Article

www.acsnano.org

Self-Driven Electron Transfer Biomimetic

Enzymatic Catalysis of Bismuth-Doped PCN-
222 MOF for Rapid Therapy of Bacteria-
Infected Wounds
Lihua Wu, Yue Luo, Chaofeng Wang, Shuilin Wu, Yufeng Zheng, Zhaoyang Li, Zhenduo Cui,
Yanqin Liang, Shengli Zhu, Jie Shen, and Xiangmei Liu*
Cite This: ACS Nano 2023, 17, 1448−1463 Read Online

ACCESS Metrics & More Article Recommendations *

sı Supporting Information

ABSTRACT: In this work, a biomimetic nanozyme catalyst

with rapid and efficient self-bacteria-killing and wound-healing
performances was synthesized. Through an in situ reduction
reaction, a PCN-222 metal organic framework (MOF) was
doped with bismuth nanoparticles (Bi NPs) to form Bi-PCN-
222, an interfacial Schottky heterojunction biomimetic nano-
zyme catalyst, which can kill 99.9% of Staphylococcus aureus (S.
aureus). The underlying mechanism was that Bi NP doping can
endow Bi-PCN-222 MOF with self-driven charge transfer
through the Schottky interface and the capability of oxidase-
like and peroxidase-like activity, because a large number of free
electrons can be captured by surrounding oxygen species to
produce radical oxygen species (ROS). Furthermore, once
bacteria contact Bi-PCN-222 in a physiological environment, its appropriate redox potential can trigger electron transfer
through the electron transport pathway in bacterial membranes and then the interior of the bacteria, which disturbs the
bacterial respiration process and subsequent metabolism. Additionally, Bi-PCN-222 can also accelerate tissue regeneration by
upregulating fibroblast proliferation and angiogenesis genes (bFGF, VEGF, and HIF-1α), thereby promoting wound healing.
This biomimetic enzyme-catalyzed strategy will bring enlightenment to the design of self-bacterial agents for efficient
disinfection and tissue reconstruction simultaneously.
KEYWORDS: biomimetic enzyme catalysis, antibacterial, wound healing, bismuth doping, electron transfer

D espite the availability of antibiotics, bacterial Therefore, developing a fast and durable antimicrobial
infections are some of the ringleaders of death all platform is of great significance.
over the world.1 Each year, more than 700,000 people In recent years, catalytic systems have been considered as
die from sepsis, endocarditis, osteomyelitis, and other bacterial good substitutes for antibiotics because of their good
antibacterial properties and no bacterial resistance.6,7 Since
diseases.2 Wound infection occurs after pathogenic bacteria
Fe3O4 with peroxidase-like activity was discovered in 2007,8
(usually Staphylococcus aureus (S. aureus)) invade the damaged more and more inorganic nanomaterials, such as Cu2WS4,9
tissues, and these wounds provide a nourishing environment MoS2,10,11 V2O5,12,13 and some precious metals (gold, silver,
for the growth of microorganisms.3 In general, clinical platinum, etc.) have exhibited enzyme-like activity.14−16 With
symptoms such as redness, suppuration, and tissue damage
will greatly increase when the bacterial load in 1 g of tissue Received: October 13, 2022
exceeds 105 colony forming units (CFU).4 This in turn triggers Accepted: January 5, 2023
an increase inflammatory oxidative stress, which then impedes Published: January 9, 2023
the natural progression of healing and reduces the effectiveness
of wound healing. What is worse, it can lead to chronic wounds
that are difficult to heal and even induce systematic infection.5

© 2023 American Chemical Society https://doi.org/10.1021/acsnano.2c10203

1448 ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Scheme 1. Schematic Diagram of the Antibacterial Mechanism and Promotion of Cell Proliferation and Differentiation to
Promote Wound Healing

the upsurge of nanozyme research, many organic nanomaterial cellular ROS, thus hindering cell growth.32 It is recognized that
systems have emerged, such as some MOFs (Cu-TCPP, NH2- an increasing number of bacteria can pass electrons across their
MIL-88B, MnTCPP-HF-FA),17−19 which have the capability cellular envelopes, but the details of the molecular mechanisms
to mimic the catalytic reactions of enzymes in addition to the that underpin this process are poorly understood and mostly
traditional antibacterial methods. Natural enzymes were involve Gram-negative bacteria.33 Therefore, we hope to
modified on the surface of the MOF by covalent coupling or design a system that has a suitable redox potential that can
electrostatic interaction (GO x -ICG@ZIF@CM, PCN- interfere with Gram-positive bacterial metabolic electron
224(Cu)-GOx@MnO2, UCNPs/MB@ZIF-8@Catalase),20−22 transfer and possesses enzymatic catalysis to rapidly self-
and nanoenzyme engineering (MnFe2O4@MOFs, Pda-Pt@ sterilize without external sources.
PCN-FA, PMCS) was also found to have enzyme-like Bismuth nanoparticles (Bi NPs) are usually used on
activity.23−25 Compared with natural enzymes, nanoenzymes semiconductor surfaces to improve photocatalytic activity
(artificial enzymes) are more stable in harsh environments, due to their surface plasmon resonance (SPR) effect.34 And Bi
providing great opportunities for the manufacture of design- NPs can be used as both electron acceptors and plasma-like
able nanoenzyme engineering.26 The catalytic mechanism of electron donors. This involves the interaction of electrons with
nanozymes based on various nanomaterials can generally be the metal Bi and semiconductor CB, promoting the separation
summarized as an electron transfer process.27 For example, the of photogenerated electron−hole pairs.35 It is reported that Bi
oxidase-like properties of nanomaterials can catalyze the has dual medicinal properties in wound (including post-
oxidation of substrates (electron donors) and produce H2O operative) and burn dressings as well as many cosmetics.36 Bi
or H2O2 in the presence of O2, which acts as the electron has relatively low toxicity to mammals, which is in direct
acceptor. The electron transfer process and the formation of contrast with many other heavy metals.37 However, since Bi
intermediate radical oxygen species (ROS) have been NPs are very unstable and easily agglomerated, they are easily
demonstrated to have pivotal effects on the properties of oxidized to Bi ions under physiological conditions, which
these nanozymes.28 Actually, the electron transfer plays a key greatly hinders their practical application.38 Considering the
role in the physiological activity of bacteria as well. Bacteria excellent property of a porous MOF, we chose a biocompatible
breathe on the cell membrane through electron transport, zirconium-based porphyrin MOF, PCN-222, as the carrier
which provides energy for cell growth, proliferation, and based on our previous work to greatly improve the stability and
maintenance.29 The outer membrane c-type cytochrome is a dispersion of Bi NPs,39 and as well as the fact that the standard
key electron transport protein in bacterial respiration. White et potential of Zr is more negative than that of Bi,40 we proposed
al. purified a pivotal electron transfer protein complex from the a hypothesis whether Bi NPs doping can endow the PCN-222
outer membrane of Shewanella oneidensis, which contained MOF with the biomimetic oxidase-like and peroxidase-like
three subunits: MtrA, MtrB, and MtrC.30 They also showed enzymatic capability by spontaneous transfer of electrons from
that this Mtr complex can conduct electrons in both directions Bi NPs to the PCN-222 MOF. In addition, due to the
and maintain an electron transfer rate of 8500 e s−1.30 incorporation of Bi into PCN-222, its redox potential provides
Liposome studies have shown that the relative redox potential sufficient conditions for electron flow into bacteria, thus
across the membrane is the determining factor for the direction achieving great bacteria-killing efficacy without exogenous
of electron transfer.31 Therefore, interference with electron stimuli or release of antibacterial factors. In this work, we
transport in bacteria can increase the production of intra- fabricated Bi NP doped PCN-222 MOF (Bi-PCN-222) by a
1449 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Figure 1. Morphology and structural characterization. (A) SEM image of PCN-222. (B, C) HRTEM images of 8 Bi-PCN-222. (D) Energy-
dispersive X-ray spectroscopy elemental mapping of 8 Bi-PCN-222. (E) XRD patterns of PCN-222, 4 Bi-PCN-222, and 8 Bi-PCN-222. (F) ζ
potential of PCN-222, 4 Bi-PCN-222, and 8 Bi-PCN-222. (G) XPS full spectrum and the corresponding high-resolution XPS spectra of (H)
Zr 3d and (I) Bi 4f. (J) FTIR spectra of PCN-222, 4 Bi-PCN-222, and 8 Bi-PCN-222.

simple in situ reduction reaction. This is accompanied by a RESULTS AND DISCUSSION

“bacterial current” similar to the photocurrent between
Morphology and Structure. PCN-222 was synthesized
bacteria and Bi-PCN-222, which is caused by an electron
from zirconium chloride (ZrCl4), TCPP, benzoic acid, and
transfer process.41 The above conjecture was confirmed, and
trace water by a thermal reaction in N,N-dimethylformamide
DFT showed that Bi NPs act as electron donors and electrons
flow to PCN-222 spontaneously due to the formed Schottky (DMF) solvent at 120 °C. Then, Bi NPs with different
barrier when they are in contact. Benefiting from their suitable contents were synthesized by in situ stirring and reduction. The
redox potential, electrons on Bi NPs can also flow to bacteria morphology and composition of materials were studied by
through the bacterial Mtr pathway, making the intracellular various characterization techniques. The transmission electron
ROS increase and accelerating sterilization. At the same time, microscopy (TEM, Figure S1A) and field emission scanning
the doping of Bi NPs on PCN-222 upregulated fibroblast electron microscopy (FESEM, Figure 1A) images showed that
proliferation and angiogenesis genes such as VEGF, bFGF, and the synthesized PCN-222 and Bi-PCN-222 (4 Bi-PCN-222
HIF-1α in the system, effectively treating wound infection on and 8 Bi-PCN-222, Figure S1B,C) exhibited a mixed structure
mice. The mechanism of antibacterial activity and repair of S. of nanocubes and a small amount of nanorods due to the
aureus infected wounds in vivo is shown in Scheme 1. Bi-PCN- addition of an acid modulator.42Figure 1B indicates that Bi
222 is a biomimetic nanozyme material that can quickly self- NPs were successfully loaded on PCN-222. And it was seen
sterilize without external interference due to skillfully that Bi NPs with nano size on the surface of PCN-222 had a
connecting the electron transfer in the process of bacterial lattice spacing of about 0.329 nm (Figure 1C). This
life activities with the electron transfer of the materials itself, corresponded to the (012) plane of Bi NPs.43 This showed
triggering a series of redox reactions. Such catalytic strategies the successful introduction of Bi NPs. Energy dispersive
will enlighten the design of self-antibacterial agents for efficient spectroscopy (EDS) element mapping showed that the Bi NPs
disinfection and tissue reconstruction simultaneously. obtained by in situ reduction were evenly distributed on PCN-
1450 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Figure 2. Material basic properties. Mott−Schottky plots of (A) PCN-222 and (B) 4 Bi-PCN-222 and 8 Bi-PCN-222. (C) Schematic diagram
of the spontaneous flow of electrons over the Schottky barrier. (D) Schematic diagram of the energy band structure. (E) UV−visible diffuse
reflection spectra of PCN-222, 4 Bi-PCN-222, and 8 Bi-PCN-222. (F) Band gaps of PCN-222, 4 Bi-PCN-222 and 8 Bi-PCN-222 from UV−
visible diffuse reflection spectra. Ultraviolet photoelectron spectra (UPS) of (G) PCN-222 and (H) 8 Bi-PCN-222. (I) Energy level diagram
of PCN-222 and 8 Bi-PCN-222. The light blue area indicates the range of the BRP.

222 (Figure 1D). Similarly, this result was also confirmed in 4 Zr3/2. This result revealed that the introduction of Bi NPs to
Bi-PCN-222 (Figure S2). In addition, to further determine the PCN-222 led to an increase in the electron density of Zr
phase, X-ray diffraction (XRD) was used. The XRD pattern clusters, proving the charge transfer from Bi NPs to the
confirmed that the diffraction peak of the sample was well MOF.48,49 In the C 1s spectrum, the binding energies of O−
matched with the PCN-222 diffraction peak in the literature.44 C�O, C−O, C−N, and C−C functional groups were 288.8,
When Bi NPs were introduced into PCN-222, the miscella- 286.4, 285.2, and 284.4 eV, respectively (Figure S3A).50Figure
neous peaks in the spectrogram decreased and the peak S3B shows two peaks at binding energies of 399.8 and 397.6
intensity weakened, indicating a strong interaction between Bi eV in the XPS spectrum of N 1s. This corresponded to −NH
NPs and PCN-222 (Figure 1E). No peaks were found and �N−, respectively.48 Moreover, the N 1s peak did not
associated with Bi NPs, which may be related to the smaller decrease from the original two peaks due to the addition of Bi
size of nanoparticles.45 Therefore, the crystal structure of NPs, indicating that Bi NPs did not coordinate with N on the
PCN-222 was retained in Bi-PCN-222. It has been reported porphyrin ring. In the O 1s spectrum of 8 Bi-PCN-222, the
that the ζ potential of Bi NPs is negative.46 From Figure 1F, peaks at 533.3, 531.9, 531.0, and 530.0 eV were assigned to
the ζ potentials of PCN-222, 4 Bi-PCN-222, and 8 Bi-PCN- O−H, C�O, Zr−O and Bi−O bonds,50 respectively (Figure
222 were 4.75, −4.37, and −4.54 eV, respectively, indicating S3C). Compared with PCN-222, there was an additional Bi−O
that Bi NPs and PCN-222 have an electrostatic interaction. peak after adding Bi NPs. The formation of the Bi−O bond
To confirm the compositions of the materials, XPS was prevented the oxidation of Bi metal.51 It was seen from Fourier
utilized, showing the existence of C, O, N, Bi, and Zr elements transform infrared spectroscopy (FTIR, Figure 1J) that PCN-
in Bi-PCN-222 (Figure 1G), which was consistent with the 222 had C−O and C�O bonds corresponding to carboxyl
results of EDS mapping. And the content of each element in 4 groups at 1412 and 1659 cm−1, respectively, suggesting the
Bi-PCN-222 and 8 Bi-PCN-222 is shown in Table S1. In existence of the TCPP ligand.52 The characteristic absorption
addition, the Bi 4f spectrum of Bi-PCN-222 (Figure 1H) peak of PCN-222 at 475 cm−1 was due to the Zr−O bond in
clearly showed that there were two peaks at 164.6 and 159.3 the Zr-oxo cluster.53 Compared with PCN-222, after adding Bi
eV, belonging to Bi0 4f5/2 and Bi0 4f7/2, respectively. This NPs, there was no additional peak in the infrared spectrum of
indicated the existence of Bi NPs.47 An analysis of the Zr 3d Bi-PCN-222, but the peak red-shifted compared with the pure
spectrum in Figure 1I showed that the addition of Bi NPs PCN-222, indicating the strong interaction between MOF and
caused a negative shift in the binding energies of Zr5/2 and Bi NPs.54 In addition, no peak of COO vibration was found,
1451 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Figure 3. DFT calculation and antibacterial ability. Structure optimization model of (A) PCN-222 and (B) Bi10 adsorption on it. DOS states
of (C) PCN-222 and (D) Bi-PCN-222. (E) Electron density difference plot at the PCN-222 and Bi NP interface. (F) Antibacterial ratio of S.
aureus and MRSA after culture at 37 °C for 4 h. n = 3 experiments per group. n.s. denotes p > 0.05, and ****p < 0.0001.

indicating no coordination of Bi with carboxylic acid groups. corroborated the band gap position calculated by the M-S
Therefore, based on the above analysis, Bi NPs did not replace spectra. Considering the presence of disulfide bonds on
Zr in this experiment. bacterial membranes, bacteria have a biological redox potential
Properties of Doped Bi NPs on PCN-222 and (BRP), which ranges from −4.12 to −4.84 eV.57 The potential
Antibacterial Performance of Bi-PCN-222. Furthermore, of 8 Bi-PCN-222 was within the scope of the BRP, and the
to evaluate the heterojunction type of Bi-PCN-222, the Mott− tendency of electron flow to bacteria becomes stronger due to
Schottky (M-S) spectra were tested by using a three-electrode the enhanced electron-donating ability by doping with Bi NPs,
working system in anhydrous sodium sulfate solution (0.5 M). which ensures the transfer of electrons from 8 Bi-PCN-222 to
As shown in Figure 2A,B, Bi-PCN-222 was an n-type Schottky bacteria.
heterojunction due to the positive spectral slope. This meant To demonstrate the interfacial interaction between Bi NPs
that once Bi NPs and PCN-222 were in contact, the electrons and PCN-222, density functional theory (DFT) calculations
on Bi NPs would flow spontaneously toward PCN-222 until an were carried out. Bi NPs were adsorbed on the optimized
equilibrium state was established due to the existence of the PCN-222 model (Figure 3A,B), and the electron distribution
Schottky barrier (Figure 2C).55 This was also consistent with at the interface between Bi NPs and PCN-222 was calculated.
the results in XPS. From the M-S spectra, the flat band Compared to PCN-222, more Fermi-level hybridization was
potentials of PCN-222 and 8 Bi-PCN-222 are −0.30 and observed from Bi-PCN-222, which was due to an interfacial
−0.21 V (versus RHE), respectively. Generally speaking, the reaction (Figure 3C,D). The electron distribution of Bi-PCN-
potential of the conduction band (CB) is more negative by 222 was further elucidated by calculating the electron density
0.1−0.2 V compared to the flat band of the n-type difference; as shown in Figure 3E, the yellow and blue regions
semiconductor.56 We took 0.1 V for our calculation. Therefore, were the electron accumulation region and the electron
the CBs of PCN-222 and 8 Bi-PCN-222 are −0.40 and −0.31 depletion region, respectively. Notably, the redistribution
V (versus RHE), respectively. The corresponding band gap between electrons occurs at the Bi NP and Zr-oxo interface.
positions at the vacuum level were −4.10 and −4.19 eV, Electron (1.18 e−) transfer from Bi NPs to PCN-222 results in
respectively (Figure 2D). The UV−visible diffuse reflection electron stacking on PCN-222, which was consistent with the
spectra of PCN-222, 4 Bi-PCN-222, and 8 Bi-PCN-222 are XPS results. Free electrons in this process were captured by the
shown in Figure 2E. The addition of Bi NPs induced the surrounding oxygens, thereby generating ROS.
absorption enhancement of the material after 525 nm. Based on the above experimental and computational basis,
According to the Tauc plot method and the UV−vis DRS, we cocultured common Gram-positive bacteria (including S.
the forbidden band widths of PCN-222, 4 Bi-PCN-222, and 8 aureus and methicillin-resistant Staphylococcus aureus (MRSA))
Bi-PCN-222 were 1.84, 1.79, and 1.77 eV, respectively (Figure with different material groups in the dark. As shown in Figure
2F). Moreover, the ultraviolet photoelectron spectra (UPS) 3F, the antibacterial rate of 4 Bi-PCN-222 and 8 Bi-PCN-222
showed that the secondary cutoff edges of PCN-222 and 8 Bi- groups can be as high as 99.95 ± 0.05% in two species of
PCN-222 were 16.32 and 16.33 eV, respectively; thus, the bacteria after being cultured for 4 h. The corresponding photos
work functions were calculated to be 4.88 and 4.87 eV, of spread plates are shown in Figure S4, and the changes of
respectively (Figure 2G,H). Then the CBs of PCN-222 and 8 antibacterial rate under different time gradients are shown in
Bi-PCN-222 were −4.12 and −4.17 eV (versus vacuum), Figure S5A,B, respectively. The results suggested that the
respectively, so the corresponding valence bands (VBs) were dopeing of Bi NPs on PCN-222 had excellent resistance to
−5.96 and −5.94 eV, respectively (Figure 2I). This, this well Gram-positive bacteria. In addition, we also evaluated the
1452 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Figure 4. Research on the mechanism of antibacterial activity. (A) FESEM pictures of S. aureus after coculture with samples for 4 h in the
dark. Cumulative amounts of (B) Zr ions and (C) Bi ions released from the materials after soaking in PBS at 37 °C for 96 h. (D) Oxidase-
like catalytic property of Bi-PCN-222 through L-ascorbic acid (AA). (E) Detection of peroxidase-like activities of Bi-PCN-222 through TA
and H2O2. The corresponding (F) •O2− and (G) •OH detected by ESR. n = 3 experiments per group.

antibacterial performance of high loading amounts of Bi-PCN- zirconium ions, which was consistent with the content of Bi
222 (20 Bi-PCN-222, 30 Bi-PCN-222) as well as bare Bi NPs; NPs in the material (Figure 4C). Metal ions released from
as shown in Figure S6, the antibacterial effect of a high content metal-containing nanomaterials have been shown to have a
of Bi-PCN-222 was greatly reduced due to the tendency of pivotal role in their antibacterial activity,58 and zirconium-
agglomeration of too many nanoparticles, while bare Bi NPs based metal composites have been widely used in antimicrobial
alone had no antibacterial properties. When Bi NPs were applications. It has been reported that positively charged
aggregated, it caused them to not provide good electron- zirconium ions can destroy negatively charged bacterial cell
donating ability when they were doped into MOF; thus, 4 Bi- walls as silver ions do, leading to the death of Gram-negative
PCN-222 and 8 Bi-PCN-222 with well-dispersed Bi NPs have bacteria (K. pneumoniae).59 However, for Bacillus subtilis, up to
about the same performance. 500 μg mL−1 ZrO2 was required to achieve a bactericidal effect
Research on the Mechanism of the Antibacterial through the destruction of the bacterial membrane by
Activity. FESEM was utilized to visualize the morphologies of zirconium ions, and this concentration has no inhibitory effect
MRSA and S. aureus after treatment with different materials. As on S. aureus.60 This meant that the small amount of zirconium
shown in Figure 4A, compared to the rounded morphology of ions released in this experiment was far from sufficient to
the control group and slight shrinkage showed by the PCN- produce bacterial toxicity. Actually, upregulation of the
222 group, 4 Bi-PCN-222 and 8 Bi-PCN-222 showed the bacterial efflux pump can improve the removal of released
shrinkage and deformation of the bacterial membrane, and metal ions. Moreover, bacteria can also disable metal ions by
even the content flowed out after rupture. Figure 4B shows the binding D-alanine or lipid A, thereby reducing the net negative
concentration of zirconium ions released into PBS (pH = 7.4) charge of the membrane or increasing the positive charge of
at 37 °C for different times of different materials (PCN-222 the membrane, respectively.61 Based on this, we verified
and 8 Bi-PCN-222). The two materials showed a similar whether ion release plays a leading role in sterilization. After
release behavior with a relatively rapid release for the first 24 h, the materials were cultured in a 37 °C oven for 4 h, the clear
followed by a slow release for the subsequent 72 h. The release supernatants were obtained by centrifugation and then used for
of zirconium ions in 8 Bi-PCN-222 was greater than that of antibacterial tests. As shown in Figure S7A,B, the supernatant
PCN-222, which may be due to the fact that 8 Bi-PCN-222 is of Bi-PCN-222 had no antibacterial effect when it was cultured
more easily degraded in a healthy body fluid environment. The in a 37 °C oven for 4 h; thus, ionic antibacterial activity was
release of Bi ions in 8 Bi-PCN-222 was much less than that of excluded.
1453 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Figure 5. Electron transfer between bacteria and materials. (A) Structure optimization model of heme c and (B) its adsorption on Bi-PCN-
222. Electron density difference plots at the heme c and Bi NP interface from a (C) top view and (D) side view, respectively. (E) Bi 4f peaks
of 8 Bi-PCN-222 before and after antibacterial treatment. (F) I−V curves of PCN-222 and Bi-PCN-222. (G) EIS of PCN-222 and Bi-PCN-
222. (H) Membrane potential of Bi-PCN-222 tested with the membrane-potential-sensitive dye DiBAC4(3). (I) ATP level of S. aureus of
different samples after culture for 4 h in the dark. (J) Intracellular ROS detection using DCFH-DA of S. aureus. (K) Protein leakage of S.
aureus. (L) ONPG membrane permeability test. (M) Schematic diagram of the antibacterial mechanism. n = 3 experiments per group; n.s.
denotes p > 0.05, and **p < 0.01, ***p < 0.001, and ***p < 0.0001.

In recent years, numerous reports have demonstrated that the ROS species.64 As shown in Figure S8, 4 Bi-PCN-222 and
some nanomaterials can kill bacteria by generating ROS 8 Bi-PCN-222 both produced more •O2− than PCN-222 after
through enzyme-like catalytic reactions.17,62 Due to the 4 h of dark culture. The oxidase-like and peroxidase-like
electrons flowing spontaneously from Bi NPs to PCN-222, properties were also verified by electron spin resonance (ESR,
therefore, we explored the oxidase-like activity of Bi-PCN-222. Figure 4F,G). Hence, the addition of Bi NPs on PCN-222
L-Ascorbic acid (AA) was used as an index to study the endows Bi-PCN-222 with excellent oxidase-like and perox-
oxidase-like property of Bi-PCN-222 due to it serving as an idase-like properties.
antioxidant in cellular redox reactions.62 After we put the In order to explore whether ROS produced by enzyme-like
samples in the oven with an AA solution at 37 °C for 4 h, the catalysis play a leading role in antibacterial activity, we
absorbance of AA in Bi-PCN-222 groups was significantly conducted an ROS consumption experiment. Melatonin is
lower than that in PCN-222 and almost completely well-known for its powerful ROS-scavenging ability;65 there-
disappeared (Figure 4D), which indicated the oxidase-like fore, we added different materials together with 200 mg mL−1
property of Bi-PCN-222. Since terephthalic acid (TA) can be melatonin to bacteria for coculture. As shown in Figure S9,
oxidized by •OH to form a fluorescent substance, 2- after adding melatonin, the Bi-PCN-222 still had a strong effect
hydroxyTA,63 the •OH production of the material was further on killing S. aureus, indicating that the electron inflow of the
studied with TA. As shown in Figure 4E, the yield of •OH was material into bacteria was the main cause of bacterial death.
greatly improved after 4 h of culture, indicating the peroxidase- Furthermore, we also explored whether common MOFs have
like property of Bi-PCN-222. Then, nitrotetrazolium chloride antibacterial ability after adding Bi NPs, and we selected MIL-
blue (NBT) was used as a sensitive •O2− indicator to detect 125-NH2, UiO-66, and Ni-CAT as the research objects. As
1454 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Figure 6. In vitro biocompatibility and ability to promote fibroblast migration and differentiation. (A) MTT assay to determine the cell
viability after coculture with the material. (B) Hemolysis rate of erythrocytes in each group after 4 h of incubation. (C) Fluorescence images
of cells after culture with different materials. (D) Cell scratch images of cell migration measured at 0, 12, and 24 h of culture (scale bars 200
μm). Gene expression of fibroblasts cultured for 5 days under different treatment conditions measured by Q-RT-PCR of angiogenic genes
(E) bFGF, (F) VEGF, and (G) HIF-1α. (H) SEM images of degradation of 8 Bi-PCN-222 under different SBF (scale bars 1 μm). n ≥ 3
experiments per group; n.s. denotes p > 0.05, and **p < 0.01, **p < 0.001, and ****p < 0.0001.

shown in Figure S10, these MOFs had little antibacterial shown in Figure 5A,B. The electron flow direction in heme c
properties after 4 h of incubation before and after the addition and Bi-PCN-222 were further elucidated by calculating the
of Bi NPs. Among them, UiO-66 is also a Zr-based MOF. This electron density difference (Figure 5C,D). The electron
further indicated that this was because of the proper redox accumulation region and the electron depletion region are
potential of Bi-PCN-222 and the electron transfer to bacteria shown as the yellow and blue regions, respectively. Notably,
transfer related proteins on the bacterial membrane that can be the redistribution between electrons occurs at the interface of
useful for efficient antibacterial activity. heme c with Bi NPs. Electrons (1.73 e−) are transferred from
Electron Transfer between Bacteria and Materials. Bi NPs to heme c, resulting in electron stacking in heme c.
The electron transport pathway in the bacterial outer This disturbs the electronic homeostasis of bacterial life
membrane is called the Mtr pathway by researchers.66 The activities and leads to bacterial death. Then, we detected the Bi
ducts of multiheme c-type cytochromes (MtrA and MtrC), and 4f peaks of 8 Bi-PCN-222 before and after antibacterial
the nonheme OM β-barrel (MtrB) connecting these treatment by XPS. As shown in Figure 5E, after antibacterial
cytochromes make up the complete Mtr pathway.67 And treatment, the two peaks of Bi 4f moved in the direction of
these c-type cytochromes are composed of large amounts of high binding energy, further proving that Bi NPs lost electrons,
heme c.68 Therefore, we simulated the electron flow between consistent with DFT calculations. Not only that, Figure 5F
heme c and Bi-PCN-222 by DFT calculations. The structure shows the current potential (I−V) curves of the materials
optimization of heme c and its adsorption on Bi-PCN-222 are under different treatments. When live S. aureus was spread on 8
1455 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Bi-PCN-222, a result similar to that of the photocurrent was Biocompatibility of Bi-PCN-222. We studied the
obtained in the dark environment. It is generally accepted that biocompatibility in vitro by methyl thiazolyl tetrazolium
the radius of the arc in the EIS impedance is proportional to (MTT) assay and hemolysis tests. NIH-3T3 cells are
the resistance of the material; a smaller arc radius indicates less commonly used for in vitro toxicity evaluation,71,73 and NIH-
resistance to electron transfer in the material and higher 3T3 cells were also used in this study. After coculture with
electron mobility.69 As demonstrated by the EIS, 8 Bi-PCN- PCN-222, 4 Bi-PCN-222, and 8 Bi-PCN-222 for 24 h, the
222 displayed lower electrochemical impedance, which average survival rates of cells were 91.5%, 80.2%, and 82.7%,
indicated its stronger electron transport capacity than PCN- respectively. This showed that the number of Bi NPs has little
222 (Figure 5G). Since the potential of Bi-PCN-222 was effect on cell survival (Figure 6A).
higher than that of the bacterial membrane, electrons in the n- The hemolytic properties of rat erythrocytes were studied.
type semiconductor Bi-PCN-222 will flow to the bacterial H2O and NaCl were selected as positive and negative controls,
membrane, thus balancing the potential difference between respectively, because red blood cells would dissolve in H2O
them.55 As the electrons in the material continue to enter the during hypertonic treatment but not in NaCl. As shown in
bacteria, the electrons are consumed in the surface region on Figure 6B, the hemolysis rates of PCN-222, 4 Bi-PCN-222,
one side of the semiconductor, so that only a positive charge and 8 Bi-PCN-222 were all lower than the international
remains, enabling the formation of a built-in electric field.70 standard requirement (5%), which indicated that the samples
Therefore, we can draw conclusion that once S. aureus was in have no obvious hemolysis phenomenon. The cell morphology
contact with Bi-PCN-222, electrons will move from the (Figure 6C) showed that the cells in each group expanded well
material to the bacteria through direct contact at the and the cells extended abundantly. There was no sign of cell
bacteria−material interface. We then used DiBAC4(3) to death, which further showed that the biocompatibility of the
detect the cell membrane potential.70 As shown in Figure 5H, material was excellent.
the Bi-PCN-222 groups showed stronger fluorescence In Vitro Fibroblast Growth-Promoting and Biodegra-
compared to the control group, which indicated that electrons dation Behavior. It has been shown that bismuth ions
were transferred from Bi-PCN-222 to the bacterial membrane, increase the growth of gastric mucosal epithelial cells via a
resulting in a change in the cell membrane potential of S. Ca2+/MAP-kinase-dependent pathway,74 and bismuth sulfide/
aureus. In addition, ATP of S. aureus activity was further hydroxyapatite films have promoted osteogenic differentiation
analyzed after treatment with different materials (Figure 5I). by regulating genes downstream of osteogenic differentiation
ATP is the energy molecule of bacteria involved in respiration through a Wnt/Ca2+ signaling pathway.75 These results made it
in the essential activities of bacterial life. ATP levels drop when possible for bismuth ions to promote the proliferation and
bacteria are necrotic or apoptotic.71 As shown in Figure 5I, differentiation of other cells. To evaluate the effect of Bi-PCN-
among all groups, the ATP levels of bacteria after interaction 222 on cell proliferation, we selected NIH-3T3 cells as the
with the Bi-PCN-222 groups were the lowest, which further research object, as shown in Figure 6D; after artificially
indicated that Bi-PCN-222 effectively disrupted the normal creating a scratch, NIH-3T3 cells cocultured with Bi-PCN-222
respiration of bacteria. groups were observed to undergo significant cell migration at
Antibacterial Mechanism. For the purpose of further 12 and 24 h, indicating that Bi-PCN-222 had a positive effect
proving the effect of Bi-PCN-222 on the bacterial metabolism, on promoting proliferation. Therefore, we further used Q-RT-
ROS in S. aureus were detected by 2,7-dichlorodihydrofluor- PCR to explore the expression of angiogenesis-related genes
escein diacetate (DCFH-DA). As shown in Figure 5J, 4 Bi- such as glyceraldehyde 3-phosphate dehydrogenase (GAPDH),
PCN-222 and 8 Bi-PCN-222 showed a strong green basic fibroblast growth factor (bFGF), fibroblast vascular
fluorescence signal after 4 h of culture, indicating that Bi- endothelial growth factor (VEGF), and hypoxia-inducible
PCN-222 caused severe oxidative stress in bacteria due to an factor (HIF-1α). As shown in Figure 6E−G, the relative
electron influx. In addition, the BCA protein leakage and gene expressions of bFGF, VEGF, and HIF-1α were all
ONPG hydrolysis tests of 4 Bi-PCN-222 and 8 Bi-PCN-222 upregulated after 5 days of coculture with Bi-PCN-222.
shown in Figure 5K,L were increased significantly. Figure 5M VEGF and bFGF are important factors in angiogenesis, and
illustrates the complete process of bacterial death caused by Bi- their gene expression is closely linked to the angiogenic
PCN-222. For Bi-PCN-222, electrons in Bi NPs would transfer response. HIF-1α mimics hypoxia and has a critical role in cell
to PCN-222 due to the Schottky barrier formed between Bi differentiation, recruitment, and angiogenesis.76 Stimulation of
NPs and PCN-222. Some free electrons would be captured by gene expression indicated that Bi-PCN-222 had a strong
surrounding oxygens to generate toxic ROS during the process. stimulatory effect on the upregulation of angiogenic growth
Meanwhile, the potential between Bi-PCN-222 and bacteria factors.
led to the electron flow from Bi-PCN-222 to bacteria. The The biodegradation and biocompatibility of Bi-PCN-222
respiratory chain protein complexes I on the bacterial determine the possible future in vivo applications. Therefore,
membrane derived the pumping out of H+, and protein the biodegradation behavior of 8 Bi-PCN-222 under neutral
complexes I and II derived the electrons transferred to protein (pH = 7.4) and weakly acidic environment (pH = 6.5)
complex III. These electron transfer processes were interfered simulated body fluids (SBFs) was preliminarily evaluated,
by electrons from Bi-PCN-222 to internal bacteria from the which were used to simulate neutral healthy body fluids and
Mtr pathway. The extra electrons combine with oxygen to mildly acidic bacterial infection body fluids in vivo, respectively.
increase the ROS in bacteria. Thus, protons on protein The structures of 8 Bi-PCN-222 in different SBFs are shown in
complex III cannot be pumped out to IV to react with oxygen, Figure 6H. The 8 Bi-PCN-222 group showed degradation and
resulting in the decreased formation of ATP, a disordered agglomeration behavior in acidic medium for 2 days, and the
internal metabolism of bacteria, and an enhanced oxidative morphology of the material was almost invisible after 10 days.
stress.72 Therefore, bacterial permeability increased and there However, the material in the neutral medium always preserved
was protein efflux. Finally, the bacteria were dead. a better morphology and only showed a wide range of
1456 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Figure 7. In vivo biocompatibility testing. (A) Schematic diagram of the anti-infection effect of Bi-PCN-222 in a wound infection model. (B)
Wound tissue slices of H&E staining and (C) Giemsa staining images on 2, 5, and 10 days of treatment (scale bars 50 μm). (D) Photographs
of wounds in the control group, 3M group, and Bi-PCN-222 groups at 0, 2, 5, and 10 days of treatment. (E) Physical images were used to
calculate the changes of wound area in different days. (F) Masson’s trichrome images on 2 and 10 days of treatment (scale bars 50 μm). (G)
H&E stained slices of heart, liver, spleen, lung, and kidney on day 10 (scale bars 50 μm).

degradation behavior on the 10th day. Therefore, the after 8 h. Therefore, the bactericidal effect of the material was
degradation rate of the material in acidic medium was higher still excellent in the infected environment of body fluid.
than that in neutral medium. This indicated that the Bi-PCN- Wound Treatment by Bi-PCN-222 In Vivo. Based on the
222 can be degraded more quickly when the body suffered a good ability of Bi-PCN-222 to self-sterilize, upregulate
bacterial infection, without causing toxic accumulation of the fibrovascular genes, and degrade, we evaluated the therapeutic
material to the organism. To test whether the degradation of ability of Bi-PCN-222 on bacterial infection wounds in vivo. A
the material will have an effect on the antibacterial effect, the 15 μL portion of S. aureus solution (2 × 108 CFU mL−1) was
antibacterial performance of the material in the simulated dropped into a mice wound to create a wound infection model.
infected body fluid environment was determined. As shown in The therapeutic effect of Bi-PCN-222 on the wound infection
Figure S11, under the SBF environment of infection, the of S. aureus in mice is shown in Figure 7A. And as shown in
antibacterial effect at 4 h was also obvious and even improved Figure 7B,C, the hematoxylin−eosin (H&E) staining and
1457 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Giemsa staining were conducted on days 2, 5, and 10 of EXPERIMENTAL METHODS

infected tissues, respectively, to assess the in vivo antibacterial Materials. All the chemicals used in this experiment were used
activity of Bi-PCN-222. H&E-stained wound tissue (Figure directly without further purification. Bismuth nitrate pentahydrate,
7B) showed a good deal of neutrophils in the wound tissue of zirconium chloride, benzoic acid, meso-tetracarboxyphenyl porphin
the control group on day 2, which represented severe (TCPP), N,N-dimethylformamide (DMF), and ethylene glycol were
inflammation and bacterial infection. Although neutrophils all purchased from Aladdin.
decreased over time in all groups, at the 10th day, the control Preparation of PCN-222. The synthesis method of PCN-222 is
and 3M groups still had some inflammatory cells. In contrast, consistent with previous reports.44 A 60 mg portion of zirconium
chloride, 1.5 g of benzoic acid, and 1.2 mL of deionized water were
in the Bi-PCN-222 groups, there were almost no inflammation blended in 12 mL of DMF, and then the mixture was dissolved by an
cells, which indicated that Bi-PCN-222 had a significant ultrasonic cell disruptor (vcx500; Sonics). Next, 60 mg of TCPP was
antibacterial effect. This result was further confirmed by the mixed into the above solution and then the ultrasonic cell disruptor
Giemsa staining shown in Figure 7C. A large number of was maintained for a few minutes. The homogenized solution was put
bacteria were found at the infection site in the control group into an autoclave and then heated at 120 °C for 24 h. The dark purple
even after 10 days, while only very small amounts of bacteria product was collected, washed three times with DMF and ethanol at
were observed in the Bi-PCN-222 groups after 2 or 5 days and 1000 rpm for 5 min, and finally dried overnight in a 60 °C oven.
Preparation of 4 Bi-PCN-222 and 8 Bi-PCN-222. A 20 mg
normal tissues were detected after 10 days. Figure 7D portion of PCN-222 was weighed in a centrifuge tube, dissolved with
visualizes the wound-healing process on different days. After 5 mL of deionized water, and crushed with an ultrasonic cell disruptor
2 days of bacterial infection, both the control group and 3M for 5 min, then the solution was transferred to a 50 mL beaker,
group showed obvious suppuration. Over time, due to the bismuth nitrate of different weights (4 mg, 8 mg) was added,
mice’s own self-healing ability, the festering wounds began to dissolved in 5 mL of glycol and then added to the above solution, and
scab over and showed obvious signs of recovery. In contrast, then an additional 12.5 mL of deionized water and 2.5 mL of glycol
the Bi-PCN-222 group showed good anti-inflammatory and were added with stirring. The mixture was stirred for 2 h at room
rapid wound healing from the outset. On day 10, the wound temperature. Then, 1 or 2 mL of the NaBH4 solution (4 mg mL−1)
prepared with ice water was added separately under the condition of
had healed and a lot of hair had grown around the wound. The agitation, respectively. Five minutes later, the solution was centrifuged
wound area recovery shown in Figure 7E more intuitively at 1200 rpm and 5 min, and then it was subjected to several washes
reflected the treatment level of each group. Further evaluation with deionized water and ethanol to remove impurities and unreacted
of nascent tissue was carried out with Masson’s trichrome materials. The synthesis of bare Bi NPs has the same steps except that
staining. As shown in Figure 7F, the images showed that the there was no addition of PCN-222. The obtained materials were dried
wound epithelium of the Bi-PCN-222 groups was more for 12 h in a 60 °C oven.
complete with more collagen fibers, while the regrowth Characterization. A field emission scanning electron microscope
(ZEISS Sigma 500) with SEM (JSM-6510LV) and EDS was used to
epidermis and epithelium of the wounds of the 3M group get the microstructure and elemental composition of the materials.
and control group were still rough and irregular on the 10th The phase structure of the samples was analyzed by XRD (D8A25,
day. Therefore, Bi-PCN-222 could effectively treat S. aureus Bruker, Germany). X-ray photoelectron spectroscopy (XPS, ESCA-
wound infections by its self-sterilizing and promote angio- LAB 250Xi, Thermo Scientific, USA) was used to analysis the
genesis abilities. composition. Ion release was determined by inductively coupled
In addition, the biosafety was assessed by staining of major plasma optical emission spectroscopy (ICP-OES, PQ9000, Jena,
organs such as heart, liver, spleen, lung, and kidney on the 10th Germany). A UV−vis−NIR spectrometer (UV-3600, Shimadzu,
day after treatment. All organs presented a normal state, Japan) was used to measure the UV−vis−DRS of materials. Fourier
transform infrared (FTIR, NICOLET iS10) was used to determine
indicating that Bi-PCN-222 had good biosafety in vivo (Figure the position of characteristic functional groups of the MOFs.
7G). This result was also fully validated by Giemsa staining of Fluorescence images were observed with an inverted fluorescence
major organs (Figure S12). microscope (Olympus, IX73, Japan). Electron spin resonance (ESR)
was tested with a JES-FA200 instrument (JEOL, Tokyo, Japan).
CONCLUSION In Vitro Antibacterial Experiments. A bacterial suspension (160
μL, 4 × 106 CFU) was evenly mixed with 40 μL of material (1 mg
In summary, we have developed a biomimetic biocatalytic mL−1) in a 96-well plate, and the control group was replaced by sterile
system with self-bacteria-killing and would healing simulta- Luria−Bertani (LB) medium. Then the whole plate was shaken on a
neously. On one hand, the electrons on Bi-PCN-222 were 37 °C shaking table for 4 h, and the antibacterial trend was observed
acquired by bacteria after bacteria attached to Bi-PCN-222, every 1 h. At every point of time, 10 μL of bacterial solution was
which disturbed bacterial respiratory and metabolic pathways taken, diluted 400 times, and spread on LB agar plates. Then the
samples were incubated for 24 h in 37 °C oven, and photos were
and enhanced oxidative stress in bacteria. On the other hand, taken. After counting the number of colonies (N), the antibacterial
the spontaneous flow of electrons on Bi NPs to PCN-222 efficiency was calculated by using the formula
enabled Bi-PCN-222 to have biomimetic enzyme-like activity,
effectively catalyzing O2 and H2O2 to generate ROS (•OH, Nc N
• antibacterial rate (%) = × 100%
O2−). Not only that, Bi-PCN-222 also has excellent ability to Nc
upregulate gene expression such as bFGF, VEF, and HIF-1α
and thus promote fibroblast proliferation, differentiation, and In the formula, Nc is the colony number of the control, and N is the
angiogenesis. This series of self-derived electron transfer colony number of the experimental group.
The morphology of S. aureus was observed by FESEM. After 4 h
processes from Bi NPs to MOF and bacteria leads to rapid
coculture with the material, the LB was discarded and the S. aureus
bacterial elimination in vitro and in vivo and rapid treatment of attached to the material surface was fixed with 2.5% C5H8O2 in a
S. aureus-infected wound tissues. Hence, this work may light-proof environment for 2 h. Then the sample was dehydratedwith
enlighten the design of other materials of self-driven electron graded ethanol. After drying, S. aureus was observed by FESEM with a
transfer for efficient disinfection and tissue reconstruction. platinum sputtering coating.

1458 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Ion Release. To test the trend of Zr and Bi ion release from the And the RHE potential can be converted to the energy level position
material, the material was packed into dialysis bags and then under vacuum by the equation
completely put in phosphate buffer saline (pH = 7.4) at human
Evs vacuum = 4.5 E RHE
body temperature. Materials (1.5 mL, 2 mg mL−1) were immersed in
a total volume of 30 mL of PBS. At time points of 4, 8, 10, 24, 48, and Bacterial Membrane Potential Test. S. aureus was centrifuged
96 h, 3 mL of the ion precipitation liquid was collected and refreshed at 4 °C at 6000 rpm and washed three times with saline, the OD of
with a new same liquid. And the concentrations of leached of Zr4+ and the bacteria was adjusted to about 0.25 with saline, and then diluted
Bi3+ were tested by ICP-OES. DiBAC4(3) (5 μM) was added to it. After culturing for 30 min at 37
Oxidase-Like and Peroxidase-Like Activity of 4 Bi-PCN-222 °C, 40 μL of material (the final concentration of the material was 200
and 8 Bi-PCN-222. The oxidase-like properties of 4 Bi-PCN-222 and ppm) was added to 160 μL of the above bacterial solution; the change
8 Bi-PCN-222 were studied using L-ascorbic acid (AA) as a substrate. in fluorescence intensity of S. aureus potential within 45 min was read
A 1.5 mL portion of 1 mg mL−1 material aqueous solution was added on a microplate reader with an excitation wavelength of 622 nm and
to 1.5 mL of an AA (0.03 mg mL−1) aqueous solution. Then, the an emission wavelength of 670 nm.70
UV−vis absorption spectrum after 4 h of incubation was recorded by Adenosine Triphosphate (ATP) Test. S. aureus was centrifuged
a UV−vis−NIR spectrometer. at 4 °C at 6000 rpm and washed three times with PBS. Then, fresh
The formation of 2-hydroxyl terephthalate from terephthalic acid PBS was added to adjust the OD of the bacteria to OD = 0.2−0.6.
(TA) and •OH was studied by using TA as a fluorescent indicator. The above bacterial solution was cultured with the materials for 4 h.
There were five groups evaluated, including TA (5 mM), H2O2 + TA Then the mixture was collected and centrifuged at 4 °C at 1200 rpm,
and material (PCN-222, 4 Bi-PCN-222, 8 Bi-PCN-222) + TA + and the pellet was added to the lysate. The lysis buffer was transferred
H2O2. The mixture was cocultured at 37 °C for 4 h, after which the to a sonicated cell disruptor and set for 5 min at a power of 30%, on
mixture was detected for fluorescence at a wavelength of 312 nm. The for 3 s, and off for 5 s in an ice−water bath. The supernatant was
fluorescence peak at around 460 nm is related to •OH production. added to the same volume of ATP working solution, and the
•
Superoxide Anion ( O2−) and Hydroxyl Radical (•OH)
d

fluorescence intensity was measured on a microplate reader.

Detection. Nitrogen tetrazole blue chloride (NBT) was used as a Membrane Permeability and Protein Leakage. The mem-
sensitive •O2− indicator. The •O2− production of PCN-222, 4 Bi- brane permeability was determined by the o-nitrophenyl-β-galactoside
PCN-222, and 8 Bi-PCN-222 was evaluated. Specifically, 500 μL of (ONPG) hydrolysis method. The bacteria were first cocultured with
material (1 mg mL−1) was placed in a prepared dialysis bag, and the isopropyl β-D-1-thiogalactoside (IPTG) for 12 h, collected by
dialysis bag was placed into a 4 mL centrifuge tube with 3 mL of NBT centrifugation at 5000 rpm for 5 min and washed several times
(0.002 mg mL−1) solution. Then, the centrifuge tube was heated at 37 with sterile PBS, and then diluted until OD = 0.05−0.1. After the
°C for 4 h, and 200 μL was taken to read the absorption curve normal antibacterial activity, 15 μL of the postantibacterial suspension
spectrum. During the experiment, the whole process was treated was added to a mixture of 10 μL of DMSO (7%), 110 μL of PBS, and
without light. 15 μL of ONPG (12.5 mM). The OD values were read on a
In addition, the generation of •O2− and •OH signals were further microplate reader at a wavelength of 420 nm.
detected by ESR. To a 0.2 mL portion of the material aqueous To detect the protein leakage of S. aureus, the Enhanced BCA
solution (2 mg mL−1) was added 20 μL of H2O2 and the mixture Protein Assay Kit (cat. no. P0010, Beyotime) was used. After
cultured at 37 °C for 4 h. After that, 1 μL of DMPO was added to the antibacterial activity, the mixture in the 96-well plate was collected in
mixture and then the •OH signal was immediately tested. For •O2−, a 1.5 mL centrifuge tube and centrifuged at 1000 rpm for 5 min in a
the material was dissolved in methanol, except that no H2O2 was refrigerated centrifuge, and then 20 μL of the supernatant after
added; the rest of the operations were the same as those for measuring centrifugation was mixed with 200 μL of BCA reagent AB mixture and
•
OH. placed at 37 °C for 30 min before reading the OD value at 562 nm.
DFT Calculations. A typical PCN-222 cluster in a cubic box with Intracellular ROS Determination. For this experiment, we used
a periodic side length of 25 Å was used as the model (model 1).44 the Reactive Oxygen Species (ROS) kit (cat. no. S0033; Beyotime) to
Model 2 was built by adding a Bi10 cluster to model 1. During detect intracellular ROS. In short, 107 CFU mL−1 bacteria and
structural optimizations, the Γ point in the Brillouin zone was used for DCFH-DA diluter (10 mM) were incubated in darkness in a 37 °C
k-point sampling, and all atoms were allowed to relax.73 shaker for 30 min, and then materials were added for another 4 h of
Bacteria Current and Impedance Spectroscopy (EIS) coculture. After that, the bacteria were left standing for 1 h, and then
Detection. The current potential (I−V) curves were tested from the medium was discarded and excess dye was washed off with PBS
the samples on a three-electrode (platinum electrode, reference for several times. After natural drying, fluorescence pictures were
electrode, and working electrode; CHI-660E) electrochemical work- obtained by an inverted fluorescence microscope.
station with K3[Fe(CN)6] (5 mM) solution as the redox system. The In Vitro Cell Toxicity and Cell Morphology Observation. The
samples served as the working electrode, while the Ag/AgCl electrode cytotoxicity of NIH-3T3 cells was detected by an MTT assay (n = 3).
and platinum electrode worked as the reference electrode and counter The cells that grew adherent for 1 day in the 96-well plate had the
electrode, respectively. The samples tested included 8 Bi-PCN-222 + DMEM medium discarded, and at the same time, the material
S. aureus, 8 Bi-PCN-222, PCN-222 + S. aureus, and PCN-222. For aqueous solution was prepared at 200 ppm with the DMEM medium,
and 200 μL of the material and medium mixture was added to each
samples with live S. aureus, 60 μL of a mixture of bacteria (CFU (2−
well of adherent cells. After the materials and cells were cocultured for
3) × 105) and the material was dropped on the sample surface and
1 day in a 37 °C cell incubator, the supernatant was discarded and the
dried at 37 °C for 1 h to form a uniform film. Then the I−V curves
same volume of MTT solution was added (0.5 mg mL−1). After
and EIS were tested.
incubation for 4 h, the MTT solution was discarded and the same
Mott−Schottky Test. Mott−Schottky plots were acquired in
volume of DMSO was added and shaken well. After standing for 2 h,
sodium sulfate solution (0.5 M) at 10 Hz. The resulting potential
100 μL of the purple supernatant solution was taken and added to
applied to Ag/AgCl was converted to the RHE potential by the
another well plate, and the OD values were measured at 490 or 570
formula
nm.
For the observation of cell morphology, cells grew adherently for 1
ERHE = EAg/AgCl + 0.0591pH + EAg/AgCl EAg/AgCl = 0.199 day in 96-well plates, the DMEM culture medium was discarded, and
diluted samples (200 ppm) with cell culture solution were added to
From the Mott−Schottky diagram we can obtain the flat band the walled NIH3T3. After coculturing for 24 h, the adherent cells
potential (Efb), which is obtained from the x intercept of the linear were gently washed with sterilized PBS twice and then fixed with 4%
region.56 The formula for calculating the minimum conduction band formaldehyde solution at 37 °C, 10 min. WThe excess formaldehyde
potential (ECBM) is ECBM = Efb − 0.1, where 0.1 is an empirical value. was washed twice with phosphate buffer saline. The cells were then

1459 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

stained with an FITC (diluted 1000 times) solution for 30 min and ASSOCIATED CONTENT
were reignited with DAPI (diluted 100 times) about 30 s. After
drying, an inverted fluorescence microscope was used to take
*
sı Supporting Information

fluorescence pictures. The Supporting Information is available free of charge at

Cell Scratch Assay. After the cell resuspension was added to a 6- https://pubs.acs.org/doi/10.1021/acsnano.2c10203.
well plate for 24 h of adherent growth, a channel was drawn with a 1 Percentage content of each element in 4 Bi-PCN-222
mL pipet tip perpendicular to the bottom of the well plate, and then and 8 Bi-PCN-222, primer sequences used in real time
the medium was discarded and the scraped off cells were washed with Q-RT-PCR, morphology of different materials, morphol-
PBS. Different materials (control, PCN-222, 4 Bi-PCN-222, and 8 Bi-
ogy and structural characterization of 4 Bi-PCN-222,
PCN-222) were added for treatment, and after the cells were
cocultured with the materials for different time periods, the cells were XPS high-resolution spectra of C 1s, N 1s, and O 1s,
stained with FITC and the migration of cells at different moments was spread plates of S. aureus and MRSA coculture with
observed with an inverted fluorescence microscope. different materials for 4 h, time gradient antibacterial
Q-RT-PCR Test. The cell resuspension was placed on a 6-well spread plates of different samples, antibacterial spread
plate. After 24 h of cell adherent growth, the cells were treated with plates of Bi NPs, 20 Bi-PCN-222, and 30 Bi-PCN-222,
different materials (control, PCN-222, 4 Bi-PCN-222, and 8 Bi-PCN- antibacterial results on S. aureus of supernatant from
222) and cocultured for another 5 days, and then the total RNA was different materials, generation of •O2− from different
extracted from the cells by a total RNA kit. A 500 ng portion was materials detected by NBT, spread plates of S. aureus on
extracted from the extracted cellular RNA, and cDNA was obtained coculture with different materials and melatonin for 4 h,
by reverse transcription via PrimeScript RT Master Mix. The obtained spread plates of different MOFs against S. aureus after
cDNA was used as Q-RT-PCR templates for GAPDH, bFGF, VEGF, culture for 4 h, antimicrobial effect of different materials
and HIF-1α. The relative expression levels of the internal reference
in simulated body fluid infection situations, and Giemsa
gene GAPDH were used to normalize the relative expression levels of
these genes. Real-time fluorescence quantification was conducted with
staining images of the heart, liver, spleen, lung, and
a CFX Connect Real-Time PCR Detection System (Bio-Rad). All kidney tissues at the 10th day of treatment (PDF)
groups were subjected to more than three replicates and independent
experiments. In Table S2 we have summarized the primer sequences. AUTHOR INFORMATION
Hemolysis Test. A hemolysis test was performed with fresh rat
blood. The blood was centrifuged at 3000 rpm at 4 °C for 15 min, and Corresponding Author
the supernatant was discarded and the remainder was washed three Xiangmei Liu − Biomedical Materials Engineering Research
times with NaCl to collect red blood cells. They were then dispersed Center, Hubei Key Laboratory of Polymer Materials,
in NaCl to a 5% concentration for later use. Subsequently, the Ministry-of-Education Key Laboratory for the Green
samples (400 ppm) were mixed with 500 μL of 5% red blood. After Preparation and Application of Functional Materials, School
coculture at 37 °C for 4 h, the mixture was kept in a refrigerated of Materials Science & Engineering, Hubei University,
centrifuge at 3000 rpm for 15 min, and the OD values of the Wuhan 430062, People’s Republic of China; School of
supernatant after centrifugation were read by a microplate reader at Health Science and Biomedical Engineering, Hebei University
570 nm. Deionized water was set as the positive control, while NaCl of Technology, Tianjin 300401, People’s Republic of China;
was the negative control. The hemolysis rate (RHR%) of the sample orcid.org/0000-0002-6469-2363;
was calculated as
Email: [email protected]
A sample ANaCl
RHR (%) = × 100% Authors
A water ANaCl Lihua Wu − Biomedical Materials Engineering Research
Center, Hubei Key Laboratory of Polymer Materials,
Animal Experiments In Vivo. Male BALB/C mice (18−20 g Ministry-of-Education Key Laboratory for the Green
body weight) used in this experiment were ordered from The Animal Preparation and Application of Functional Materials, School
Hospital of Huazhong Agricultural University. The animal experiment of Materials Science & Engineering, Hubei University,
project was approved by the Animal Research Committee of Tongji
Wuhan 430062, People’s Republic of China
Medical College, Huazhong University of Science and Technology,
Wuhan, China. The experimental procedures were in accordance with Yue Luo − Biomedical Materials Engineering Research Center,
the Regulations on Animal Management of the Ministry of Health of Hubei Key Laboratory of Polymer Materials, Ministry-of-
the People’s Republic of China and the China Guide for the Care and Education Key Laboratory for the Green Preparation and
Use of Laboratory Animals. All mice were fed for 1 week before Application of Functional Materials, School of Materials
surgery and then divided randomly into four groups, including a Science & Engineering, Hubei University, Wuhan 430062,
control group, a 3M group, and material (4 Bi-PCN-222, 8 Bi-PCN- People’s Republic of China
222) groups. After anesthesia, wounds with a diameter of 6 mm were Chaofeng Wang − School of Health Science and Biomedical
created in each group, and 10 μL of S. aureus (2 × 107 CFU mL−1) Engineering, Hebei University of Technology, Tianjin
was dropped into mice wounds to build aninfection model. Then 50 300401, People’s Republic of China
μL of a sample (1 mg mL−1) was added to the wound surface for Shuilin Wu − School of Materials Science and Engineering,
therapy. After 2, 5, and 10 days, the injured tissues were photographed Peking University, Beijing 100871, People’s Republic of
and taken for histological analysis, Giemsa staining, and H&E China; orcid.org/0000-0002-1270-1870
staining. Besides, on the 10th day, the heart, liver, spleen, lung, and
kidney of mice were stained with Giemsa and H&E to assess the
Yufeng Zheng − School of Materials Science and Engineering,
biocompatibility of the materials on mice. Peking University, Beijing 100871, People’s Republic of
Statistics. All quantitative data in this work were assessed and China; orcid.org/0000-0002-7402-9979
analyzed by one-way or two-way ANOVA, and the data were shown Zhaoyang Li − School of Materials Science & Engineering, The
as mean ± standard deviation for n ≥ 3. Furthermore, when *p < Key Laboratory of Advanced Ceramics and Machining
0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001, statistical Technology by the Ministry of Education of China, Tianjin
significance was considered. University, Tianjin 300072, People’s Republic of China
1460 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Zhenduo Cui − School of Materials Science & Engineering, (6) Xu, H.; Huang, W. P.; Ren, K. F.; Tang, Y. M. Spraying Layer-
The Key Laboratory of Advanced Ceramics and Machining by-Layer Assembly of Tannin-Fe3+ and Polyethyleneimine for
Technology by the Ministry of Education of China, Tianjin Antibacterial Coating. Colloid Interface Sci. Commun. 2021, 42,
University, Tianjin 300072, People’s Republic of China 100422.
(7) Wang, S.; Fang, Y.; Zhang, Z.; Jin, Q.; Ji, J. Bacterial Infection
Yanqin Liang − School of Materials Science & Engineering,
Microenvironment Sensitive Prodrug Micelles with Enhanced Photo-
The Key Laboratory of Advanced Ceramics and Machining dynamic Activities for Infection Control. Colloid Interface Sci.
Technology by the Ministry of Education of China, Tianjin Commun. 2021, 40, 100354.
University, Tianjin 300072, People’s Republic of China; (8) Gao, L.; Zhuang, J.; Nie, L.; Zhang, J.; Zhang, Y.; Gu, N.; Wang,
orcid.org/0000-0001-6317-8314 T.; Feng, J.; Yang, D.; Perrett, S.; Yan, X. Intrinsic Peroxidase-Like
Shengli Zhu − School of Materials Science & Engineering, The Activity of Ferromagnetic Nanoparticles. Nat. Nanotechnol. 2007, 2,
Key Laboratory of Advanced Ceramics and Machining 577−583.
Technology by the Ministry of Education of China, Tianjin (9) Shan, J.; Li, X.; Yang, K.; Xiu, W.; Wen, Q.; Zhang, Y.; Yuwen,
University, Tianjin 300072, People’s Republic of China; L.; Weng, L.; Teng, Z.; Wang, L. Efficient Bacteria Killing by Cu2WS4
orcid.org/0000-0002-0190-2626 Nanocrystals with Enzyme-Like Properties and Bacteria-Binding
Jie Shen − Shenzhen Key Laboratory of Spine Surgery, Ability. ACS Nano 2019, 13, 13797−13808.
(10) Yin, W.; Yu, J.; Lv, F.; Yan, L.; Zheng, L. R.; Gu, Z.; Zhao, Y.
Department of Spine Surgery, Peking University Shenzhen
Functionalized Nano-MoS2 with Peroxidase Catalytic and Near-
Hospital, Shenzhen 516473, People’s Republic of China Infrared Photothermal Activities for Safe and Synergetic Wound
Complete contact information is available at: Antibacterial Applications. ACS Nano 2016, 10, 11000−11011.
https://pubs.acs.org/10.1021/acsnano.2c10203 (11) Wang, L.; Gao, F.; Wang, A.; Chen, X.; Li, H.; Zhang, X.;
Zheng, H.; Ji, R.; Li, B.; Yu, X.; Liu, J.; Gu, Z.; Chen, F.; Chen, C.
Author Contributions Defect-Rich Adhesive Molybdenum Disulfide/rGO Vertical Hetero-
structures with Enhanced Nanozyme Activity for Smart Bacterial
L.W. and T.L. are co-first authors. L.W., Y.L., and X.L. Killing Application. Adv. Mater. 2020, 32, 2005423.
conceived this project. L.W. synthesized the samples and (12) Natalio, F.; André, R.; Hartog, A. F.; Stoll, B.; Jochum, K. P.;
characterized them. L.W., Y.L., X.L., C.W., and S.W. analyzed Wever, R.; Tremel, W. Vanadium Pentoxide Nanoparticles Mimic
the data and cowrote the manuscript. Y.Z., Z.C., Y.L., S.Z., J.S., Vanadium Haloperoxidases and Thwart Biofilm Formation. Nat.
and Z.L. provided important experimental insights. All the Nanotechnol. 2012, 7, 530−535.
authors contributed to the discussion during the entire paper. (13) Ghosh, S.; Roy, P.; Karmodak, N.; Jemmis, E. D.; Mugesh, G.
Nanoisozymes: Crystal-Facet-Dependent Enzyme-Mimetic Activity of
Notes
V2O5 Nanomaterials. Angew. Chem., Int. Ed. 2018, 130, 4600−4605.
The authors declare no competing financial interest. (14) Shen, X.; Liu, W.; Gao, X.; Lu, Z.; Wu, X.; Gao, X. Mechanisms
of Oxidase and Superoxide Dismutation-Like Activities of Gold,
ACKNOWLEDGMENTS Silver, Platinum, and Palladium, and Their Alloys: A General Way to
the Activation of Molecular Oxygen. J. Am. Chem. Soc. 2015, 137,
This work was jointly supported by the National Natural 15882−15891.
Science Foundation of China (Nos. 52173251, 51871162, and (15) Long, R.; Mao, K.; Ye, X.; Yan, W.; Huang, Y.; Wang, J.; Fu, Y.;
82002303), the China National Funds for Distinguished Wang, X.; Wu, X.; Xie, Y.; Xiong, Y. Surface Facet of Palladium
Young Scientists (No. 51925104), NSFC-Guangdong Province Nanocrystals: A Key Parameter to the Activation of Molecular
Joint Program (Key Program No. U21A2084), the Central Oxygen for Organic Catalysis and Cancer Treatment. J. Am. Chem.
Guidance on Local Science and Technology Development Soc. 2013, 135, 3200−3207.
Fund of Hebei Province (226Z1303G), and the Guangdong (16) Tao, Y.; Ju, E.; Ren, J.; Qu, X. Bifunctionalized Mesoporous
Basic and Applied Basic Research Foundation Silica-Supported Gold Nanoparticles: Intrinsic Oxidase and Perox-
(2021A1515220093, 2022A1515011536). idase Catalytic Activities for Antibacterial Applications. Adv. Mater.
2015, 27, 1097−1104.
(17) Han, D.; Liu, X.; Wu, S. Metal Organic Frameworks Based
REFERENCES Antibacterial Agents and Their Underlying Mechanisms. Chem. Soc.
(1) Yan, X.; Yang, J.; Wu, J.; Su, H.; Sun, G.; Ni, Y.; Sun, W. Rev. 2022, 51, 7138−7169.
Antibacterial Carbon Dots/Iron Oxychloride Nanoplatform for (18) Yang, B.; Ding, L.; Yao, H.; Chen, Y.; Shi, J. A Metal-Organic
Chemodynamic and Photothermal Therapy. Colloid Interface Sci. Framework (MOF) Fenton Nanoagent-Enabled Nanocatalytic
Commun. 2021, 45, 100552. Cancer Therapy in Synergy with Autophagy Inhibition. Adv. Mater.
(2) Hou, X.; Zeng, H.; Chi, X.; Hu, X. Pathogen Receptor 2020, 32, 1907152.
Membrane-Coating Facet Structures Boost Nanomaterial Immune (19) Chen, Y.; Zhong, H.; Wang, J.; Wan, X.; Li, Y.; Pan, W.; Li, N.;
Escape and Antibacterial Performance. Nano Lett. 2021, 21, 9966− Tang, B. Correction: Catalase-Like Metal-Organic Framework
9975. Nanoparticles to Enhance Radiotherapy in Hypoxic Cancer and
(3) Zhang, Z.; Yan, H.; Qiu, B.; Ran, P.; Cao, W.; Jia, X.; Huang, K.; Prevent Cancer Recurrence. Chem. Sci. 2020, 11, 6098−6098.
Li, X. Persistent Luminescence-Based Theranostics for Real-Time (20) Gao, P.; Shi, M.; Wei, R.; Pan, W.; Liu, X.; Li, N.; Tang, B. A
Monitoring and Simultaneously Launching Photodynamic Therapy of Biomimetic MOF Nanoreactor Enables Synergistic Suppression of
Bacterial Infections. Small 2022, 18, 2200813. Intracellular Defense Systems for Augmented Tumor Ablation. Chem.
(4) Kasza, K.; Gurnani, P.; Hardie, K. R.; Camara, M.; Alexander, C. Commun. 2020, 56, 924−927.
Challenges and Solutions in Polymer Drug Delivery for Bacterial (21) Wang, Z.; Liu, B.; Sun, Q.; Dong, S.; Kuang, Y.; Dong, Y.; He,
Biofilm Treatment: A Tissue-by-Tissue Account. Adv. Drug Delivery F.; Gai, S.; Yang, P. Fusiform-Like Copper (II)-Based Metal-Organic
Rev. 2021, 178, 113973. Framework through Relief Hypoxia and GSH-Depletion Co-
(5) Zhou, L.; Zheng, H.; Liu, Z.; Wang, S.; Liu, Z.; Chen, F.; Zhang, Enhanced Starvation and Chemodynamic Synergetic Cancer Therapy.
H.; Kong, J.; Zhou, F.; Zhang, Q. Conductive Antibacterial ACS Appl. Mater. Interfaces 2020, 12, 17254−17267.
Hemostatic Multifunctional Scaffolds Based on Ti3C2Tx MXene (22) Cai, H. J.; Shen, T. T.; Zhang, J.; Shan, C. F.; Jia, J. G.; Li, X.;
Nanosheets for Promoting Multidrug-Resistant Bacteria-Infected Liu, W. S.; Tang, Y. A Core-Shell Metal-Organic-Framework (MOF)-
Wound Healing. ACS Nano 2021, 15, 2468−2480. Based Smart Nanocomposite for Efficient NIR/H2O2-Responsive

1461 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

Photodynamic Therapy Against Hypoxic Tumor Cells. J. Mater. (41) Wang, G.; Tang, K.; Meng, Z.; Liu, P.; Mo, S.; Mehrjou, B.;
Chem. B 2017, 5, 2390−2394. Wang, H.; Liu, X.; Wu, Z.; Chu, P. K. A Quantitative Bacteria
(23) Yin, S. Y.; Song, G.; Yang, Y.; Zhao, Y.; Wang, P.; Zhu, L. M.; Monitoring and Killing Platform Based on Electron Transfer from
Yin, X.; Zhang, X. B. Persistent Regulation of Tumor Microenviron- Bacteria to a Semiconductor. Adv. Mater. 2020, 32, 2003616.
ment via Circulating Catalysis of MnFe2O4@Metal-Organic Frame- (42) Chen, J.; Lin, S.; Zhao, D.; Guan, L.; Hu, Y.; Wang, Y.; Lin, K.;
works for Enhanced Photodynamic Therapy. Adv. Funct. Mater. 2019, Zhu, Y. Palladium Nanocrystals-Engineered Metal-Organic Frame-
29, 1901417. works for Enhanced Tumor Inhibition by Synergistic Hydrogen/
(24) Wang, X. S.; Zeng, J. Y.; Zhang, M. K.; Zeng, X.; Zhang, X. Z. A Photodynamic Therapy. Adv. Funct. Mater. 2021, 31, 2006853.
Versatile Pt-Based Core-Shell Nanoplatform as a Nanofactory for (43) Li, S.; Yang, Y.; Liu, L.; Zhao, Q. Electron Transfer-Induced
Enhanced Tumor Therapy. Adv. Funct. Mater. 2018, 28, 1801783. Catalytic Enhancement over Bi NPs Supported by N-Doped
(25) Xu, B.; Wang, H.; Wang, W.; Gao, L.; Li, S.; Pan, X.; Wang, H.; Graphene. Chem. Eng. J. 2018, 334, 1691−1698.
Yang, H.; Meng, X.; Wu, Q.; Zheng, L.; Chen, S.; Shi, X.; Fan, K.; (44) He, T.; Chen, S.; Ni, B.; Gong, Y.; Wu, Z.; Song, L.; Gu, L.; Hu,
Yan, X.; Liu, H. A Single-Atom Nanozyme for Wound Disinfection W.; Wang, X. Zirconium-Porphyrin-Based Metal-Organic Framework
Applications. Angew. Chem., Int. Ed. 2019, 58, 4911−4916. Hollow Nanotubes for Immobilization of Noble-Metal Single Atoms.
(26) Jiang, D.; Ni, D.; Rosenkrans, Z. T.; Huang, P.; Yan, X.; Cai, W. Angew. Chem., Int. Ed. 2018, 57, 3493−3498.
Nanozyme: New Horizons for Responsive Biomedical Applications. (45) Zhang, L.; Yang, C.; Lv, K.; Lu, Y.; Li, Q.; Wu, X.; Li, Y.; Li, X.;
Chem. Soc. Rev. 2019, 48, 3683−3704. Fan, J.; Li, M. SPR Effect of Bismuth Enhanced Visible Photo-
(27) Liu, Q.; Zhang, A.; Wang, R.; Zhang, Q.; Cui, D. A Review on reactivity of Bi2WO6 for NO Abatement. Chin. J. Catal. 2019, 40,
Metal-and Metal Oxide-Based Nanozymes: Properties, Mechanisms, 755−764.
and Applications. Nano-Micro Lett. 2021, 13, 154. (46) Ren, X.; Yang, S.; Yu, N.; Sharjeel, A.; Jiang, Q.; Macharia, D.
(28) Xu, X.; Wu, S.; Guo, D.; Niu, X. Construction of a Recyclable K.; Yan, H.; Lu, C.; Geng, P.; Chen, Z. Cell Membrane Camouflaged
Oxidase-Mimicking Fe3O4@ MnOx-Based Colorimetric Sensor Array Bismuth Nanoparticles for Targeted Photothermal Therapy of
for Quantifying and Identifying Chlorophenols. Anal. Chim. Acta Homotypic Tumors. J. Colloid Interface Sci. 2021, 591, 229−238.
2020, 1107, 203−212. (47) Qiu, J.; Li, S.; Su, X.; Wang, Y.; Xu, L.; Yuan, S.; Li, H.; Zhang,
(29) Lovley, D. R.; Coates, J. D.; Blunt-Harris, E. L.; Phillips, E. J. P.; S. Bismuth Nano-Spheres Encapsulated in Porous Carbon Network
Woodward, J. C. Humic Substances as Electron Acceptors for for Robust and Fast Sodium Storage. Chem. Eng. J. 2017, 320, 300−
Microbial Respiration. Nature 1996, 382, 445−448. 307.
(30) White, G. F.; Shi, Z.; Shi, L.; Clarke, T. A.; et al. Rapid Electron (48) Zhai, G.; Liu, Y.; Lei, L.; Wang, J.; Wang, Z.; Zheng, Z.; Wang,
Exchange Between Surface-Exposed Bacterial Cytochromes and Fe P.; Cheng, H.; Dai, Y.; Huang, B. Light-Promoted CO2 Conversion
(III) Minerals. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 6346−6351. from Epoxides to Cyclic Carbonates at Ambient Conditions over a Bi-
(31) Edwards, M. J.; White, G. F.; Lockwood, C. W.; Lawes, M. C.; Based Metal-Organic Framework. ACS Catal. 2021, 11, 1988−1994.
(49) Tan, Y.; Zhou, Y.; Deng, Y.; Tang, H.; Zou, H.; Xu, Y.; Li, J. A
Martel, A.; Harris, G.; Scott, D. J.; Richardson, D. J.; Butt, J. N.;
Novel UiO-66-NH2/Bi2WO6 Composite with Enhanced Pollutant
Clarke, T. A. Structural Modeling of an Outer Membrane Electron
Photodegradation through Interface Charge Transfer. Colloids Surf. A
Conduit from a Metal-Reducing Bacterium Suggests Electron
Physicochem. Eng. Aspects 2021, 622, 126699.
Transfer via Periplasmic Redox Partners. J. Biol. Chem. 2018, 293,
(50) Xia, Z.; Shi, B.; Zhu, W.; Lü, C. Temperature-Responsive
8103−8112.
Polymer-Tethered Zr-Porphyrin MOFs Encapsulated Carbon Dot
(32) Wang, G.; Feng, H.; Hu, L.; Jin, W.; Hao, Q.; Gao, A.; Peng, X.;
Nanohybrids with Boosted Visible-Light Photodegradation for
Li, W.; Wong, K. Y.; Wang, H.; Li, Z.; Chu, P. K. An Antibacterial
Organic Contaminants in Water. Chem. Eng. J. 2021, 426, 131794.
Platform Based on Capacitive Carbon-Doped TiO2 Nanotubes after (51) Dong, F.; Zhao, Z.; Sun, Y.; Zhang, Y.; Yan, S.; Wu, Z. An
Direct or Alternating Current Charging. Nat. Commun. 2018, 9, 2055. Advanced Semimetal-Organic Bi Spheres-g-C3N4 Nanohybrid with
(33) Edwards, M. J.; White, G. F.; Butt, J. N.; Richardson, D. J.; SPR-Enhanced Visible-Light Photocatalytic Performance for NO
Clarke, T. A. The Crystal Structure of a Biological Insulated Purification. Environ. Sci. Technol. 2015, 49, 12432−12440.
Transmembrane Molecular Wire. Cell 2020, 181, 665−673. (52) Da Silva, E. S.; Moura, N. M.; Neves, M. G. P.; Coutinho, A.;
(34) Chang, F.; Xie, Y.; Zhang, J.; Chen, J.; Li, C.; Wang, J.; Luo, J.; Prieto, M.; Silva, C. G.; Faria, J. L. Novel Hybrids of Graphitic
Denga, B.; Hu, X. Construction of Exfoliated g-C3N4 Nanosheets- Carbon Nitride Sensitized with Free-Base Meso-Tetrakis (Carbox-
BiOCl Hybrids with Enhanced Photocatalytic Performance. RSC Adv. yphenyl) Porphyrins for Efficient Visible Light Photocatalytic
2014, 4, 28519−28519. Hydrogen Production. Appl. Catal. B Environ. 2018, 221, 56−69.
(35) Zhang, X.; Ji, G.; Liu, Y.; Zhou, X.; Zhu, Y.; Shi, D.; Zhang, P.; (53) Sapawe, N.; Jalil, A. A.; Triwahyono, S.; Adam, S. H.; Jaafar, N.
Cao, X.; Wang, B. The Role of Sn in Enhancing the Visible-Light F.; Satar, M. A. H. Isomorphous Substitution of Zr in the Framework
Photocatalytic Activity of Hollow Hierarchical Microspheres of the of Aluminosilicate HY by an Electrochemical Method: Evaluation by
Bi/BiOBr Heterojunction. Phys. Chem. Chem. Phys. 2015, 17, 8078− Methylene Blue Decolorization. Appl. Catal. B Environ. 2012, 125,
8086. 311−323.
(36) Barillo, D. J.; Barillo, A. R.; Korn, S.; Lam, K.; Attar, P. S. The (54) Li, L.; Yu, X.; Xu, L.; Zhao, Y. Fabrication of a Novel Type
Antimicrobial Spectrum of Xeroform®. Burns 2017, 43, 1189−1194. Visible-Light-Driven Heterojunction Photocatalyst: Metal-Porphyr-
(37) Li, H.; Wang, R.; Sun, H. Systems Approaches for Unveiling the inic Metal Organic Framework Coupled with PW12/TiO2. Chem. Eng.
Mechanism of Action of Bismuth Drugs: New Medicinal Applications J. 2020, 386, 123955.
beyond Helicobacter Pylori Infection. Acc. Chem. Res. 2019, 52, 216− (55) Li, J.; Li, Z.; Liu, X.; Li, C.; Zheng, Y.; Yeung, K. W. K.; Cui, Z.;
227. Liang, Y.; Zhu, S.; Hu, W.; Qi, Y.; Zhang, T.; Wang, X.; Wu, S.
(38) Cao, C.; Ge, W.; Yin, J.; Yang, D.; Wang, W.; Song, X.; Hu, Y.; Interfacial Engineering of Bi2S3/Ti3C2Tx MXene Based on Work
Yin, J.; Dong, X. Mesoporous Silica Supported Silver-Bismuth Function for Rapid Photo-Excited Bacteria-Killing. Nat. Commun.
Nanoparticles as Photothermal Agents for Skin Infection Synergistic 2021, 12, 1224.
Antibacterial Therapy. Small 2020, 16, 2000436. (56) Liu, D.; Wang, J.; Bai, X.; Zong, R.; Zhu, Y. Self-Assembled
(39) Yu, Y.; Cheng, Y.; Tan, L.; Liu, X.; Li, Z.; Zheng, Y.; Wu, T.; PDINH Supramolecular System for Photocatalysis under Visible
Liang, Y.; Cui, Z.; Zhu, S.; Wu, S. Theory-Screened MOF-Based Light. Adv. Mater. 2016, 28, 7284−7290.
Single-Atom Catalysts for Facile and Effective Therapy of Biofilm- (57) Nel, A. E.; Mädler, L.; Velegol, D.; Xia, T.; Hoek, E.;
Induced Periodontitis. Chem. Eng. J. 2022, 431, 133279. Somasundaran, P.; Klaessig, F.; Castranova, V.; Thompson, M.
(40) Vanysek, P.Electrochemical Series. CRC Handbook of Chemistry Understanding Biophysicochemical Interactions at the Nano-Bio
and Physics; CRC Press: 2000; Vol. 8, pp 8−33. Interface. Nat. Mater. 2009, 8, 543−557.

1462 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463
ACS Nano www.acsnano.org Article

(58) Miller, K. P.; Wang, L.; Benicewicz, B. C.; Decho, A. W. Responsive Extracellular Matrix for Bone Engineering. ACS Nano
Inorganic Nanoparticles Engineered to Attack Bacteria. Chem. Soc. 2019, 13, 13581−13594.
Rev. 2015, 44, 7787−7807. (76) Li, M.; Liu, X.; Tan, L.; Cui, Z.; Yang, X.; Li, Z.; Zheng, Y.;
(59) Tabassum, N.; Kumar, D.; Verma, D.; Bohara, R. A.; Singh, M. Yeung, K. W. K.; Chu, P. K.; Wu, S. Noninvasive Rapid Bacteria-
P. Zirconium Oxide (ZrO2) Nanoparticles from Antibacterial Activity Killing and Acceleration of Wound Healing through Photothermal/
to Cytotoxicity: A Next-Generation of Multifunctional Nanoparticles. Photodynamic/Copper Ion Synergistic Action of a Hybrid Hydrogel.
Mater. Today Commun. 2021, 26, 102156. Biomater. Sci. 2018, 6, 2110−2121.
(60) Yadav, L. S. R.; Shilpa, B. M.; Suma, B. P.; Venkatesh, R.;
Nagaraju, G. Synergistic Effect of Photocatalytic, Antibacterial and
Electrochemical Activities on Biosynthesized Zirconium Oxide
Nanoparticles. Eur. Phys. J. Plus 2021, 136, 764.
(61) Godoy-Gallardo, M.; Eckhard, U.; Delgado, L. M.; de Roo
Puente, Y. J.; Hoyos-Nogués, M.; Gil, F. J.; Perez, R. A. Antibacterial
Approaches in Tissue Engineering Using Metal Ions and Nano-
particles: From Mechanisms to Applications. Bioact. Mater. 2021, 6,
4470−4490.
(62) Fang, G.; Li, W.; Shen, X.; Perez-Aguilar, J. M.; Chong, Y.; Gao,
X.; Chai, Z.; Chen, C.; Ge, C.; Zhou, R. Differential Pd-Nanocrystal
Facets Demonstrate Distinct Antibacterial Activity Against Gram-
Positive and Gram-Negative Bacteria. Nat. Commun. 2018, 9, 129.
(63) Hu, W. C.; Younis, M. R.; Zhou, Y.; Wang, C.; Xia, X. H. In
Situ Fabrication of Ultrasmall Gold Nanoparticles/2D MOFs Hybrid
as Nanozyme for Antibacterial Therapy. Small 2020, 16, 2000553.
(64) Liu, Y.; Cheng, Y.; Zhang, H.; Zhou, M.; Yu, Y.; Lin, S.; Jiang,
B.; Zhao, X.; Miao, L.; Wei, C. W.; Liu, Q.; Lin, Y. W.; Du, Y.; Butch,
C. J.; Wei, H. Integrated Cascade Nanozyme Catalyzes in Vivo ROS
Scavenging for Anti-Inflammatory Therapy. Sci. Adv. 2020, 6,
No. eabb2695.
(65) Vaccaro, A.; Dor, Y. K.; Nambara, K.; Pollina, E. A.; Lin, C.;
Greenberg, M. E.; Rogulja, D. Sleep Loss Can Cause Death through
Accumulation of Reactive Oxygen Species in the Gut. Cell 2020, 181,
1307−1328.
(66) Shi, L.; Squier, T. C.; Zachara, J. M.; Fredrickson, J. K.
Respiration of Metal (Hydr) Oxides by Shewanella and Geobacter: A
Key Role for Multihaem C-Type Cytochromes. Mol. Microbiol. 2007,
65, 12−20.
(67) Ross, D. E.; Flynn, J. M.; Baron, D. B.; Gralnick, J. A.; Bond, D. Recommended by ACS
R. Towards Electrosynthesis in Shewanella: Energetics of Reversing
the Mtr Pathway for Reductive Metabolism. PLoS One 2011, 6, Piezoelectric Metal–Organic Frameworks Based
No. e16649. Sonosensitizer for Enhanced Nanozyme Catalytic and
(68) Breuer, M.; Rosso, K. M.; Blumberger, J.; Butt, J. N. Multi- Sonodynamic Therapies
Haem Cytochromes in Shewanella oneidensis MR-1: Structures,
Functions and Opportunities. J. R. Soc. Interface 2015, 12, 20141117. Lihan Cai, Xiaojun Peng, et al.
(69) Li, B.; Tan, L.; Liu, X.; Li, Z.; Cui, Z.; Liang, Y.; Zhu, S.; Yang, APRIL 13, 2023

X.; Yeung, K. W. K.; Wu, S. Superimposed Surface Plasma Resonance ACS NANO READ
Effect Enhanced the Near-Infrared Photocatalytic Activity of Au@
Bi2WO6 Coating for Rapid Bacterial Killing. J. Hazard. Mater. 2019, Flower-like Nanozyme with Highly Porous Carbon Matrix
380, 120818. Induces Robust Oxidative Storm against Drug-Resistant
(70) Fu, J.; Zhu, W.; Liu, X.; Liang, C.; Zheng, Y.; Li, Z.; Liang, Y.; Cancer
Zheng, D.; Zhu, S.; Cui, Z.; Wu, S. Self-Activating Anti-Infection
Yuxin Xing, Jixi Zhang, et al.
Implant. Nat. Commun. 2021, 12, 6907.
MARCH 22, 2023
(71) Wang, X.; Su, K.; Tan, L.; Liu, X.; Cui, Z.; Jing, D.; Yang, X.;
ACS NANO READ
Liang, Y.; Li, Z.; Zhu, S.; Yeung, K. W. K.; Zheng, D.; Wu, S. Rapid
and Highly Effective Noninvasive Disinfection by Hybrid Ag/CS@
MnO2 Nanosheets Using Near-Infrared Light. ACS Appl. Mater. Aluminum Porphyrin-Based Ionic Porous Aromatic
Interfaces 2019, 11, 15014−15027. Frameworks Having High Surface Areas and Highly
(72) Kaila, V. R. I.; Wikström, M. Architecture of Bacterial Dispersed Dual-Function Sites for Boosting the Catalytic ...
Respiratory Chains. Nat. Rev. Mater. 2021, 19, 319−330. Min Chen, Rongchang Luo, et al.
(73) Li, Y.; Liu, X.; Tan, L.; Cui, Z.; Jing, D.; Yang, X.; Liang, Y.; Li, FEBRUARY 02, 2023
Z.; Zhu, S.; Zheng, Y.; Yeung, K. W. K.; Zheng, D.; Wang, X.; Wu, S. ACS APPLIED MATERIALS & INTERFACES READ
Eradicating Multidrug-Resistant Bacteria Rapidly Using a Multi
Functional g-C3N4@ Bi2S3 Nanorod Heterojunction with or without Structural Engineering of Ionic MOF@COF Heterointerface
Antibiotics. Adv. Funct. Mater. 2019, 29, 1900946. for Exciton-Boosting Sunlight-Driven Photocatalytic Filter
(74) Gilster, J.; Bacon, K.; Marlink, K.; Sheppard, B.; Deveney, C.;
Rutten, M. Bismuth Subsalicylate Increases Intracellular Ca2+, MAP- Yite Li, Zhigang Xie, et al.
Kinase Activity, and Cell Proliferation in Normal Human Gastric FEBRUARY 01, 2023

Mucous Epithelial Cells. Dig. Dis. Sci. 2004, 49, 370−378. ACS NANO READ
(75) Fu, J.; Liu, X.; Tan, L.; Cui, Z.; Zheng, Y.; Liang, Y.; Li, Z.; Zhu,
Get More Suggestions >
S.; Yeung, K. W. K.; Feng, X.; Wang, X.; Wu, S. Photoelectric-

1463 https://doi.org/10.1021/acsnano.2c10203
ACS Nano 2023, 17, 1448−1463