
reduce undesired side effects during cancer treatment, there
are still many challenges to be addressed. For example, the
multidrug resistance during chemotherapy, the limitations of
monotherapy, as well as the heterogeneity and incredible com-
plexity of tumors have promoted the emergence and develop-
ment of multifunctional DDSs to meet the abovementioned
complicated requirements.[4c,30] Among them, various MOF-
based diagnostic and/or therapeutic platforms with control-
lable drug release, multimodal synergetic treatment, such as
photothermal therapy (PTT), photodynamic therapy (PDT), and
others, have shown enormous potentials in cancer treatment
and diagnosis.[31]
As an emerging treatment method, PTT with noninvasive-
ness, high selectivity, and tissue-penetrating depth was capable
of converting near-infrared laser into hyperthermia by means
of photothermal agents, resulting in photothermal ablation of
tumor cells.[32] Taking these into account, our group developed a
multifunctional supramolecular nanohybrids constructed from
core–shell MOFs and pillararene nanogates for targeted chemo-
photothermal treatment of cervical cancer (Figure 4a).[31b] Such
a system highly integrated a polypyrrole nanoparticle (PPy
NP) core with ideal photothermal conversion capability, to be
more specific, Py-modified UiO-66-based drug reservoir with
high drug-loading capacity as shell, pH/temperature-stimuli-
responsive water-soluble pillar[6]arene (WP6) nanovalves on the
MOF surface, and folic acid (FA)-modified polyethyleneimine
(PEI-FA) as active targeting group coated in the outermost layer
by electrostatic interactions to meet multimodal synergetic
treatment of tumors and controlled drug release.
PDT is a noninvasive treatment method that combines 3
nontoxic ingredients, photosensitizer (PS), light irradiation,
and oxygen in tissue. The mechanism of PDT relies on the
activation of PS accumulated at the tumor site under particular
light irradiation that transfers energy to oxygen and other
molecules to produce reactive oxygen species (ROS), especially
singlet oxygen (1O2), inducing cell toxicity through apoptosis
or necrosis pathway.[33] To date, MOF-based diagnostic and/
or therapeutic systems combined with PDT have been widely
used in cancer therapy. In 2014, Lin and co-workers reported a
highly effective Hf-porphyrin NMOF PS, DBP-UiO, consisting
of 5,15-di(p-benzoato)porphyrin (H2DBP) ligands and Hf4+
for resistant head and neck cancer via PDT.[34] Subsequently,
they designed and reported the first chlorin-based NMOF
with enhanced photophysical properties and more efficient
Small 2020, 16, 1906846

1906846 (9 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
1O2 generation ability, namely DBC-UiO, which was built
from Hf4+ and 5,15-di(p-methylbenzoato)porphyrin (Me2DBP)
ligands (Figure 4b).[35] Notably, compared to the DBP-UiO, chlo-
rin-based DBC-UiO showed a red-shift of 13 nm and an 11-fold
improvement in the extinction coefficient of the lowest-energy
Q band, thus causing three times higher 1O2 generation and
enhanced PDT effect on CT26 and HT29 tumor-bearing mice.
To tackle the problem of hypoxia and usage efficiency of
ROS during PDT in the TME, Zhang and co-workers designed
a core–shell nanofactory based on MOF hybrids for enhanced
treatment of colon cancer in mice (Figure 4c).[36] In the as-pre-
pared Pda-Pt@PCN-FA nanofactory, the Pt nanoparticles (NPs)
on the surface of polydopamine (Pda) core were used to catalyze
the conversion of endogenous H2O2 to O2 to alleviate hypoxia
in the TME and increase effect of PDT, the PCN shell consisted
of tetrakis(4-carboxyphenyl)porphyrin (H2TCPP) and Zr4+ and
attached with FA via coordination between Zr6 and carboxyl
groups of FA was used to reduce the interference between
reactions, for converting O2 into 1O2, and shortening the dif-
fusion distance of ROS. Recently, Lei and co-workers reported
a tandem catalytic MOF-based platform combining PTT and
PDT to enlarge the therapeutic effect of hypoxic tumor cells.[37]
BQ-MIL@cat-MIL heterostructure was built from a layered
MIL-101-NH2 that encapsulated black phosphorus quantum
dot (BQ) as inner and catalase (CAT) as outer, respectively. Fur-
thermore, the surface of BQ-MIL@cat-MIL was modified with
PEG-FA and cyanine 3 (Cy3)-labeled caspase substrate peptide
(Cy3-pep) to obtain BQ-MIL@cat-fMIL for the enhanced tar-
geting capacity and visualization (Figure 4d). Under laser irra-
diation, H2O2 could be catalyzed by the outer layer to produce
O2, and then O2 was directly transferred into the inner layer
to generate high-yield 1O2. The PTT/PDT synergistic treatment
demonstrated excellent therapeutic effect for HeLa-bearing
mice owing to the efficient 1O2 production and potent hyper-
thermia, providing an efficient method for developing a prom-
ising theranostics system against hypoxic in the TME.
For another instance, Wang et al. reported ultrasmall por-
phyrin-MOF nanodots (MOF QDs) with high ROS generation,
efficient tumor accumulation, and rapid renal clearance in
vivo, which could enhance the therapeutic effect of PDT and
overcome the long-term toxicity (Figure 5a).[38] The MOF QDs
were prepared from PCN-224 NMOFs via a liquid phase exfo-
liation method, and then PEG was modified on the surface
by the coordination interactions between Zr6 and the carboxyl
Small 2020, 16, 1906846
Figure 4. a) Schematic representation for the preparation of DDS based on WP6-capped core–shell MOFs and its application for synergistic chemo-
photothermal therapy. Reproduced with permission.[31b] Copyright 2018, American Chemical Society. b) Schematic diagram of DBC-UiO to generate 1O2
under light irradiation for PDT. Reproduced with permission.[35] Copyright 2015, American Chemical Society. c) Schematic description of Pda-Pt@PCN-FA
nanofactory used to improve the usage efficiency of ROS during PDT in the TME. Reproduced with permission.[36] Copyright 2011, Wiley-VCH. d) Sche-
matic illustration for the preparation of tandem catalytic MOF-based platform and its application in enhancing the therapeutic effect of hypoxic tumor
cells by PDT and PTT. Reproduced with permission.[37] Copyright 2019, Wiley-VCH.

1906846 (10 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
groups of PEG. Experimental results showed that MOF QDs
could generate two times ROS under 650 nm laser irradiation,
greatly improving the effect of PDT. In vivo results indicated
that MOF QDs mainly excreted from mice through the kidneys
after intravenous administration with low side effects.
In recent years, microwave hyperthermia has been widely
regarded as a promising treatment because of its simple opera-
tion and slight side effects. A biocompatible and biodegradable
Mn2+ doped Zr-MOF nanocube (Mn-ZrMOF NCs) prepared by
hydrothermal method was reported by Meng and co-workers[39]
for the synergistic treatment of tumors via combining micro-
wave dynamic therapy (MDT) and microwave thermal therapy
(MTT) (Figure 5b). The Mn-ZrMOF NCs possessed high thermal
conversion efficiency of 28.7% and the ability to generate cyto-
toxic hydroxyl radicals (•OH) under microwave irritation, which
lays a foundation for the development of microwave-responsive
platforms to be utilized in cancer therapy.
As a major energy source in cells, glucose plays a key role in
providing energy for tumor metabolism. Therefore, blocking
the glucose supply of tumor cells is an effective strategy in
tumor therapy. Qu and co-workers fabricated a biomimetic
MOF-based nanoreactor (TGZ@eM) coated with erythrocyte
membrane for encapsulation of the prodrug tirapazamine
(TPZ) and glucose oxidase (GOx) in starvation-activated treat-
ment of colon cancer.[40] In this core–shell structure of MOF-
based nanoreactor, GOx was efficiently delivered to the tumor
sites with high catalytic activity to cause tumor hypoxia by
exhausting the endogenous glucose and oxygen, and then the
TPZ was released and activated in the TME for inducing cell
apoptosis. Furthermore, the coating of erythrocyte membrane
endowed the nanoreactor with immunity-escaping and pro-
longed blood circulation abilities. Both in vitro and in vivo
results indicated that such MOF-based nanoreactor could
be cleared from the mice and used for starvation-activated
treatment of colon cancer through a powerful synergistic cas-
cade effect.
Radiotherapy (RT), as a common treatment has been widely
introduced in cancer therapy. On this basis, Lin and co-workers
reported a Hf-MOF, Hf-DBB-Ru, consisting of Hf4+ and bis(2,2′-
bipyridine)(5,5′-di(4-benzoato)-2,2′-bipyridine)ruthenium(II)
chloride linkers (DBB-Ru) for mitochondria-targeted RT and
radiodynamic therapy (RDT).[31d] The addition of Ru endowed
the Hf-DBB-Ru with a highly positive charge and strong mito-
chondria-targeting property. Hf-DBB-Ru enhanced RT-RDT
through generating abundant •OH from Hf clusters and 1O2
from Ru-based ligands under low dose and high penetration
Small 2020, 16, 1906846
Figure 5. a) Schematic illustration of the preparation of MOF QDs with high-efficiency renal clearance for cancer therapy. Reproduced with permis-
sion.[38] Copyright 2019, American Chemical Society. b) Schematic representation of Mn-ZrMOF NCs serving as nanoplatform for synergistic MDT
and MTT of tumors. Reproduced with permission.[39] Copyright 2017, American Chemical Society. c) Schematic diagram of Hf-DBB-Ru-initiated mito-
chondria-targeted RT and RDT to induce apoptosis of tumor cells. Reproduced with permission.[31d] Copyright 2018, Springer Nature. d) Schematic
illustration of the main components of the PEGylated porphyrin Au-NMOF-based nanohybrid and the mechanism of O2-evolving synergistic chemora-
diotherapy for tumor treatment. Reproduced with permission.[41] Copyright 2019, Wiley-VCH.

1906846 (11 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
X-ray irradiation. Meanwhile, experimental studies showed that
Hf-DBB-Ru induced mitochondrial membrane depolarization,
cytochrome c release for programmed cell death, which was
also verified in colorectal tumor models on mice (Figure 5c).
This work provides a powerful guidance for cancer RT-RDT
with the preparation of cationic MOF.
Recently, Chen and co-workers fabricated a PEGylated por-
phyrin Au-NMOF-based nanohybrid with biodegradability,
stimuli-responsive O2 generation, and controllable drug release
to achieve O2-evolving chemoradiotherapy (Figure 5d).[41] Au
NPs were grown in situ on the surface of MOFs, which brought
about several remarkable advantages, such as increased sensi-
tization of RT, enhanced stability of nanohybrid and alleviated
hypoxia during tumor therapy. Afterwards, DOX as anticancer
drug was loaded in the MOFs reservoir and combined with
Au NPs to form chemoradiotherapy system. Both in vitro and
in vivo experiments illustrated that the as-prepared nanoplat-
form with negligible side effects could significantly enhance
RT effect, reduce tumor hypoxia and achieve synergistic
chemoradiotherapy.
3.2. MOF-Based Bioimaging Nanoplatforms
The rapid development of bioimaging technologies provide an
important device to explore the pathological characteristics and
metabolic functions of biological tissues, greatly encouraging
the diagnosis of diseases. Imaging agents, such as fluorescent
small molecules and imaging contrast agents, are employed
to generate signals or enhance the signal contrast in targeted
tissues. In the past several years, owing to the facile function-
alization, diversiform structures and compositions, and large
porosities of MOFs, MOF-based nanocomposites are widely
used in fluorescence imaging (FL), computed tomography (CT),
magnetic resonance imaging (MRI), and positron emission
tomography (PET) imaging.[42] In this section, we will highlight
the applications and potential advantages of MOF-based nano-
composites as imaging contrast agents or imaging contrast car-
riers in monomodal and multimodal bioimaging applications.
3.2.1. Monomodal Bioimaging
As a universally used imaging method, FL has been employed
to acquire visualized information of the biological distribution
and content via optical molecules, which has the advantages of
high sensitivity, excellent resolution, and facile operation. Mao
and co-workers constructed a simple MOF-based fluorescent
probe, consisting of Zn2+ and imidazole-2-carboxyaldehyde
ligands, namely RhB/ZIF-90, for FL of mitochondria adenosine
triphosphate (ATP) in living cells.[43] Rhodamine (RhB) was
encapsulated into ZIF-90, and its fluorescence was quenched
due to the self-quenching effect. In the presence of ATP,
the RhB/ZIF-90 was decomposed, causing the release and
fluorescence recovery of RhB for intracellular ATP imaging.
Subsequently, Zhang and co-workers first reported two-photon
MOF-based fluorescent probe 1/2 (Tp-MOF) for bioimaging
hydrogen sulfide (H2S) and Zn2+ in living cells and tissue,
respectively.[44] The surface of PCN-58 was modified with two
organic probes (alkynyl-BR-NH2 for H2S and alkynyl-DL for
Zn2+) via click chemistry to form TP-MOF probe 1 and TP-MOF
probe 2, respectively. The experimental results showed that
TP-MOF probes exhibited outstanding photostability, excellent
selectivity, and good biocompatibility as well as desirable
penetration depth (up to 130 µm) in rat liver tissue, which pro-
vides a way for the detection of active components in biological
tissues using MOF probes.
CT, a 3D grayscale reconstructed image, is formed by the
difference of X-ray attenuation among scanned tissues, which
provides a powerful diagnostic basis for the visualization of
the internal structure of the tissues. Currently, the applica-
tion of small molecule contrast agents with high X-ray-atten-
uated in clinical field, such as iodine and barium, is severely
restricted because of their unsatisfactory distribution, rapid
clearance rate, and ultrahigh dose requirements (tens of
grams). However, MOF-based contrast agents are able to solve
these problems and provide high contrast enhancement. Farha
and co-workers synthesized a new MOF, bismuth (Bi)-NU-
901, composed of [Bi6O4(OH)4(NO3)6(H2O)](H2O) nodes and
tetratopic 1,3,5,8-(p-benzoate)pyrene (H4TBAPy) ligands for
CT imaging.[45] According to the nitrogen adsorption–desorp-
tion isotherms and the density functional theory, the surface
area and the pore size of Bi-NU-901 were determined to be
320 m2 g−1 and ≈11 Å, respectively. In vitro results demon-
strated that the Bi-NU-901 contrast intensity with high chem-
ical and thermal stability showed ≈7 times and ≈14 times better
than the Zr-MOF with the same topology and the commercially
available CT contrast agent, respectively. Therefore, this work
provides a new option for clinical CT contrast agents.
MRI is a powerful technique that employs radio-frequency
signals generated by the interactions between external magnetic
field/radio waves and the protons (typically of hydrogen atoms)
of detected soft tissues for high spatial resolution imaging.
Compared with CT, MRI exhibits the advantages of superior
resolution, wide application range, and noninvasiveness. MRI
contrast agents can transform the longitudinal (T1) and lateral
(T2) relaxation rates of water protons for disease diagnosis. To
date, numerous MOFs that contain Gd, Mn, Fe, iron oxide, and
their derivatives have been used in the development of MRI con-
trast agents to achieve high-resolution MRI effects.[42a,b,46] For
example, Steunou and co-workers designed a superparamag-
netic mesoporous MIL-100(Fe) composite decorated by magh-
emite (
γ
-Fe2O3) NPs for MRI imaging and cancer treatment.[47]
The composite performed good stability and MRI ability under
physiological conditions. Meanwhile, it is worth noting that
when the
γ
-Fe2O3 NPs content was 10 wt%, the relative relax-
ometric value was nine times better than that of MIL-100(Fe),
which was related to the high saturation magnetization of the
composite. In addition, this composite showed great biocom-
patibility and high antitumor activity after being loaded with
DOX, and could be used as an effective MRI contrast agent and
DDS in vivo. Recently, we reported an intelligent theranostic
nanoplatform based on Fe3O4@UiO-66 core–shell structure and
pillar[6]arene nanovalves, which possessed “four-in-one” func-
tions of multi-stimuli-responsiveness (including pH, tempera-
ture, and competitive binding agent), prominent MRI guidance,
sustained drug release, and effective chemotherapy (Figure 6a).
The core–shell hybrids of Fe3O4@MOF were fabricated by in
Small 2020, 16, 1906846

1906846 (12 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
situ growth method of UiO-66-NH2 shell with high loading
capacity on the surface of Fe3O4 core with superior abilities of
MRI and magnetic separation. Then, WP6 was introduced to the
surface of 5-Fu-loaded Fe3O4@MOF hybrids as tightness-adjust-
able nanovalves via the host–guest interactions with Py stalks.
Notably, such an intelligent theranostic nanoplatform exhibited
good biocompatibility, excellent T2-weighted MRI ability, and
superior anticancer effect on HeLa cells (Figure 6b,c). Inter-
estingly, the tight nanovalve system achieved sustained drug
release over 7 days, which indicated that controllable sustained
release can be achieved by adjusting the host–guest interactions
to change the tightness of the nanovalves.[48]
Compared to other imaging technologies, PET imaging
bears the advantages of rapid imaging speed, superior sensi-
tivity, deep penetration, and outstanding quantitative ability.
Hong and co-workers reported an intrinsically radiolabeled
NMOF-based nanoplatform (89Zr-UiO-66/Py-PGA-PEG-F3) for
PET imaging of triple-negative breast tumors (Figure 6d).[49]
After loading the anticancer drug DOX, 89Zr-UiO-66, consisting
of Zr6 as metal clusters and 1,4-benzene-dicarboxylate and
benzoic acid as ligand linkers, was functionalized by pyrene-
derived polyethylene glycol (Py-PGA-PEG) and F3 peptide
(KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK) to enhance the
stability and active targeting of NMOF, respectively. In this work,
DOX with high loading capacity could be used as a drug for anti-
tumor therapy, and moreover, as a fluorescence visualizer for
FL. Meanwhile, the long half-life advantage of 89Zr (t1/2 = 78.4 h)
could be used to monitor the distribution and clearance process
of 89Zr-UiO-66/Py-PGA-PEG-F3 for up to 120 h after intraperito-
neal injection in vivo (Figure 6e). Experimental results indicated
that MOF-based material could serve as a safe and stable nano-
platform for PET imaging and tumor therapy.
Small 2020, 16, 1906846
Figure 6. a) Schematic representation of the preparation of Fe3O4@UiO-66@WP6 and its application for MRI imaging and chemotherapy in tumors.
b) Magnetic hysteresis curves of Fe3O4 NPs (black) and 5-Fu-loaded Fe3O4@UiO-66@WP6, and the transverse relaxivity of Fe3O4@UiO-66@WP6
against different (Fe) concentrations. c) MRI images of HeLa cells incubated with Fe3O4@UiO-66@WP6. Reproduced with permission.[48] Copyright
2018, Wiley-VCH. d) The fabrication process and the crystal structure of 89Zr-UiO-66/Py-PGA-PEG-F3 nanoplatform. e) Coronal PET images of tumor-
bearing mice at different times after injection of 89Zr-UiO-66/Py-PGA-PEG-F3 and other treatment groups. Reproduced with permission.[49] Copyright
2017, American Chemical Society.

1906846 (13 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
3.2.2. Multimodal Bioimaging
The drawbacks of monomodal bioimaging technologies seri-
ously limit the further application of imaging technology in
disease diagnosis. Integrated multimodal diagnostic technolo-
gies in one system are long-term challenges in the diagnosis of
disease. Significantly, multimodal bioimaging, superimposed
by two or more monomodal bioimaging, can comprehensively
reflect the pathological information, and has been rapidly devel-
oped as a glorious technique of clinical diagnosis and disease
detection.[42c]
FL
&
MRI: Tang and co-workers prepared a core–shell
structured MOF-based nanocarrier, PEG-FA-coated UCNP@
Fe-MIL-101-NH2 (denoted as UMP-FA), for upconversion lumi-
nescence and T2-weighted MRI dual-mode imaging of tumor
in KB tumor-bearing mice.[50] This system was constructed
from NaYF4:Yb,Er NPs as core and Fe-MIL-101-NH2 as shell
with a thickness of ≈9 nm, followed by coating with PEG-FA
or PEG at outermost layer. In vivo experiments revealed that
the nanocarriers had good biocompatibility and could enhance
the intracellular internalization ability of FA overexpressed cells
by FA-mediated endocytosis pathway. After intravenous injec-
tion of UMP-FA for 24 h, the MRI signal at tumor site was
darkened by ≈35% and the fluorescence intensity was almost
10 times higher than that of the control group, which further
demonstrated the efficient accumulation of UMP-FA at the
tumor site. Recently, Wang and co-workers reported a Fe2+-
adsorbed NMOF-based system for FL and T2-weighted MRI
bioimaging of cancer cells for early diagnosis of cancer.[51] The
authors found that Fe2+ could be rapidly adsorbed on the sur-
face or pores of ZIF-8 in the presence of Fe2+. Under the syner-
gistic effect of ROS, GSH, and acidic condition in tumor cells,
Fe2+-adsorbed ZIF-8 was easily transformed into fluorescent
ZnO and superparamagnetic Fe3O4 for FL and T2-weighted
MRI in vivo due to the release of Zn2+ from ZIF-8 and the
oxidation of Fe2+ to Fe3+. Obviously, this phenomenon only
occurred in cancer cells but not in normal cells, which could be
attributed to the difference in the microenvironment between
normal cells and tumor cells. This work provides the possibility
to construct Fe2+-adsorbed NMOF-based nanoplatforms for effi-
cient and rapid multimodal imaging of tumors in vivo.
CT
&
MRI
&
PAI: In addition to CT and MRI, PAI is a novel
noninvasive and nonionized biomedical imaging method,
which significantly increases imaging depth and spatial reso-
lution. Integrating the advantages of CT, MRI, and PAI into
one, Tian and co-workers structured a core–shell NMOFs nano-
probe based on PEG-decorated Au nanorods and MIL-88(Fe)
for high, enhanced CT, MRI, and PAI imaging of glioma in
vivo (Figure 7a).[52] The results showed that the nanoprobe
concentrations and the signal intensities of CT, MRI, and PAI
exhibited positive linear relationships within a certain range.
Notably, Au@MIL-88(Fe) with low cytotoxicity provided high
contrast in CT, MRI, and PAI (Figure 7b), which significantly
improved imaging sensitivity, high penetration depth, and
spatial resolution of glioma imaging in vivo, providing opportu-
nities for advanced multimodal imaging applications of tumors
from preclinical to clinical research.
FL
&
PAI
&
MRI: A versatile and biocompatible MOF-based
nanohybrid based on hyaluronic acid (HA) and indocyanine
green (ICG)-loaded MOF scaffolds, namely MOF@HA@ICG,
was fabricated for FL, PAI, and T2-weighted MRI imaging and
tumor therapy by PTT (Figure 7c).[53] In this work, ICG was
loaded in the pores of MIL-100(Fe) with a loading capacity of
40%, which was beneficial for PTT and FL (Figure 7d). HA, as
a ligand molecule recognized by CD44, was encapsulated in the
outer layer of the nanohybrid to improve the stability and cel-
lular uptake of CD44-positive cells (MCF-7 cells). MIL-100(Fe)
provided MRI and PAI abilities for the MOF@HA@ICG
system (Figure 7e,f). As a proof of concept, both in vitro and in
vivo studies indicated that the MOF-based nanohybrid exhibited
low toxicity and excellent inhibition effect on MCF-7 xenograft
tumors growth using multimodal imaging-guided PTT, which
provides significant contribution for MOF-based nanohybrids
in multimodal imaging-guided PTT in solid tumors.
FL
&
CT
&
MRI: Recently, Yin and co-workers reported a smart
NMOF-based theranostic system integrating CT, MRI, and FL
to guide precise chemotherapy of cancer.[54] The NMOFs were
constructed by 5-boronobenzene-1,3-dicarboxylic acid (BBDC)
ligands and Gd/Yb metal nodes. After DOX loading and facile
surface coating of glucose by diol-borate condensation, the
DOX@MOF-Glu bearing good biocompatibility demonstrated
MRI-, CT-, and FL-guided pH-responsive controllable drug
release. Similarly, this method could be extended to the design
of CT of gastrointestinal tract with Yb-MOFs-Glu.
3.3. MOF-Based Antibacterial Nanomaterials
Since antibiotic penicillin was applied for the treatment of infec-
tions caused by pathogenic bacteria in the 1930s, multidrug
resistance of bacteria has been triggered by the irregular abuse
and long-term overuse of most natural, semisynthetic or total
synthetic antibiotics.[55] Moreover, undesired side effects such
as nephrotoxicity, ototoxicity, and rapid clearance in vivo have
severely affected the therapeutic efficacy. Therefore, numerous
methods have been proposed to overcome some of the afore-
mentioned shortcomings. MOF-based antimicrobial nanoplat-
forms generally contain one or more of the following features:
1) metal nodes in MOFs (such as Ag, Cu, Ni, Zn, etc.) exhib-
iting antibacterial activity that could undergo sustained release
during the degradation of MOFs to achieve high effective anti-
bacterial effect,[56] 2) the excellent containment of antimicrobial
molecules based on the high surface areas and adjustable pore
sizes of MOFs,[57] 3) the organic linkers used to build the MOF
scaffolds, such as porphyrin derivatives, offering a potential to
combine PDT for bacterial infections,[58] 4) flexible post-mod-
ification methods that promote the further functionalization
of MOFs.[59] In this part, we will introduce the application pro-
gress of MOF-based nanoplatforms in antibacterial field.
3.3.1. Individual MOFs as Antibacterial Agents
In 2011, Jaffrès and co-workers reported a 3D Ag-MOFs
(Ag3(1)), which consists of Ag+ and 3-phosphonobenzoic acid
bearing both carboxylic and phosphonic acid functional groups,
for effective killing of bacteria via sustainable release of Ag+.[60]
The Ag-MOF showed negligible toxicity to human red cells.
Small 2020, 16, 1906846

1906846 (14 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
Importantly, antimicrobial results showed that the Ag-MOF
displayed broad bactericidal effect against six types of bacteria,
including three Staphylococcus aureus strains RN4220, Newman,
and methicillin-resistant S. aureus (MRSA), one Escherichia coli
strain MG1655, two Pseudomonas aeruginosa strains PA130709
and PA240709. The antibacterial activity of Ag3(1) from the
sustained release of Ag+ was measured by cathodic stripping
voltammetry.
Subsequently, Zamaro and co-workers found that Cu-MOF
composed of Cu2+ and trimesic acid (TMA) ligands, denoted as
HKUST-1, exerted strong inhibition against Saccharomyces cer-
evisiae and Geotrichum candidum.[61] Similar to that of Ag-MOF,
the inhibitory effect of Cu-MOF against yeast and mold was
related to the release of Cu2+ via MOF scaffold degradation,
thus involving the formation of surface extra-framework Cu(I).
The sustained release of metal ions from MOF degradation for
antimicrobial opens new prospects for the application of MOFs
in the field of antibacterial therapy.
Interestingly, Wang and co-workers reported a series of MOFs
with photocatalytic bactericidal performances in air pollution
and personal protection (Figure 8a).[62] Among them, a Zn-MOF,
ZIF-8, consisting of Zn2+ and 2-methylimidazole (2-H-MeIM)
ligands, demonstrated almost complete antibacterial efficacy
(>99.9999%) of gram-negative E. coli in saline solution of sim-
ulated sunlight irradiation for 2 h. A series of experimental
results indicated that the excellent bactericidal performance of
Small 2020, 16, 1906846
Figure 7. a) Schematic representation of the preparation of Au@MIL-88(Fe) for the application of CT, MRI, and PAI imaging on glioma diagnosis.
b) CT (b1,2), MRI (b3,4), and PAI (b5,6) images of U87 MG-bearing mice before and after intravenous injection with Au@MIL-88(Fe) nanoplatform.
Reproduced with permission.[52] Copyright 2016, Wiley-VCH. c) Schematic diagram for the construction of MOF@HA@ICG system and the applica-
tions of FL, PAI, and T2-weighted MRI imaging in MCF-7 tumor-bearing mice treatment. The images of d) FL, e) PAI, and f) MRI after injection of
various materials in vivo. Reproduced with permission.[53] Copyright 2016, American Chemical Society.

1906846 (15 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
ZIF-8 was mainly attributed to the ROS and H2O2 generated
by photocatalysis, rather than the bactericidal effect of Zn2+
released from ZIF-8 scaffolds. Subsequently, MOFilter mask
containing ZIF-8 was developed to study the bactericidal proper-
ties under actual protective conditions. After spraying artificial
pathogenic aerosols for 5 min and being exposed on the simu-
lated sunlight irradiation for 30 min, almost no E. coli survived
on three layers of MOFilter mask, which was better than the
commercial mask (N95). This work opens a door to the air dis-
infection and basic protection applications of MOF-based nano-
platforms with photocatalytic antibacterial effects.
3.3.2. MOFs as Nanocarriers of Antibacterial Agents
In addition to the release of metal ions from the degradation of
MOFs scaffolds, the sustained inhibitory effects of MOF-based
nanoplatforms on pathogenic bacteria can also be achieved by
encapsulating natural antibacterial agents in the pores of MOFs.
In 2017, Wu and co-workers reported a nontoxicity vancomycin-
loaded MOF-53(Fe) system, namely MOF-53(Fe)@Van, for
sustained antimicrobial therapy.[63] MOF-53(Fe) carrier exhib-
ited negligible degradation under acidic conditions (pH 6.5 and
5.5). Experimental results demonstrated that MOF-53(Fe)@Van
had controllable drug release behavior, remarkable antibacterial
efficiency (up to 90%), good chemical stability, and negligible
cytotoxicity. Interestingly, the sustained release of iron ions
during the degradation of MOF-53(Fe) promoted the prolifera-
tion and osteogenic differentiation of MC3T3 cells.
Liu and co-workers designed a 3-azido-D-alanine (D-AzAla)-
loaded MOF carrier, D-AzAla@MIL-100(Fe) NPs, with good
dispersity in physiological conditions for image-guided precise
antibacterial therapy in vivo.[64] MIL-100(Fe) with a diameter of
120 nm was built from Fe3+ and TMA ligands. After intravenous
injection, MOF carrier accumulated in the inflammation
region with high expression of H2O2 via EPR effect, and the
Small 2020, 16, 1906846
Figure 8. Schematic illustrations of a) the application of MOFilter based on ZIF-8 for photocatalytic high efficiency sterilization in air pollution and
personal protection. Reproduced with permission.[62] Copyright 2019, Springer Nature. b) The fabrication of the nanoplatform based on MIL-100(Fe)
and the proposed strategy for image-guided precise antibacterial therapy in vivo. Reproduced with permission.[64] Copyright 2018, Wiley-VCH. c) The
preparation process of ultrafine Ag NPs growth in the pores of CD-MOF and the surface modification of CD-MOF. Reproduced with permission.[66]
Copyright 2019, Wiley-VCH. d) The synthesis of ZIF-8-PAA-MB@AgNPs@Van-PEG and the application of endophthalmitis treatment. Reproduced
with permission.[67] Copyright 2019, Wiley-VCH.

1906846 (16 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
coordination bonds between Fe3+ and TMA were broken by
H2O2, thus resulting in the degradation of MIL-100(Fe) and the
release of D-AzAla. At the same time, D-AzAla was integrated
on the bacterial cell wall and exposed the azide groups. As sug-
gested, 2-(1-(5-(4-(1,2,2-tris(4-methoxyphenyl)vinyl)phenyl)thio-
phen-2-yl)ethylidene)malononitrile PS, with aggregation-induced
emission properties, was injected and combined with the azide
group by bioorthogonal reaction and PDT to achieve selec-
tive fluorescent labeling and effective antimicrobial effects in
vivo (Figure 8b). This work combined the unnatural functional
groups with bacteria in vivo for the first time, providing a unique
approach for simultaneous bacterial detection and treatment.
Another sustained-release therapeutic platform was reported
by Sava Gallis et al. on the basis of the encapsulation of antibacte-
rial agent ceftazidime into ZIF-8 MOF for continuous treatment
of intracellular infections.[57] Ceftazidime was successfully loaded
into ZIF-8 through simple encapsulation strategy and demon-
strated a long-term drug release up to 1 week. As a therapeutic
platform, ceftazidime@ZIF-8 showed good biocompatibility on
A549 cells and RAW 264.7 cells, and excellent antibacterial effect
against E. coli. Importantly, the direct internalization of ZIF-8
and drug release in cells were definitely demonstrated by 3D
reconstructions of z-stacks using confocal microscopy, owing to
the immanent emission characteristics of ZIF-8.
Qu and co-workers fabricated an enzyme-respon-
sive on-demand antimicrobial porphyrin MOF-based
system (PCN-224-Ag-HA) consisting of Zr6 clusters and
5,10,15,20-tetrakis(4-methoxycarbonylphenyl)porphyrin (TCPP)
ligands for synergistic bacteria killing and wound disinfection
upon combination with PDT.[65] Thanks to the large surface area
and unreacted carboxylic groups, Ag+ was efficiently encapsu-
lated in the pores of MOF carrier. Subsequently, the negatively
charged HA was coated on the MOFs by coordination effect
and electrostatic interactions to form a corona layer to prevent
the release of Ag+. The host MOFs demonstrated negligible Ag+
release and good biocompatibility on nontargeted bacterial and
mammal cells under normal conditions. However, in the pres-
ence of targeted bacteria, the HA on the surface of carrier could
be degraded by secreted hyaluronidase, triggering the release of
Ag+ and the binding of resulted positively charged NPs toward
the bacteria by charge interaction. In addition, the porphyrin
derivative in the MOF scaffold acted as PS to generate ROS
under light irradiation, causing PDT to kill bacteria.
Interestingly, Zhang and co-workers described a water-
soluble cyclodextrin MOF (CD-MOF) as synthetic template,
namely GS5-CL-Ag@CD-MOF, which was loaded with ultrafine
Ag NPs with Gly-Arg-Gly-Asp-Ser (GRGDS) peptide function-
alization to promote antibacterial effect and wound healing
(Figure 8c).[66] The CD-MOF was composed of
γ
-CDs as ligands
and K+ with a pore size of 0.78 nm. Ag NPs immobilized in
the apertures of CD-MOF exhibited ultrafine particle sizes of
2 nm, high aqueous dispersion, and efficient antibacterial effect
against both gram-negative and gram-positive bacteria. Wound
healing results demonstrated that the MOF-based hybrid mate-
rial had enhanced hemostatic effect and effective bactericidal
ability, showing promising potential for the rational design of
effective wound repair devices.
For another instance, together with Wang and co-workers,
we reported a pH-responsive MOF-based nanoplatform
(ZIF-8-PAA-MB@AgNPs@Van-PEG, denoted as ZPMAVP NPs)
combined with PDT for bacterial infection and biofilm eradica-
tion of endophthalmitis.[67] The MOF reservoir containing poly-
acrylic acid ensured high-efficiency loading and pH-responsive
release of PS antibacterial agent methylbenzene blue (MB). After
loading of MB, the carrier was modified by AgNO3 and dopamine
for in situ formation of Ag NPs to enhance antibacterial proper-
ties, followed by secondary modification with vancomycin/NH2-
PEG to enhance the biocompatibility of the nanoplatform. In
vitro experiments showed that ZPMAVP NPs had high efficiency
of bacteria killing and biofilm eradication on E. coli, S. aureus,
and MRSA under 650 nm laser irradiation. Meanwhile, in vivo
studies indicated that such platform had good biocompatibility
and therapeutic effect on endophthalmitis (Figure 8d).
3.4. MOF-Based Biosensors
Detection and monitor of the changes of the concentrations and
types of substances in organisms will help diagnose diseases
and reveal the underlying pathological mechanisms. There-
fore, the development of multitudinous biosensors capable of
sensing biomolecules and cells is of great importance in bio-
medical applications. MOF-based biosensors demonstrate the
advantages of high sensitivity, good repeatability, and low detec-
tion limit in the sensing of substances due to the high surface
area, easy functionalization, and high stability of MOFs.[12e,68]
Meanwhile, several disadvantages including weak stability, low
recycling ratio, and high cost also need to be considered in the
preparation of MOF biosensors.[68d,e] In this section, we mainly
introduce the biomedical applications of MOF-based biosensors
and the potential of MOFs as biosensors will also be highlighted.
3.4.1. Glucose Biosensing
As an important energy source in cells, glucose plays a key role
in the metabolism of organisms and the diagnosis and treat-
ment of diseases. Wei and co-workers designed two GOx/lactate
oxidase (LOx)-loaded MOF-based biosensors with high sensi-
tivity and selectivity by in situ growing AuNPs into MIL-101 to
measure glucose and lactic acid in living tissues (Figure 9a).[69]
The mechanism of the in vitro glucose/lactic detection by as-
prepared biosensors of Au NPs@MIL-101@GOx/LOx was to
oxidize the Raman-inactive molecule leucomalachite green
into the Raman-active probe malachite green to enhance the
Raman detection signals (Figure 9b). Meanwhile, the obtained
biosensors were also used to evaluate the therapeutic effect
of astaxanthin for reducing cerebral ischemic injuries in rats
and to determine glucose and lactate metabolism in tumors.
Recently, Zhu and co-workers reported a surface-immobilized
GOx-based MOFs biosensor for ultrasensitive glucose detec-
tion in human serum.[70] After hydrothermal synthesis of
Fe-MIL-88B-NH2 (Fe-MOF), GOx was immobilized on Fe-MIL-
88B-NH2 to form Fe-MOF-GOx via EDC/NHS-induced covalent
binding. In this system, GOx on the surface of Fe-MOFs first
catalyzed the generation of gluconic acid and H2O2 in the pres-
ence of O2. Subsequently, catalyzed by Fe-MOF, 3,3′,5,5′-tetra-
methylbenzidine (TMB) was turned into ox-TMB under H2O2
Small 2020, 16, 1906846

1906846 (17 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
condition. Such a GOx-based MOF biosensor not only showed
high stability and repeatability, but also possessed a wide
linear range of detection concentration (1–500 µM) and low
detection limit of 0.478 µM as determined by colorimetric
detection method, which shows great potential for the detection
of glucose in clinical samples.
Small 2020, 16, 1906846
Figure 9. Schematic representations of a,b) the application of Au NPs@MIL-101@GOx/LOx biosensors for detection of glucose and lactic acid with SERS.
Reproduced with permission.[69] Copyright 2017, American Chemical Society. c) The synthesis process of R-UiO. d) Ratiometric imaging of CT26 cells incu-
bated with biosensor based on R-UiO under hypoxia (left), normoxia (middle), and aerated (right) conditions. The scale bar is 10 µm. Reproduced with
permission.[71] Copyright 2016, American Chemical Society. e) Schematic illustration of Eu3+/Ag+@UiO-66-(COOH)2 biosensor used for H2S gas detection.
f) Fluorescence intensity change of Eu3+/Ag+@UiO-66-(COOH)2 at 615 nm after addition of H2S from 0 to 8 min. g) The linear fitting curve of various NaHS
concentrations and the fluorescence intensity change of Eu3+/Ag+@UiO-66-(COOH)2 at 615 nm. Reproduced with permission.[73] Copyright 2019, Elsevier.
Diagrammatic schemes for h) GSPs@ZIF-8 fabrication and usage of volatile organic compound detection for lung cancer diagnosis by SERS, and i) the selec-
tion and the binding strategies for gas molecules with different sizes by GSPs@ZIF-8 biosensor. Reproduced with permission.[83] Copyright 2017, Wiley-VCH.

1906846 (18 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
Small 2020, 16, 1906846
3.4.2. Gaseous Biosensing
Various gases, such as O2 and H2S, comprise an important class of
molecules involved in the physiological and pathological processes
of living organisms, which are also associated with a variety of dis-
eases. Lin and co-workers reported a phosphorescent/fluorescent
dual-emitting ratiometric NMOF biosensor (R-UiO), consisting
of an oxygen-sensitive probe (Pt-5,15-di(p-benzoato)porphyrin,
DBP-Pt ligand) and an oxygen-insensitive probe (rhodamine B iso-
thiocyanate-conjugated quaterphenyldicarboxylate, QPDC ligand)
for intracellular O2 quantitative determination (Figure 9c).[71] The
prepared biosensor showed high stability, good biocompatibility,
and efficient cellular uptake, ensuring the feasibility of intracel-
lular O2 detection. Under hypoxia, normoxia, and aerated condi-
tions, the intracellular O2 levels measured and imaged by R-UiO
were 5.29 ± 0.12, 4.45 ± 0.09, and 2.80 ± 0.06 mmHg, respec-
tively, which was consistent with the three different O2 conditions
(Figure 9d). This work demonstrated that the NMOF biosensor
had wide detection range and good accuracy for the ratiometric
sensing of cellular O2.
Tang and co-workers proposed a heterogeneous fluores-
cent probe based on Cu(II)-metalated-NMOF for H2S detec-
tion and confocal imaging in living cells.[72] Cu(II) as the
H2S-responding site was introduced into the NMOF host that
consists of Al3+ and meso-tetrakis(4-carboxylphenyl)porphyrin
ligand (H6L) to form an aluminum-copper nanohybrid NMOF
(denoted as PAC). The PAC probe showed low toxicity, high
selectivity, and high sensitivity for in situ detection of H2S at
physiological pH and confocal imaging in living cells. Recently,
a fluorescent MOF-based composite logic nanoplatform, con-
structed from the lanthanide-luminescence sensitizer and
H2S-responding site (Ag+) and Eu3+@UiO-66(COOH)2, namely
Eu3+/Ag+@UiO-66-(COOH)2 (EAUC), for the diagnosis of
asthma by detecting biomarker H2S was established by Qian
and co-workers (Figure 9e).[73] The MOF-based logic gate exhib-
ited rapid response, low cytotoxicity, and excellent selectivity for
in situ H2S detection, reaching a detection limit of 23.53 µM
(Figure 9f,g), providing a new method for the detection of
asthma biomarker (H2S) using MOF-based logic nanoplatform.
3.4.3. Biomacromolecules Biosensing
Biomacromolecules, such as proteins and nucleic acids, play an
irreplaceable role in the biological process, and their detection
is of great significance for the diagnosis of diseases. Numerous
MOF-based biosensors have been constructed for the detec-
tion of nucleic acids and proteins.[10,68b,74] For example, Du and
co-workers designed three types of electrochemical Zr-MOF-
based biosensors with tunable pore sizes for protein detection,
and the optimized Zr-MOF-BA, constructed from Zr4+ and
4,4′,4″-s-triazine-2,4,6-triyltribenzoic acid (H3TATB) ligands,
showed high selectivity, wide detection range, and low detection
limit of 3.6 pg mL−1 for lysozyme.[75]
Ge and co-workers reported an Au NPs-modified Cu-MOF-
based origami electrochemical biosensor for ultrasensitive
detection of microRNA (miRNA) by a strand displacement reac-
tion.[76] In this system, Au NPs was grown on the paper electrode
to increase the conductivity of the electrode and to immobilize
the hairpin probe (H1). After the addition of miRNA-155, H1
was released and opened due to the stronger affinity of the
added probe H2 and miRNA-155, which caused the formation
of numerous H1-H2 duplex through the cyclic process. As a
result, after the prepared S1-AuNPs@Cu-MOFs linked with
the exposed region of H1-H2 duplex, miRNA-155 detection was
performed in the range of 1 fM–10 nM under synergistic cata-
lytic glucose by S1-AuNPs@Cu-MOFs and Au NPs, reaching a
detection limit of 0.35 fM. Analogously, a Faraday-cage electro-
chemiluminescence Ru-MOF-based nanocomposite biosensor,
consisting of Zn2+ and tris(4,4′-dicarboxylicacid-2,2′-bipyridyl)
ruthenium(II) dichloride ([Ru(dcbpy)3]2+), with high stability
and precision for detection of miRNA-141 was constructed by
Guo and co-workers.[77] This proposed biosensor for miRNA-
141 exhibited high stability, repeatability, and a wide linear
range (from 1 fM to 10 pM) with a detection limit of 0.3 fM.
Interestingly, Chen and co-workers proposed a “three-
in-one” no-wash fluorescence biosensor based on Zr-MOF
nanohybrid for ratiometric detection of p53 gene and pros-
tate-specific antigen (PSA).[78] Zr-MOF consisting of Zr4+ and
H2TCPP ligands was used as a template for in situ growth of
Au NPs via NaBH4 reduction, followed by coating of ultrathin
graphene oxide in the outermost layer via
π
–
π
interactions
and hydrogen bonds to form MOF@AuNP@GO. The signifi-
cant binding affinities and fluorescence quenching abilities of
the as-prepared biosensor toward the dye-labeled ssDNAs and
aptamers, as well as stable NIR emission of ligands enhanced
the sensitivity and signal-to-noise ratio, and shortened the
detection time for the detection of p53 gene and PSA, reaching
a detection limit of 0.005 nM and 0.01 ng mL−1, respectively.
In addition, this biosensor also displayed outstanding perfor-
mance in the detection of human serum.
3.4.4. Pathogenic Bacteria Biosensing
Pathogen contaminations are an important culprit in pollutions
of food, environment, water, and medical devices. Therefore,
efficient and accurate detection of pathogenic bacteria is of
great significance. For instance, Deep and co-workers produced
a sensitive and stable luminescent MOF-bacteriophage-
based biosensor, which was built from NH2-MIL-53(Fe) and
bacteriophages using glutaraldehyde as cross-linker, based on
photoluminescence quenching method for the efficient detec-
tion of S. aureus. The MOF-bacteriophage-based biosensor
could detect S. aureus in a linear range of 40–4 × 108 CFU mL−1,
reaching a detection limit of 31 CFU mL−1. Subsequently, they
investigated another biosensor based on NH2-MIL-53(Fe) conju-
gation with anti-S. aureus antibodies for the detection of S. aureus
with a detection range of 400–4 × 108 CFU mL−1 and a detection
limit of 85 CFU mL−1.[79]
In 2018, Shahrokhian and Ranjbar developed an electro-
chemical polyaniline/Cu-MOF-based biosensor for the direct
detection of E. coli O157:H7.[80] The pathway of this detection
was based on the change of methylene blue reduction peak cur-
rent before and after E. coli O157:H7 culture, which achieved
rapid and sensitive detection of E. coli O157:H7 in the range of
21–2.1 × 107 CFU mL−1 with a detection limit of 2 CFU mL−1.
Subsequently, Tan and co-workers reported an ultrasensitive

1906846 (19 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
Small 2020, 16, 1906846
electrochemical biosensor based on ZIF-8 and cadmium sulfide
quantum dots (CdS QDs) for detection of E. coli O157:H7 in
milk samples. The linear range was from 10 to 108 CFU mL−1
and the detection limit was 3 CFU mL−1.[81] In addition, a Cu-
Zr-based MOF, that is, Cu-ZrMOF@Aptamer@DNA, was
proved to be a highly efficient electrochemical sensor for the
detection of P. aeruginosa.[82] The high sensitivity of biosensor
to P. aeruginosa originated from the specific recognition
between the aptamer on the Cu-Zr-based MOF and the bac-
teria, and the high conductivity of the added Super P and Au
NPs, which allowed the detection of P. aeruginosa in a linear
range of 10–106 CFU mL−1 to be completed within 120 min,
reaching a detection limit of 2 CFU mL−1.
3.4.5. Others Biosensing
Wang and co-workers reported a surface-enhanced Raman scat-
tering method for the diagnosis of lung cancer by detecting
volatile organic compound biomarker using core–shell 3D
MOF-based biosensor (Figure 9h).[83] This biosensor called
GSPs@ZIF-8 was composed of Au NPs as core and ZIF-8 as
shell, and the pore size in ZIF-8 shell could be expanded from
3.4 to over 7.6 Å, which could adsorb small aromatic com-
pounds. After the Raman-active 4-ATP molecules were grafted
onto the ZIF-8 surface, 4-ethylbenzaldehyde reacted with the
amino group on 4-ATP and detected sensitively at the ppb level
(Figure 9i). Qin and Yan reported a simple, highly selective,
and recyclable MOF-based biosensor, Eu3+@MOF-253, to detect
carbaryl metabolite 1-naphthol in human urine with detection
limit of 7 µg mL−1.[84]
Interestingly, Chen and co-workers designed a sandwich-
type MOF-based biosensor for the detection of human breast
cancer cells (MCF-7 cells).[85] In this work, the biosensor was
constructed via a layer-by-layer method by decorating Pt NPs,
aptamers of AS1411 and MUC1, and hemin onto PCN-224.
Experimental results confirmed that the linear detection range
of the sensor was 20–107 cells mL−1 with a detection limit of
6 cells mL−1. This work provides a promising way for the diag-
nosis of tumors in clinical laboratory by MOF-based biosensors.
Recently, Jia and co-workers designed a fluorescent biosensor
based on 2-picolinic acid-modified UiO-66-NH2 with rapid
response, high selectivity and sensitivity for direct detection
of uric acid.[86] In this system, the fluorescence of 2-picolinic
acid-modified UiO-66-NH2 was quenched by uric acid via
hydrogen bonding, coordination, and
π
–
π
interactions. This
biosensor could detect uric acid within a linear detection range
of 0.01–400 µM and a detection limit of 2.3 nM.
3.5. MOF-Based Biocatalysts
Natural enzymes, a family of biological macromolecules pro-
duced by living cells, exhibit fascinating advantages of high
efficiency, specificity, and diversity, and are widely used in
biochemical synthesis and biomedicine.[87] However, some
intrinsic drawbacks of enzymes, such as easy deactivation, low
tolerance to organic solvents and some metal ions, and high
cost, severely limit their applications in industrial catalysis.
Additionally, enzymes generally require to be immobilized on
a solid support during the catalytic process to facilitate their
separation as well as to maintain high catalytic activity.[88] In
recent years, MOFs have been widely used as effective sup-
ports for enzyme immobilization owing to their fascinating
properties including large surface area and porosity, high
loading capacity, outstanding thermal/chemical stability, and
adjustable affinities.[89] Particularly, the hierarchical pore struc-
tures are beneficial for the effective diffusion of the substrate.
MOF-enzyme biocomposites can usually be formed by sur-
face bioconjugation, infiltration, and encapsulation strategies,
and have been applied as novel platforms for heterogeneous
catalysis with numerous advantages, such as enhanced stability
and repeatability, strong tolerance to extreme conditions, and
high catalytic selectivity.[90]
In 2017, Zhou and co-workers reported a MOF-based
nanocomposite, SC@FNPCN-333, for efficient loading of
superoxide dismutase (SOD) and CAT.[91] In this work, the
FNPCN-333, consisting of Al3+ and 1,3,5-tris(4-carboxyphenyl)
benzene (BTB) ligands, has a surface area of 2428 m2 g−1 and
three tetrahedron, dodecahedron, and hexahedral cavities with
sizes of 1.1, 4.2, and 5.5 nm, respectively. Meanwhile, the mole-
cular dimensions of SOD and CAT are 2.8 × 3.5 × 4.2 nm3 and
4.9 × 4.4 × 5.6 nm3, which match well with the pore sizes of 4.0
and 5.5 nm in FNPCN-333, respectively. Experiments showed
that SC@FNPCN-333 exhibited persistent catalytic activities in
cell culture medium for 7 days, while the solid support FNPCN-
333 protected the CAT and SOD from proteases and acidic con-
ditions in cells. Subsequently, Farha and co-workers designed
a rational strategy to enhance the cascaded catalytic capacity of
encapsulated lactate dehydrogenase (LDH) in LDH@MOFs by
modulating the channel types of Zr-MOFs.[92] Among the hier-
archical pore structures of these Zr-MOFs, large pores were
used for LDH encapsulation and small pores were used for sub-
strate/coenzyme diffusion (Figure 10a,b). Compared with free
LDH, the catalytic efficiency of LDH@NU-100x (x = 5, 6, 7)
was improved by 1.5–3 times, which was due to the cascade
catalysis effect caused by the matching of the pore sizes of
NU-100x (x = 5, 6, 7) with the sizes of coenzyme. This work
provides a powerful guide for the rational design of enzyme–
coenzyme cascade-catalyzed MOF-based catalysts.
Gkaniatsou et al. designed an ultrastable and reusable nano-
platform based on NMIL-101(Cr) and microperoxidase-8 (MP8)
(MP8@NMIL-101) for the efficient degradation of the harmful
dyes under acidic or oxidative conditions.[93] MP8, with a mole-
cular dimension of 3.3 × 1.1 × 1.7 nm, was loaded in the 3.4 nm
cage of NMIL-101(Cr) with a loading content of 5% w/w, as
determined by Fe/Cr ratio and the changes of surface areas
(Figure 10c). To study the protective effect of NMIL-101(Cr)
supports on MP8, the catalytic activity was performed by the
oxidation of 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid
ammonium salt) (ABTS) under harmful conditions. The results
indicated that MP8@NMIL-101 exhibited higher catalytic
activity toward ABTS under high H2O2 concentration (0.9 mM)
for 1 h and acidic concentrations (pH 5). Notably, MP8@NMIL-
101 had higher reaction rates for negatively charged methyl
orange (MO) than free MP8, which was caused by electrostatic
interactions between NMIL-101(Cr) and MO according to the
result of harmful dyes degradation experiments (Figure 10d).

1906846 (20 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
Small 2020, 16, 1906846
Another MOF-based composite was constructed by Martí-
Gastaldo and co-workers to improve enzyme stability and
recyclability under extreme conditions.[94] In this system,
Aspergillus saitoi protease was encapsulated in the pores of
MIL-101(Al)-NH2 with a loading capacity of 5% at organic
medium (anhydrous hexane) and mild temperatures via protein
translocation mechanism. Catalytic studies showed that the
as-prepared protease@MIL-101(Al)-NH2 demonstrated higher
catalytic activity than free protease. Importantly, the effective
protection and support of MIL-101(Al)-NH2 toward free pro-
tease could maintain the catalytic activity under a broad pH
range of 1–12, up to 95 °C, and in the presence of competitive
Figure 10. Schematic illustrations of a) top view (left) and side view (right) of interconnected hierarchical pore structures of Zr-MOFs, b) the procedure
for LDH loading in the large pores of Zr-MOFs. Reproduced with permission.[92] Copyright 2018, Elsevier. c) The deferent cages of NMIL-101(Cr) and
the structure of MP8. d) Degradation efficiency of free MP8, NMIL-101(Cr), and MP8@NMIL-101 to positively charged MB and negatively charged
MO. Reproduced with permission.[93] Copyright 2018, Wiley-VCH. e) Schematic representation of the manufacturing process of artificial cell with
ultrastability and stimuli-responsiveness. f) The UV–vis absorption curves of catalytic capacities of artificial cell loading GOx-ZIF-L-loaded artificial cells
under the conditions of UV-C, hyperthermia (65 °C), trypsin hydrolysis for 3 h, low temperature (4 °C) for 30 days, and room temperature for 7 days,
respectively. Reproduced with permission.[95] Copyright 2019, Wiley-VCH.

1906846 (21 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
Small 2020, 16, 1906846
enzymes (GOx). This work provides a simple strategy for the
fabrication of enzyme-MOFs biocatalyst with high activity,
extended stability, and easy recyclability.
Interestingly, Liang and co-workers first prepared a stable
and stimuli-responsive artificial cell composed of metal-
phenolic network (MPN) as a membrane and enzyme-MOFs as
organelles for simulating the function of natural cells, that is,
cellular metabolism, molecular transport, cell–cell communica-
tion, and programmed degradation (Figure 10e).[95] As a proof
of concept, GOx and horseradish peroxidase (HRP) were sepa-
rately loaded in ZIF-L with high encapsulation efficiency (≈94%
and ≈96%, respectively) to form 1 µm cruciate flowerlike struc-
tures and further coated with MPN membrane for catalytic
cascade reactions. Meanwhile, the H2O2 products produced
by GOx-ZIF-L-loaded artificial cells catalyzing the oxidation
of glucose could effectively induce the biocatalytic reaction in
the HRP-ZIF-L-loaded artificial cells, which strongly indicated
that the substrates and the products could penetrate through
the cell membrane to simulate the signal transduction process
between natural cells. Furthermore, programmed protein deg-
radation experiments demonstrated that the enzymes (trypsin
and DQ-ovalbumin) were accommodated in ZIF-L in the
form of trypsin-loaded ZIF-L and DQ-ovalbumin (DQ-OVA)-
loaded ZIF-L at pH 7.4, while they could be released from
ZIF-L support and trapped in the MPN membrane due to the
degradation of the ZIF-L support and the retention of biomac-
romolecules by MPN membrane at pH 6. More importantly,
this artificial cell could still have the ability of cascade reaction
under treatments, such as UV radiation, high temperature,
trypsin hydrolysis, and storage at 4 °C for 30 days or at room
temperature for 7 days (Figure 10f). This work paves a new way
to study cellular activities in real cells by constructing intelli-
gent biocatalytic systems.
4. Conclusion and Perspective
In summary, we have reviewed and discussed in detail the
recent progress of MOF-based composites in biomedical appli-
cations, including the delivery of cargos (drugs, nucleic acids,
proteins, and dyes) for cancer therapy, bioimaging, antimi-
crobials, biosensing, and biocatalysis. As described above,
numerous advanced MOF-based nanoplatforms have been
continuously developed to meet the growing variety of
demands. Meanwhile, researchers have been dedicated to the
development of MOF-based materials with great targeting and
negligible toxic side effects during biomedical applications. In
fact, MOFs as multifunctional supports in biomedicine mainly
take advantage of their adjustable structures and morphologies,
excellent surface areas, high porosities and crystallinities, great
loading capacities, enhanced thermal/chemical stabilities, and
variable affinities.
Although significant achievements have been achieved in
laboratory research, MOF-based composites still face critical
challenges in biomedical applications. First, the toxicity of
MOFs is the most urgent problem to be solved before/in clin-
ical research. Due to the diversity of structures and species
of MOFs, as well as the complicated internal environment of
organisms, the toxicity of MOFs was not only related to the
compositions, morphologies, sizes, and stabilities, but also
related to the tolerance of living tissues. Therefore, the toxicity
of various MOFs requires a comprehensive assessment. So far,
many excellent researches on the toxicity of MOFs are mainly
concentrated on short-term in vivo or/and acute toxicity experi-
ments, while long-term toxicity, the most critical point that
should be taken into consideration if MOF scaffolds were to be
outstanding candidates for biomedical application, has rarely
been reported.[96] To comprehensively determine the toxicity
of MOFs, extensive in vivo studies and long-term tissue accu-
mulation monitoring are urgently required. Additionally, using
endogenous or bioactive molecules as ligands and metal ions
with high biocompatibility (such as Fe, Ca, Zn, etc.) as metal
nodes to construct functional MOFs is of great benefit to avoid
the toxicity of MOFs.[5,10,56]
Besides, preventing aggregation and premature clearance of
MOFs during the circulation is another challenge that should
be addressed. Severe aggregation can cause additional toxic
side effects. Similarly, premature clearance is not conducive to
the optimal efficacy of MOFs.[7a] As previously stated, the sur-
face functionalization and size control are commonly applied to
address this drawback. It is an effective method to control the
MOF diameter in the nanoscale range via regulating synthetic
methods or other physicochemical strategies. Surface function-
alization of MOFs with polymers, supramolecular macrocycles,
and other entities to regulate the surface potential and binding
affinities is also an effective strategy.
Finally, the degradation mechanisms and pathways of
MOFs need to be systematically studied in vivo. Many excellent
studies combined with multimodal imaging methods for moni-
toring the degradation process of MOFs have been reported,
but this is not enough to deeply analyze the degradation mech-
anism. The accumulation of MOFs in various tissues caused
by multiple administration requires comprehensive theoretical
support through monitoring of the long-term absorption–
distribution–metabolism–excretion process. Notably, NMOFs
nanocarriers used for genes protection and delivery to achieve
efficient gene loading and enhanced therapeutic effect has
attracted widespread attention. Because of the high effective-
ness and specificity of siRNAs-mediated gene knockdown
strategies, it is foreseeable that gene therapy might benefit
various incurable diseases, such as hereditary disease, cancer,
Alzheimer’s disease, Parkinson’s disease, and diabetes.[22,97]
Moreover, employing MOFs to achieve immunotherapy might
serve as another promising strategy for diseases treatment.[98]
In short, although the utilization of MOFs still faces long-term
challenges in biomedical applications, the significant progress
made so far has provided a reference cornerstone for the study
of the toxicity, biodegradability, and degradation mechanisms
of MOFs. We envision that MOFs in clinical applications with
the multidisciplinary advantages will be further developed for
human health improvement in the near future.
Acknowledgements
The authors acknowledge the National Natural Science Foundation of
China (51673084, 21871108), the Jilin Province-University Cooperative
Construction Project–Special Funds for New Materials (SXGJSF2017-3),
and the Jilin University Talents Cultivation Program for financial support.

1906846 (22 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
Small 2020, 16, 1906846
Conflict of Interest
The authors declare no conflict of interest.
Keywords
biocatalysis, biomedicine, drug delivery, porous materials, sensing and
detection
Received: November 24, 2019
Revised: January 3, 2020
Published online: February 6, 2020
[1] a) H.-C. Zhou, J. R. Long, O. M. Yaghi, Chem. Rev. 2012, 112, 673;
b) A. Kirchon, L. Feng, H. F. Drake, E. A. Joseph, H.-C. Zhou,
Chem. Soc. Rev. 2018, 47, 8611.
[2] a) P. Horcajada, R. Gref, T. Baati, P. K. Allan, G. Maurin,
P. Couvreur, G. Férey, R. E. Morris, C. Serre, Chem. Rev. 2012, 112,
1232; b) T. D. Bennett, A. K. Cheetham, A. H. Fuchs, F.-X. Coudert,
Nat. Chem. 2017, 9, 11; c) Z. Chang, D.-H. Yang, J. Xu, T.-L. Hu,
X.-H. Bu, Adv. Mater. 2015, 27, 5432; d) K. Shen, L. Zhang,
X. Chen, L. Liu, D. Zhang, Y. Han, J. Chen, J. Long, R. Luque,
Y. Li, B. Chen, Science 2018, 359, 206; e) L. Jiao, J. Y. R. Seow,
W. S. Skinner, Z. U. Wang, H.-L. Jiang, Mater. Today 2019, 27, 43.
[3] a) H. Furukawa, K. E. Cordova, M. O’Keeffe, O. M. Yaghi, Science
2013, 341, 1230444; b) A. C. McKinlay, R. E. Morris, P. Horcajada,
G. Férey, R. Gref, P. Couvreur, C. Serre, Angew. Chem., Int. Ed.
2010, 49, 6260; c) B. Li, H.-M. Wen, Y. Cui, W. Zhou, G. Qian,
B. Chen, Adv. Mater. 2016, 28, 8819; d) H. Furukawa, O. M. Yaghi,
J. Am. Chem. Soc. 2009, 131, 8875; e) S. Begum, Z. Hassan,
S. Bräse, C. Wöll, M. Tsotsalas, Acc. Chem. Res. 2019, 52, 1598.
[4] a) K. Lu, T. Aung, N. Guo, R. Weichselbaum, W. Lin, Adv. Mater.
2018, 30, 1707634; b) J. Zhou, G. Tian, L. Zeng, X. Song,
X.-W. Bian, Adv. Healthcare Mater. 2018, 7, 1800022; c) M.-X. Wu,
Y.-W. Yang, Adv. Mater. 2017, 29, 1606134.
[5] T. Simon-Yarza, A. Mielcarek, P. Couvreur, C. Serre, Adv. Mater.
2018, 30, 1707365.
[6] a) Y. Chen, P. Li, J. A. Modica, R. J. Drout, O. K. Farha, J. Am.
Chem. Soc. 2018, 140, 5678; b) Q. Wu, M. Niu, X. Chen, L. Tan,
C. Fu, X. Ren, J. Ren, L. Li, K. Xu, H. Zhong, X. Meng, Biomaterials
2018, 162, 132; c) S. Yuan, L. Feng, K. Wang, J. Pang, M. Bosch,
C. Lollar, Y. Sun, J. Qin, X. Yang, P. Zhang, Q. Wang, L. Zou,
Y. Zhang, L. Zhang, Y. Fang, J. Li, H.-C. Zhou, Adv. Mater. 2018, 30,
1704303.
[7] a) C.-Y. Sun, C. Qin, X.-L. Wang, Z.-M. Su, Expert Opin. Drug Deliv.
2013, 10, 89; b) S. Peng, B. Bie, Y. Sun, M. Liu, H. Cong, W. Zhou,
Y. Xia, H. Tang, H. Deng, X. Zhou, Nat. Commun. 2018, 9, 1293.
[8] a) X.-G. Wang, Q. Cheng, Y. Yu, X.-Z. Zhang, Angew. Chem., Int.
Ed. 2018, 57, 7836; b) W. Cai, C.-C. Chu, G. Liu, Y. X.-J. Wáng,
Small 2015, 11, 4806; c) A. Pichon, A. Lazuen-Garay, S. L. James,
CrystEngComm 2006, 8, 211; d) N. Stock, S. Biswas, Chem. Rev.
2012, 112, 933; e) J. Park, Q. Jiang, D. Feng, L. Mao, H. C. Zhou,
J. Am. Chem. Soc. 2016, 138, 3518.
[9] S. Beg, M. Rahman, A. Jain, S. Saini, P. Midoux, C. Pichon,
F. J. Ahmad, S. Akhter, Drug Discovery Today 2017, 22, 625.
[10] M. Giménez-Marqués, T. Hidalgo, C. Serre, P. Horcajada, Coord.
Chem. Rev. 2016, 307, 342.
[11] a) S. Wang, C. M. McGuirk, A. d’Aquino, J. A. Mason, C. A. Mirkin,
Adv. Mater. 2018, 30, 1800202; b) S. M. Cohen, Chem. Rev. 2012,
112, 970.
[12] a) W. Morris, W. E. Briley, E. Auyeung, M. D. Cabezas, C. A. Mirkin,
J. Am. Chem. Soc. 2014, 136, 7261; b) A. Zimpel, N. Al Danaf,
B. Steinborn, J. Kuhn, M. Höhn, T. Bauer, P. Hirschle, W. Schrimpf,
H. Engelke, E. Wagner, M. Barz, D. C. Lamb, U. Lächelt,
S. Wuttke, ACS Nano 2019, 13, 3884; c) L. Garzón-Tovar,
S. Rodríguez-Hermida, I. Imaz, D. Maspoch, J. Am. Chem. Soc.
2017, 139, 897; d) B. Li, B. Gui, G. Hu, D. Yuan, C. Wang, Inorg.
Chem. 2015, 54, 5139; e) X. Huang, Y. Liu, B. Yung, Y. Xiong,
X. Chen, ACS Nano 2017, 11, 5238.
[13] a) I. Abánades Lázaro, S. Haddad, S. Sacca, C. Orellana-Tavra,
D. Fairen-Jimenez, R. S. Forgan, Chem 2017, 2, 561;
b) M. Giménez-Marqués, E. Bellido, T. Berthelot, T. Simón-Yarza,
T. Hidalgo, R. Simón-Vázquez, Á. González-Fernández, J. Avila,
M. C. Asensio, R. Gref, P. Couvreur, C. Serre, P. Horcajada, Small
2018, 14, 1801900.
[14] a) W. Ning, Z. Di, Y. Yu, P. Zeng, C. Di, D. Chen, X. Kong, G. Nie,
Y. Zhao, L. Li, Small 2018, 14, 1703812; b) J. Zhuang, A. P. Young,
C.-K. Tsung, Small 2017, 13, 1700880.
[15] a) Z. Li, N. Song, Y.-W. Yang, Matter 2019, 1, 345; b) N. Song,
X.-Y. Lou, L. Ma, H. Gao, Y.-W. Yang, Theranostics 2019, 9, 3075;
c) N. Song, T. Kakuta, T.-A. Yamagishi, Y.-W. Yang, T. Ogoshi,
Chem 2018, 4, 2029; d) X.-Y. Lou, Y.-P. Li, Y.-W. Yang, Biotechnol. J.
2019, 14, 1800354; e) N. Song, Y.-W. Yang, Chem. Soc. Rev. 2015,
44, 3474.
[16] a) J. Zhou, G. Yu, F. Huang, Chem. Soc. Rev. 2017, 46, 7021;
b) J. A. Barreto, W. O’Malley, M. Kubeil, B. Graham, H. Stephan,
L. Spiccia, Adv. Mater. 2011, 23, H18; c) L. Cheng, X. Wang,
F. Gong, T. Liu, Z. Liu, Adv. Mater. 2019, 31, 1902333.
[17] a) N. Zhao, L. Yan, X. Zhao, X. Chen, A. Li, D. Zheng, X. Zhou,
X. Dai, F.-J. Xu, Chem. Rev. 2019, 119, 1666; b) G. Yang,
S. Z. F. Phua, A. K. Bindra, Y. Zhao, Adv. Mater. 2019, 31, 1805730.
[18] a) Y. Liu, Y. Zhao, X. Chen, Theranostics 2019, 9, 3122;
b) Z. Dong, Y. Sun, J. Chu, X. Zhang, H. Deng, J. Am. Chem.
Soc. 2017, 139, 14209; c) S. Wuttke, M. Lismont, A. Escudero,
B. Rungtaweevoranit, W. J. Parak, Biomaterials 2017, 123, 172.
[19] P. Horcajada, C. Serre, M. Vallet-Regí, M. Sebban, F. Taulelle,
G. Férey, Angew. Chem., Int. Ed. 2006, 45, 5974.
[20] a) P. Horcajada, C. Serre, G. Maurin, N. A. Ramsahye, F. Balas,
M. Vallet-Regí, M. Sebban, F. Taulelle, G. Férey, J. Am. Chem. Soc.
2008, 130, 6774; b) Q. Hu, J. Yu, M. Liu, A. Liu, Z. Dou, Y. Yang,
J. Med. Chem. 2014, 57, 5679; c) S. Li, K. Wang, Y. Shi, Y. Cui,
B. Chen, B. He, W. Dai, H. Zhang, X. Wang, C. Zhong, H. Wu,
Q. Yang, Q. Zhang, Adv. Funct. Mater. 2016, 26, 2715; d) Y. Yang,
Q. Hu, Q. Zhang, K. Jiang, W. Lin, Y. Yang, Y. Cui, G. Qian, Mol.
Pharmaceutics 2016, 13, 2782.
[21] C.-Y. Sun, C. Qin, C.-G. Wang, Z.-M. Su, S. Wang, X.-L. Wang,
G.-S. Yang, K.-Z. Shao, Y.-Q. Lan, E.-B. Wang, Adv. Mater. 2011, 23,
5629.
[22] C. He, K. Lu, D. Liu, W. Lin, J. Am. Chem. Soc. 2014, 136, 5181.
[23] X. Lian, Y. Huang, Y. Zhu, Y. Fang, R. Zhao, E. Joseph, J. Li,
J.-P. Pellois, H.-C. Zhou, Angew. Chem., Int. Ed. 2018, 57, 5725.
[24] a) W. Zhou, L. Wang, F. Li, W. Zhang, W. Huang, F. Huo, H. Xu,
Adv. Funct. Mater. 2017, 27, 1605465; b) W.-H. Chen, W.-C. Liao,
Y. S. Sohn, M. Fadeev, A. Cecconello, R. Nechushtai, I. Willner,
Adv. Funct. Mater. 2018, 28, 1705137; c) W. Cai, J. Wang, C. Chu,
W. Chen, C. Wu, G. Liu, Adv. Sci. 2019, 6, 1801526; d) Y. Wang,
J. Yan, N. Wen, H. Xiong, S. Cai, Q. He, Y. Hu, D. Peng, Z. Liu,
Y. Liu, Biomaterials 2019, 230, 119619.
[25] L.-L. Tan, H. Li, Y.-C. Qiu, D.-X. Chen, X. Wang, R.-Y. Pan, Y. Wang,
S. X.-A. Zhang, B. Wang, Y.-W. Yang, Chem. Sci. 2015, 6, 1640.
[26] L.-L. Tan, H. Li, Y. Zhou, Y. Zhang, X. Feng, B. Wang, Y.-W. Yang,
Small 2015, 11, 3807.
[27] L.-L. Tan, N. Song, S. X.-A. Zhang, H. Li, B. Wang, Y.-W. Yang,
J. Mater. Chem. B 2016, 4, 135.
[28] X.-G. Wang, Z.-Y. Dong, H. Cheng, S.-S. Wan, W.-H. Chen,
M.-Z. Zou, J.-W. Huo, H.-X. Deng, X.-Z. Zhang, Nanoscale 2015, 7,
16061.

1906846 (23 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
Small 2020, 16, 1906846
[29] X. Meng, B. Gui, D. Yuan, M. Zeller, C. Wang, Sci. Adv. 2016, 2,
e1600480.
[30] a) N. Vasan, J. Baselga, D. M. Hyman, Nature 2019, 575, 299;
b) T. Sun, Y. S. Zhang, B. Pang, D. C. Hyun, M. Yang, Y. Xia, Angew.
Chem., Int. Ed. 2014, 53, 12320.
[31] a) X. R. Deng, S. Liang, X. C. Cai, S. S. Huang, Z. Y. Cheng,
Y. S. Shi, M. L. Pang, P. A. Ma, J. Lin, Nano Lett. 2019, 19,
6772; b) M.-X. Wu, H.-J. Yan, J. Gao, Y. Cheng, J. Yang, J.-R. Wu,
B.-J. Gong, H.-Y. Zhang, Y.-W. Yang, ACS Appl. Mater. Interfaces
2018, 10, 34655; c) J. Jia, Y. Zhang, M. Zheng, C. Shan, H. Yan,
W. Wu, X. Gao, B. Cheng, W. Liu, Y. Tang, Inorg. Chem. 2018, 57,
300; d) K. Ni, G. Lan, S. S. Veroneau, X. Duan, Y. Song, W. Lin,
Nat. Commun. 2018, 9, 4321; e) W. Fan, B. Yung, P. Huang,
X. Chen, Chem. Rev. 2017, 117, 13566.
[32] D. Wang, H. Wu, J. Zhou, P. Xu, C. Wang, R. Shi, H. Wang,
H. Wang, Z. Guo, Q. Chen, Adv. Sci. 2018, 5, 1800287.
[33] M. Lismont, L. Dreesen, S. Wuttke, Adv. Funct. Mater. 2017, 27,
1606314.
[34] K. Lu, C. He, W. Lin, J. Am. Chem. Soc. 2014, 136, 16712.
[35] K. Lu, C. He, W. Lin, J. Am. Chem. Soc. 2015, 137, 7600.
[36] X.-S. Wang, J.-Y. Zeng, M.-K. Zhang, X. Zeng, X.-Z. Zhang, Adv.
Funct. Mater. 2018, 28, 1801783.
[37] J. Liu, T. Liu, P. Du, L. Zhang, J. Lei, Angew. Chem., Int. Ed. 2019,
58, 7808.
[38] H. Wang, D. Yu, J. Fang, C. Cao, Z. Liu, J. Ren, X. Qu, ACS Nano
2019, 13, 9206.
[39] C. Fu, H. Zhou, L. Tan, Z. Huang, Q. Wu, X. Ren, J. Ren, X. Meng,
ACS Nano 2018, 12, 2201.
[40] L. Zhang, Z. Wang, Y. Zhang, F. Cao, K. Dong, J. Ren, X. Qu, ACS
Nano 2018, 12, 10201.
[41] Z. He, X. Huang, C. Wang, X. Li, Y. Liu, Z. Zhou, S. Wang,
F. Zhang, Z. Wang, O. Jacobson, J.-J. Zhu, G. Yu, Y. Dai, X. Chen,
Angew. Chem., Int. Ed. 2019, 58, 8752.
[42] a) M. A. Chowdhury, ChemBioEng Rev. 2017, 4, 225; b) J. D. Rocca,
D. Liu, W. Lin, Acc. Chem. Res. 2011, 44, 957; c) Z. Zhang, W. Sang,
L. Xie, Y. Dai, Coord. Chem. Rev. 2019, 399, 213022.
[43] J. Deng, K. Wang, M. Wang, P. Yu, L. Mao, J. Am. Chem. Soc. 2017,
139, 5877.
[44] C. Yang, K. Chen, M. Chen, X. Hu, S.-Y. Huan, L. Chen, G. Song,
X.-B. Zhang, Anal. Chem. 2019, 91, 2727.
[45] L. Robison, L. Zhang, R. J. Drout, P. Li, C. R. Haney, A. Brikha,
H. Noh, B. L. Mehdi, N. D. Browning, V. P. Dravid, Q. Cui,
T. Islamoglu, O. K. Farha, ACS Appl. Bio Mater. 2019, 2, 1197.
[46] a) S.-Y. Zhang, Z.-Y. Wang, J. Gao, K. Wang, E. Gianolio, S. Aime,
W. Shi, Z. Zhou, P. Cheng, M. J. Zaworotko, Chem 2019, 5, 1609;
b) P. Horcajada, T. Chalati, C. Serre, B. Gillet, C. Sebrie, T. Baati,
J. F. Eubank, D. Heurtaux, P. Clayette, C. Kreuz, J.-S. Chang,
Y. K. Hwang, V. Marsaud, P.-N. Bories, L. Cynober, S. Gil, G. Férey,
P. Couvreur, R. Gref, Nat. Mater. 2010, 9, 172.
[47] S. Sene, M. T. Marcos-Almaraz, N. Menguy, J. Scola, J. Volatron,
R. Rouland, J.-M. Grenèche, S. Miraux, C. Menet, N. Guillou,
F. Gazeau, C. Serre, P. Horcajada, N. Steunou, Chem 2017,
3, 303.
[48] M.-X. Wu, J. Gao, F. Wang, J. Yang, N. Song, X. Jin, P. Mi, J. Tian,
J. Luo, F. Liang, Y.-W. Yang, Small 2018, 14, 1704440.
[49] D. Chen, D. Yang, C. A. Dougherty, W. Lu, H. Wu, X. He, T. Cai,
M. E. Van Dort, B. D. Ross, H. Hong, ACS Nano 2017, 11, 4315.
[50] Y. Li, J. Tang, L. He, Y. Liu, Y. Liu, C. Chen, Z. Tang, Adv. Mater.
2015, 27, 4075.
[51] T. Du, C. Zhao, F. Rehman, L. Lai, X. Li, Y. Sun, S. Luo, H. Jiang,
N. Gu, M. Selke, X. Wang, Adv. Funct. Mater. 2017, 27, 1603926.
[52] W. Shang, C. Zeng, Y. Du, H. Hui, X. Liang, C. Chi, K. Wang,
Z. Wang, J. Tian, Adv. Mater. 2017, 29, 1604381.
[53] W. Cai, H. Gao, C. Chu, X. Wang, J. Wang, P. Zhang, G. Lin, W. Li,
G. Liu, X. Chen, ACS Appl. Mater. Interfaces 2017, 9, 2040.
[54] H. Zhang, Y. Shang, Y.-H. Li, S.-K. Sun, X.-B. Yin, ACS Appl. Mater.
Interfaces 2019, 11, 1886.
[55] R. Joseph, A. Naugolny, M. Feldman, I. M. Herzog, M. Fridman,
Y. Cohen, J. Am. Chem. Soc. 2016, 138, 754.
[56] G. Wyszogrodzka, B. Marszalek, B. Gil, P. Doroz˙ yn´ski, Drug
Discovery Today 2016, 21, 1009.
[57] D. F. Sava Gallis, K. S. Butler, J. O. Agola, C. J. Pearce,
A. A. McBride, ACS Appl. Mater. Interfaces 2019, 11, 7782.
[58] W. Zhou, S. Begum, Z. Wang, P. Krolla, D. Wagner, S. Bräse,
C. Wöll, M. Tsotsalas, ACS Appl. Mater. Interfaces 2018, 10, 1528.
[59] A. R. Chowdhuri, B. Das, A. Kumar, S. Tripathy, S. Roy, S. K. Sahu,
Nanotechnology 2017, 28, 095102.
[60] M. Berchel, T. L. Gall, C. Denis, S. L. Hir, F. Quentel, C. Elléouet,
T. Montier, J.-M. Rueff, J.-Y. Salaün, J.-P. Haelters, G. B. Hix,
P. Lehn, P.-A. Jaffrès, New J. Chem. 2011, 35, 1000.
[61] C. Chiericatti, J. C. Basilico, M. L. Zapata Basilico, J. M. Zamaro,
Microporous Mesoporous Mater. 2012, 162, 60.
[62] P. Li, J. Li, X. Feng, J. Li, Y. Hao, J. Zhang, H. Wang, A. Yin, J. Zhou,
X. Ma, B. Wang, Nat. Commun. 2019, 10, 2177.
[63] S. Lin, X. Liu, L. Tan, Z. Cui, X. Yang, K. W. K. Yeung, H. Pan,
S. Wu, ACS Appl. Mater. Interfaces 2017, 9, 19248.
[64] D. Mao, F. Hu, Kenry, S. Ji, W. Wu, D. Ding, D. Kong, B. Liu, Adv.
Mater. 2018, 30, 1706831.
[65] Y. Zhang, P. Sun, L. Zhang, Z. Wang, F. Wang, K. Dong, Z. Liu,
J. Ren, X. Qu, Adv. Funct. Mater. 2019, 29, 1808594.
[66] S. Shakya, Y. He, X. Ren, T. Guo, A. Maharjan, T. Luo, T. Wang,
R. Dhakhwa, B. Regmi, H. Li, R. Gref, J. Zhang, Small 2019, 15,
1901065.
[67] H. Chen, J. Yang, L. Sun, H. Zhang, Y. Guo, J. Qu, W. Jiang,
W. Chen, J. Ji, Y.-W. Yang, B. Wang, Small 2019, 15, 1903880.
[68] a) Y. Cui, B. Li, H. He, W. Zhou, B. Chen, G. Qian, Acc. Chem.
Res. 2016, 49, 483; b) K. Vikrant, N. Bhardwaj, S. K. Bhardwaj,
K.-H. Kim, A. Deep, Biomaterials 2019, 214, 119215; c) J. Wu, S. Li,
H. Wei, Chem. Commun. 2018, 54, 6520; d) L. Liu, Y. Zhou, S. Liu,
M. Xu, ChemElectroChem 2018, 5, 6; e) F.-Y. Yi, D. Chen, M.-K. Wu,
L. Han, H.-L. Jiang, ChemPlusChem 2016, 81, 675.
[69] Y. Hu, H. Cheng, X. Zhao, J. Wu, F. Muhammad, S. Lin, J. He,
L. Zhou, C. Zhang, Y. Deng, P. Wang, Z. Zhou, S. Nie, H. Wei, ACS
Nano 2017, 11, 5558.
[70] W. Xu, L. Jiao, H. Yan, Y. Wu, L. Chen, W. Gu, D. Du, Y. Lin, C. Zhu,
ACS Appl. Mater. Interfaces 2019, 11, 22096.
[71] R. Xu, Y. Wang, X. Duan, K. Lu, D. Micheroni, A. Hu, W. Lin, J. Am.
Chem. Soc. 2016, 138, 2158.
[72] Y. Ma, H. Su, X. Kuang, X. Li, T. Zhang, B. Tang, Anal. Chem. 2014,
86, 11459.
[73] X. Zhang, L. Fang, K. Jiang, H. He, Y. Yang, Y. Cui, B. Li, G. Qian,
Biosens. Bioelectron. 2019, 130, 65.
[74] D. I. Osman, S. M. El-Sheikh, S. M. Sheta, O. I. Ali, A. M. Salem,
W. G. Shousha, S. F. El-Khamisy, S. M. Shawky, Biosens. Bioelec-
tron. 2019, 141, 111451.
[75] C.-S. Liu, Z.-H. Zhang, M. Chen, H. Zhao, F.-H. Duan, D.-M. Chen,
M.-H. Wang, S. Zhang, M. Du, Chem. Commun. 2017, 53, 3941.
[76] H. Wang, Y. Jian, Q. Kong, H. Liu, F. Lan, L. Liang, S. Ge, J. Yu,
Sens. Actuators, B 2018, 257, 561.
[77] H. Shao, J. Lu, Q. Zhang, Y. Hu, S. Wang, Z. Guo, Sens. Actuators,
B 2018, 268, 39.
[78] X. Huang, Z. He, D. Guo, Y. Liu, J. Song, B. C. Yung, L. Lin, G. Yu,
J.-J. Zhu, Y. Xiong, X. Chen, Theranostics 2018, 8, 3461.
[79] a) N. Bhardwaj, S. K. Bhardwaj, J. Mehta, K.-H. Kim, A. Deep,
ACS Appl. Mater. Interfaces 2017, 9, 33589; b) N. Bhardwaj,
S. K. Bhardwaj, D. Bhatt, S. K. Tuteja, K.-H. Kim, A. Deep, Anal.
Methods 2019, 11, 917.
[80] S. Shahrokhian, S. Ranjbar, Analyst 2018, 143, 3191.
[81] M. Zhong, L. Yang, H. Yang, C. Cheng, W. Deng, Y. Tan, Q. Xie,
S. Yao, Biosens. Bioelectron. 2019, 126, 493.

1906846 (24 of 24)
www.advancedsciencenews.com
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.small-journal.com
Small 2020, 16, 1906846
[82] X. Zhang, G. Xie, D. Gou, P. Luo, Y. Yao, H. Chen, Biosens. Bioelec-
tron. 2019, 142, 111486.
[83] X. Qiao, B. Su, C. Liu, Q. Song, D. Luo, G. Mo, T. Wang, Adv.
Mater. 2018, 30, 1702275.
[84] S.-J. Qin, B. Yan, Sens. Actuators, B 2018, 259, 125.
[85] D. Ou, D. Sun, Z. Liang, B. Chen, X. Lin, Z. Chen, Sens. Actuators,
B 2019, 285, 398.
[86] S. Qu, Z. Li, Q. Jia, ACS Appl. Mater. Interfaces 2019, 11, 34196.
[87] S. J. Benkovic, S. Hammes-Schiffer, Science 2003, 301, 1196.
[88] a) X. Lian, Y. Fang, E. Joseph, Q. Wang, J. Li, S. Banerjee,
C. Lollar, X. Wang, H.-C. Zhou, Chem. Soc. Rev. 2017, 46, 3386;
b) J. Wu, X. Wang, Q. Wang, Z. Lou, S. Li, Y. Zhu, L. Qin, H. Wei,
Chem. Soc. Rev. 2019, 48, 1004; c) L. Wang, W. Zhi, J. Wan,
J. Han, C. Li, Y. Wang, ACS Sustainable Chem. Eng. 2019, 7,
3339; d) V. Lykourinou, Y. Chen, X. S. Wang, L. Meng, T. Hoang,
L.-J. Ming, R. L. Musselman, S. Ma, J. Am. Chem. Soc. 2011, 133,
10382.
[89] a) M. Bilal, M. Adeel, T. Rasheed, H. M. N. Iqbal, J. Mater. Res.
Technol. 2019, 8, 2359; b) L. Jiao, Y. Wang, H.-L. Jiang, Q. Xu, Adv.
Mater. 2018, 30, 1703663.
[90] a) C. Doonan, R. Riccò, K. Liang, D. Bradshaw, P. Falcaro, Acc.
Chem. Res. 2017, 50, 1423; b) E. Gkaniatsou, C. Sicard, R. Ricoux,
J.-P. Mahy, N. Steunou, C. Serre, Mater. Horiz. 2017, 4, 55.
[91] X. Lian, A. Erazo-Oliveras, J.-P. Pellois, H.-C. Zhou, Nat. Commun.
2017, 8, 2075.
[92] P. Li, Q. Chen, T. C. Wang, N. A. Vermeulen, B. L. Mehdi,
A. Dohnalkova, N. D. Browning, D. Shen, R. Anderson,
D. A. Gómez-Gualdrón, F. M. Cetin, J. Jagiello, A. M. Asiri,
J. F. Stoddart, O. K. Farha, Chem 2018, 4, 1022.
[93] E. Gkaniatsou, C. Sicard, R. Ricoux, L. Benahmed, F. Bourdreux,
Q. Zhang, C. Serre, J. P. Mahy, N. Steunou, Angew. Chem., Int. Ed.
2018, 57, 16141.
[94] J. Navarro-Sánchez, N. Almora-Barrios, B. Lerma-Berlanga,
J. J. Ruiz-Pernía, V. A. Lorenz-Fonfria, I. Tuñón, C. Martí-Gastaldo,
Chem. Sci. 2019, 10, 4082.
[95] J. Liu, Z. Guo, K. Liang, Adv. Funct. Mater. 2019, 29, 1905321.
[96] a) S. Wuttke, A. Zimpel, T. Bein, S. Braig, K. Stoiber, A. Vollmar,
D. Müller, K. Haastert-Talini, J. Schaeske, M. Stiesch, G. Zahn,
A. Mohmeyer, P. Behrens, O. Eickelberg, D. A. Bölükbas,
S. Meiners, Adv. Healthcare Mater. 2017, 6, 1600818; b) W. Chen,
C. Wu, Dalton Trans. 2018, 47, 2114.
[97] M. H. Teplensky, M. Fantham, C. Poudel, C. Hockings,
M. Lu, A. Guna, M. Aragones-Anglada, P. Z. Moghadam,
P. Li, O. K. Farha, S. Bernaldo de Quirós Fernández,
F. M. Richards, D. I. Jodrell, G. Kaminski Schierle, C. F. Kaminski,
D. Fairen-Jimenez, Chem 2019, 5, 2926.
[98] a) J. Nam, S. Son, K. S. Park, W. Zou, L. D. Shea, J. J. Moon,
Nat. Rev. Mater. 2019, 4, 398; b) K. Ni, T. Luo, G. Lan, A. Culbert,
Y. Song, T. Wu, X. Jiang, W. Lin, Angew. Chem., Int. Ed. 2020, 59,
1108.