لخّصلي

4.Firstly, H2O2 assists in breaking the outer"protective shell" of the bacteria--the phospholipid bilayer of the cell membrane, which en- ters the interior of the bacteria and reacts with the internal biomolecules such as lipid bilayer, proteins and nucleic acids, destroying the structure of the bacteria and thus leading to their death. It is encouraging to note that the modi ed ZnO composites could generate ROS under the exci- tation of visible light that was not signi cantly harmful to humans. (ii) Release of Zn2th. As a cofactor for nearly 300 enzymes in living organisms [135], Zn2th has a speci c af nity for sulfur groups and inhibit glycolytic enzymes by oxidizing their thiol groups [136]. However, as the glycolytic reactions occur in the cytoplasm, the ROS produced at this time will open channels for Zn2th to cross the cell membrane of the bacteria, and could denature their internal proteins and disrupt proliferation. Zn2th also breaks electron transport, allowing disruption of cellular respiration. It should not be overlooked that the release of Zn2th, despite being syner- gistically bactericidal, can also lead to increased toxicity to normal cells. (iii) Endocytosis. Bacterial cell walls are negatively charged, and ZnO NPs can attach to the outer surface of bacteria by the electrostatic effect of Zn2th on negatively charged membranes. This phenomenon can change the resting potential of the cell membrane and induce depolarization of the cell membrane by blocking the Kth channels [137] presented in the cell membrane, which leads to loss of phospholipid bilayer integrity and leakage of intracellular components such as lipopolysaccharides and ATP from the cell, ultimately leading to cell death (Fig. 13). Interestingly, the researchers found that the loss of cell membrane integrity was the main reason for the antibactericidal effect of ZnO NP on E. coli [138]. Pad- mavathy et al. [139] discovered that the larger the surface area of ZnO, the higher the concentrations of surface oxygen species, and the smaller the particles, the greater the antibacterial activity, thus opening the door to"non-drug" therapy.In addition, Gupta et al. [152] prepared Fe3O4@ZnO core-shell nano- particles (Fe3O4@ZnO CSNPs) using a hydrothermal method that com- bined magnetothermal and bioimaging, and the photoluminescence spectrum showed a UV emission peak at 383 nm. To investigate the imaging properties, green and red uorescence of human cervical cancer cells (HeLa) were observed by confocal microscopy.Valenzuela et al. [141] reported that the ZnO-rGO photocatalytic coating showed excellent bactericidal ability against Gram-positive bacteria Staphylococcus aureus by the reduction of e-/hth pairs recombi- nation and the enhancement of?OH production by ZnO, which showed excellent bactericidal properties and high stability in preventing bacte- rial adhesion and transmission, making it a great prospect for surface antimicrobial functionalization.In this regard, Mahmood et al. [158]

successfully prepared ZnO/Cu2O composite lms by electrodeposition and constructed composite electrodes, and EIS and IV measurements showed the lowest electron mobility at the electrode/electrolyte inter- face, high current density of ZC2, and good stability of hydrolysis reac- tion.Raghupathi and colleagues [134] found that ZnO NPs produced more ROS and exhibited more antimicrobial activity under UV illumi- nation, the reason of which was mainly attributed to that the electron leaps inside the ZnO nanoparticles could generate photogenerated e- and hth, further generating ROS through in redox reactions.Biomedical field Zinc is an essential trace metal for normal growth, development and physiological functions of organisms. 12).4.1.4.1.1.4.1.2.4.1.3.4.3.

4. Application of ZnO in photocatalysis
   Based on the above research results, as researchers continue to develop
   new ways to modify ZnO, the defects of its wide energy band gap, fast
   carrier complexation and low visible light utilization have been improved.
   In this section, we present the applications of the modi ed ZnO in
   biomedical, environmental and other elds in the last years (Fig. 12).

4.1. Biomedical field
Zinc is an essential trace metal for normal growth, development and
physiological functions of organisms. ZnO has become one of the safe
drugs approved by the Food and Drug Administration (FDA) due to its
good biocompatibility and safety. Because of the wide band gap of ZnO, it
can only be excited by harmful and poorly tissue-penetrating UV light,
which is not conducive to the treatment and monitoring of deep-seated
diseases, thus limiting its use in the biomedical eld. Therefore, many
researchers have modi ed ZnO to explore its potential applications in the
antibacterial, anticancer, bioimaging, drug delivery, etc.

4.1.1. Field of antimicrobial
For a long time, diseases caused by bacterial infections have been a
serious threat to human health. ZnO nanomaterials have been widely
studied for their broad-spectrum antibacterial properties against Gram-positive and Gram-negative bacteria, as well as their outstanding
biocompatibility in the antibacterial eld. There is still some controversy
about the antibacterial mechanism of ZnO, and the main points accepted
by the public are as follows: (i) photocatalytic generation of ROS which is
a single-electron reduction product of oxygen, including O2‧–
,‧OH and
H2O2. Raghupathi and colleagues [134] found that ZnO NPs produced
more ROS and exhibited more antimicrobial activity under UV illumi-
nation, the reason of which was mainly attributed to that the electron
leaps inside the ZnO nanoparticles could generate photogenerated e– and
hþ, further generating ROS through in redox reactions. In fact, O2‧– and‧
OH cannot penetrate bacterial cell membranes due to their negative
charge, while peroxide ions easily penetrate cell membranes and induce cell death. Firstly, H2O2 assists in breaking the outer“protective shell” of
the bacteria—the phospholipid bilayer of the cell membrane, which en-
ters the interior of the bacteria and reacts with the internal biomolecules
such as lipid bilayer, proteins and nucleic acids, destroying the structure
of the bacteria and thus leading to their death. It is encouraging to note
that the modi ed ZnO composites could generate ROS under the exci-
tation of visible light that was not signi cantly harmful to humans. (ii)
Release of Zn2þ. As a cofactor for nearly 300 enzymes in living organisms
[135], Zn2þ has a speci c af nity for sulfur groups and inhibit glycolytic
enzymes by oxidizing their thiol groups [136]. However, as the glycolytic
reactions occur in the cytoplasm, the ROS produced at this time will open
channels for Zn2þ to cross the cell membrane of the bacteria, and could
denature their internal proteins and disrupt proliferation. Zn2þ also
breaks electron transport, allowing disruption of cellular respiration. It
should not be overlooked that the release of Zn2þ, despite being syner-
gistically bactericidal, can also lead to increased toxicity to normal cells.
(iii) Endocytosis. Bacterial cell walls are negatively charged, and ZnO
NPs can attach to the outer surface of bacteria by the electrostatic effect
of Zn2þ on negatively charged membranes. This phenomenon can change
the resting potential of the cell membrane and induce depolarization of
the cell membrane by blocking the Kþ channels [137] presented in the
cell membrane, which leads to loss of phospholipid bilayer integrity and
leakage of intracellular components such as lipopolysaccharides and ATP
from the cell, ultimately leading to cell death (Fig. 13). Interestingly, the
researchers found that the loss of cell membrane integrity was the main
reason for the antibactericidal effect of ZnO NP on E. coli [138]. Pad-
mavathy et al. [139] discovered that the larger the surface area of ZnO,
the higher the concentrations of surface oxygen species, and the smaller
the particles, the greater the antibacterial activity, thus opening the door
to“non-drug” therapy.
Valenzuela et al. [141] reported that the ZnO-rGO photocatalytic
coating showed excellent bactericidal ability against Gram-positive
bacteria Staphylococcus aureus by the reduction of e–/hþ pairs recombi-
nation and the enhancement of‧OH production by ZnO, which showed
excellent bactericidal properties and high stability in preventing bacte-
rial adhesion and transmission, making it a great prospect for surface
antimicrobial functionalization. Our group [142] also introduced C into
porous ZnO with high speci c surface area by microwave induction
method, which can break the limitation and only be excited by short
wavelength light sources that are harmful to the human body. C modi ed
ZnO could be excited by yellow light with higher biosafety, improving its
photocatalytic activity. It was veri ed that the ROS generated by the
modi ed ZnO could effectively degrade the pigments on the tooth sur-
face, providing a new strategy for tooth whitening and broadening its
application in the biomedical eld. Bitar et al. [143] reported the co-doping of ZnO with La3þ and Ce3þ using EDTA as a capping agent, and
the transmission of ZnO in the visible range was increased after doping.
The antibacterial ability was also measured using the agar well diffusion
method, as well as the improved Zn1-2xLaxCexO NPs showed excellent
antibacterial effects against Gram-negative and Gram-positive bacteria.
Diseases caused by fungal invasion have seriously threatened the lives
and health of more than one billion people around the world. Antibiotics
are prone to trigger the emergence of drug resistance, and the low anti-
bacterial rate of ordinary nano antibacterial materials cannot resist its
threat to people's health [5]. Medina-Ramírez et al. [144] used a
microwave-assisted solvothermal method to dope Cu2þ into the lattice of
ZnO to reduce the energy band gap, achieving better antibacterial ca-
pacity. Then, the authors deposited Ag on the surface to disrupt the
structure of the fungus, which could inhibit bio lm formation with high
antibacterial activity against airborne fungi, thus reducing the risk of
airborne fungi invading our lungs and causing infections.

4.1.2. Field of anti-cancer
Cancer threatens human health. The great potential shown by ZnO for
the treatment of cancer is based on three main points: (i) ZnO NPs can be
used as drug carriers after surface functionalization to deliver anti-tumor
drugs to tumor cells and thus kill them. ZnO NPs can be used as drug
carriers after surface functionalization to deliver anti-tumour molecules
(such as genes, proteins, visualisers, etc.) to the lesion sites and kill
tumour cells. (ii) Cancer cells do not follow the tricarboxylic acid (TCA)
energy production cycle [145]. They produce higher levels of lactate
through the glycolytic pathway, even under hypoxic conditions, and thus
exhibit weak acidity in their biological microenvironment. In contrast,
ZnO NPs, as an amphoteric oxide, can be stable under normal physio-
logical conditions (pH¼ 7.4), while tumor microacidic conditions
(pH¼ 6.8) can trigger the release of Zn2þ from the dissolved nano-
structures of ZnO NPs with speci c effects on tumor therapy. (iii) ZnO
NPs can generate ROS under photocatalysis to induce apoptosis in cancer cells by inducing lipid peroxidation, disrupting cell membrane structure,
protein denaturation and damaging DNA. The low toxicity of ZnO NPs
combined with these three advantages is often used in cancer diagnosis,
in vivo bioimaging, smart drug delivery and targeted cancer therapy
(Fig. 14) [146]. So far, the selective toxicity of ZnO NPs on cancer cells
remains highly controversial. ZnO-mediated photodynamic therapy
(PDT) has better biocompatibility, but the limited penetration of visible
light into biological tissues limits the application of PDT in super cial
tumors or combined with optical waveguide irradiation to treat deep but
palpable cancer tissues, thus limiting its anti-tumor application [147].
So far, due to poor light penetration, ZnO NPs have been less studied as
a photocatalyst for cancer therapy, and it was often used as a carrier for
tumor-targeted drug delivery in anticancer therapy. Han et al. [148]
constructed a combination therapy combining PDT and chemotherapy by
loading anticancer drugs into ZnO NPs, which showed stronger damage to
cancer cells in vitro cytotoxicity compared with single therapy. However, it
is worth considering that this delivery system does not avoid UV damage to
human skin, thus also limiting its application in vivo. Yang et al. [149]
reported an 808 nm near infrared (NIR)-mediated pH-sensitive nanoplat-
form (α-NaYbF4:Tm@CaF2:Nd@ZnO-PAA-DOX). The 808 nm NIR has
strong tissue penetration ability and good biocompatibility. Under its excitation, Yb3þ, Tm3þ and Nd3þ in core/shell nanoparticles emit UV light
to excite ZnO to produce ROS, which provides a new idea for photody-
namic therapy. In addition, in the trend of precision medicine, researchers
have combined ZnO NPs with imaging visualization modalities through
targeted drug delivery to cancer cells, providing new ideas for cancer
treatment, which will also be discussed in detail ZnO bioimaging section.

4.1.3. Bioimaging
Based on the requirements of precision medicine, bioimaging plays an
important role in the treatment and diagnosis of diseases.
Due to their intrinsic uorescence with exciton emission in the near-
UV, blue and green regions, as well as the high stability and low-cost,
ZnO NPs have great potential for bioimaging used. However, the
visible uorescence intensity of ZnO NPs is low due to the internal de-
fects of ZnO NPs. Based on the improvement methods mentioned above
for the inherent defects of ZnO, Hang et al. [150] prepared RE metal
erbium (Er)-doped ZnO/polyethylene glycol (PEG) nanoparticles by a
sol-gel method. The introduction of rare-earth metal Er distorted the ZnO
lattice and introduced more point defects, and the luminescence intensity
of the modi ed ZnO nanoparticles in the visible range was 631.6%
higher than that of bare ZnO NPs and exhibited good stability and biosafety, thus promising for cell imaging (Fig. 15A). Meanwhile, some
researchers have synthesized Au–ZnO nanocomposites by
metal-mediated redox reactions at room temperature, which showed
bright blue uorescent images in the nucleus and cytoplasm of
HEK293 cells, exhibiting the potential of bioimaging (Fig. 15B) [151]. In
addition, Gupta et al. [152] prepared Fe3O4@ZnO core-shell nano-
particles (Fe3O4@ZnO CSNPs) using a hydrothermal method that com-
bined magnetothermal and bioimaging, and the photoluminescence
spectrum showed a UV emission peak at 383 nm. To investigate the
imaging properties, green and red uorescence of human cervical cancer
cells (HeLa) were observed by confocal microscopy. The investigators
believe its great potential for magnetothermal therapy and bioimagin

4.2. Field of environment
The environmental pollution that needs to be solved in the world
mainly includes water pollution, air pollution and soil pollution. Photo-
catalytic materials have received widespread attention as they provide
potential shortages to global energy shortage and environmental degra-
dation [153]. As a typical photocatalyst, ZnO can generates the electrical
charge under light to produce oxidation radicals for the decomposition of
water organic matter. Being a pioneering material for treating the envi-
ronment, ZnO has overcome the inherent defect of rapid compounding
rate of photogenerated electrons and holes that hinders the degradation
ef ciency, as well as enhance its ef ciency in degrading pollutants under
visible light. Shim et al. [154] deposited Pd nanoparticles onto ZnO NW
by using atomic layer deposition in a precious metal deposition method,
interfering with the generation of hole and electron complexes to extend
the lifetime of the carriers generated by ZnO for enhanced photocatalytic
performance. The high photocatalytic activity leads to the production of
large amounts of ROS, causing high oxidative stress that can oxidize
organic pollutants and kill harmful microorganisms present in the water
(Fig. 16). The degradation rate of organic pollutant 4-chlorophenol by
Pd–ZnO NW photocatalyst for water treatment was signi cantl increased from 42.5% to 62.8%. For the strong greenhouse gas CH4, Li
[155] reported a new nanocomposite (AuFe–ZnO) loaded with dispersed
Au and Fe on ZnO. The ZnO semiconductor is excited by UV light irra-
diation to generate e– and hþ to reduce O2 to H2O2. The generated
photo-generated hþ could activate CH4 to form‧CH3, Au acts as a
co-catalyst to activate CH4, and the Fe2þ of AuFe–ZnO catalyzes the
Fenton-like reaction by activating H2O2 to form‧OH, followed by the
reaction with‧CH3 to produce CH3OH. The synergistic catalysis of Au, Fe
and ZnO improved the yield of CH3OH (1365 μmol g 1 h 1) and had a
selectivity of 90.7% for CH3OH, contributing to a new strategy for solving
greenhouse gases. In the eld of soil contamination, ZnO is mainly used
to detect urea by degrading organic contaminants in soil. Dhinasekaran
and colleagues [156] reported a facile electrochemical sensing platform
using CuO/ZnO and Fe2O3/ZnO nanocomposites modi ed with pencil
graphite electrodes. This platform is capable of ef ciently, economically
and accurately detecting low concentrations of urea in water and soil to
avoid diseases caused by urea contamination. Altogether, ZnO has shown
great potential in combating environmental pollution. 4.3. Other areas
In addition to its applications in the above elds, due to its inherent
excellent photocatalytic properties, ZnO is also used in solar cells, tran-
sistors, light-emitting devices, coatings, and other applications. With the
advancement of technology and the popularity of electronic devices, Lee
and his colleagues [157] designed a transparent electrode using
quasi-amorphous ZnO/Ag/ZnO with enhanced visible light absorption,
excellent transparent conductive electrode performance and mechanical
stability. ZnO/Cu2O heterojunctions have been widely used in solar cells
due to their ability to generate an electric eld at the interface between
n-type and p-type semiconductors, effectively hindering the
hþ/e-complex and increasing the number of charge carriers involved in
photochemical reactions, and their ability to absorb light extends from
the ultraviolet to the visible range. In this regard, Mahmood et al. [158]

successfully prepared ZnO/Cu2O composite lms by electrodeposition
and constructed composite electrodes, and EIS and IV measurements
showed the lowest electron mobility at the electrode/electrolyte inter-
face, high current density of ZC2, and good stability of hydrolysis reac-
tion. The researchers concluded that ZC2 composite lm was a more
pro cient and durable electrode for photoelectrochemical cells and had
potential for development and application in the eld of batteries.
Vasilopoulou and colleagues [159] did an interesting work by inserting a
pyrene-boron dipyridine donor-acceptor dye as a thin interlayer at the
photoactive layer/ZnO interface to inhibit the degradation reaction of
the non-fullerene acceptor induced by the photocatalytic activity of ZnO.
The pyrene-boron dipyridyl-based interlayer inhibited the direct contact
between the non-fullerene acceptor and ZnO, thus preventing the former
from being decomposed by ZnO under UV light irradiation, resulting in
enhanced photostability of the device. The surface work function and
surface energy of the ZnO lm were reduced, thus improving the power
conversion ef ciency of the cell, which reached 9.86% and 11.80% for
the fullerene-based and non-fullerene-based cells, respectively.
In recent years, scratch-resistant agents, UV absorbers, pigments and
air puri ers, as well as fungicides have been described as the four main
needs of coating ingredients [160]. ZnO has been added to the develop-
ment of coatings as a“candidate antimicrobial agents”. In general, effective
sterilization is achieved by the lipid peroxidation of ROS generated by
photocatalysis, the physical damage caused by sharp nanomaterials, the
adhesion of nanomaterials on the bacterial cell wall and the release of
metal ions. However, the highly soluble ZnO nanomaterials may release
toxic Zn2þ at concentrations above 0.2 μg mL 1, thus threatening people's
health, which is the current challenge for ZnO in coatings [161].

5. Conclusion and future outlook
   In summary, we highlight the advantages of ZnO as a photocatalyst
   and discuss the construction of ZnO with ef cient photocatalytic per-
   formance. Through strategies such as doping, noble metal deposition and
   narrow band gap semiconductor coupling, the electron transfer pathway
   is altered to provide more active sites to maximized the photogenerated
   electron-hole separation with optimal light utilization. Based on its
   excellent photocatalytic performance, it has prominent performance in
   degrading organic pollutants. Simultaneously, its excellent biocompati-
   bility has led to a potential application in the biomedical eld that being
   explored and shows great possibilities for development. However, it
   should not be overlooked that the ROS produced by ZnO under light
   conditions also has two sides. The moderate amount of ROS makes ZnO a
   powerful bactericide, but excessive ROS can damage normal cells and
   cause an in ammatory response, which needs to be tackled.
   Although a lot of research work has been done to improve the pho-
   tocatalytic performance of ZnO, there is still a need to continuously
   explore the improvement of the synthesis method of ZnO and the strategy
   of performance enhancement. Besides, the improvement of the utiliza-
   tion of sunlight remains the focus of building ef cient ZnO-based pho-
   tocatalysts to broaden the scope of application in future work. For the
   extensive applications of ZnO photodynamic therapy in the eld of bio-
   materials, it must be realized that the excitation light sources should be
   harmless to the human body with the characteristics of tissue penetra-
   tion, so as to meet the needs of precision medicine and improve the
   intelligent medical system. We also rmly believe that with the contin-
   uous exploration and improvement of ZnO, photo-responsive ZnO will
   broaden its application in more elds such as environment and public
   health with lower cost, better biosafety, simpler preparation and more
   accurate photocatalytic performance.