metals
Review
Nano-Biosensors Based on Noble Metal and Semiconductor
Materials: Emerging Trends and Future Prospects
Liya Feng 1 , Shujia Song 2 , Haonan Li 1 , Renjie He 1 , Shaowen Chen 2 , Jiali Wang 1 , Guo Zhao 2, *
and Xiande Zhao 3,4, *
Citation: Feng, L.; Song, S.; Li, H.;
He, R.; Chen, S.; Wang, J.; Zhao, G.;
Zhao, X. Nano-Biosensors Based on
Noble Metal and Semiconductor
Materials: Emerging Trends and
Future Prospects. Metals 2023, 13, 792.
https://doi.org/10.3390/
met13040792
Academic Editor: Damien Fabrègue
Received: 22 March 2023
Revised: 12 April 2023
Accepted: 13 April 2023
Published: 17 April 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Metals 2023, 13, 792. https://doi.org/10.3390/met13040792
1 College of Engineering, Nanjing Agricultural University, Nanjing 210031, China;
9203010104@stu.njau.edu.cn (L.F.); 9213010217@stu.njau.edu.cn (H.L.); 9223030123@stu.njau.edu.cn (R.H.);
9203010613@stu.njau.edu.cn (J.W.)
2 College of Artificial Intelligence, Nanjing Agricultural University, Nanjing 210031, China;
9203020822@stu.njau.edu.cn (S.S.); 2022819077@stu.njau.edu.cn (S.C.)
3 Key Laboratory of Agricultural Sensors, Ministry of Agriculture and Rural Affairs, Beijing 100097, China
4 Research Center of Intelligent Equipment, Beijing Academy of Agriculture and Forestry Sciences,
Beijing 100097, China
* Correspondence: zhaoguo@njau.edu.cn (G.Z.); zhaoxd@nercita.org.cn (X.Z.); Tel.: +86-025-58606624 (G.Z.)
Abstract: The aim of this review is to gather current researches into sensors based on noble metal
and semiconductor nanomaterials in biomedical detection and elucidate the basic principle and
applications of different sorts of semiconductor nanomaterials, i.e., metal oxide NPs, transition metal
dichalcogenides (TMDs), metal-organic frameworks (MOFs) and magnetic metal oxide (MMO) NPs.
Based on the classifications of nano-biosensors, they can be summarized as electrochemical nano-
biosensors, optical nano-biosensors, calorimetric nano-biosensors, and piezoelectric nano-biosensors,
wherein, electrochemical and optical nano-biosensors acting as most popular study objects are
focused on to excavate the great improvements in excellent sensitivity, selectivity and stability based
on fabrication techniques.
Keywords: nano-biosensor; noble metal and semiconductor materials; target analyte
1. Introduction
The boosting demands for accurately and sensitively detecting a variety of bio-
molecules at low or even trace concentrations provide an impetus for inventing advanced
and sophisticated sensors. Biosensors utilize specific interactions between biological recog-
nition elements (e.g., enzymes, antibodies, etc.) and target small molecules and are therefore
highly sensitive compared with traditional physicochemical sensors. By introducing nano-
materials decorated with polymers and biometric elements, the sensitivity, specificity,
stability, and interference resistance of the biosensor are further enhanced [1–3]. The bio-
metric elements can be divided into: some lower molecular weight molecules: uric acid,
urea; nucleic acids: DNA, RNA; protein: immunoglobulin, BSA; cells: cancer cells, bacteria,
and viruses [4]. Transducer is a signal conversion device that converts the interaction
between bio-sensitive elements and target analyte into different signals, such as biological
enzymes catalyzing chemical reactions of specific substances and converting them into
corresponding electrical signals. Bio-catalysis and bio-affinity are the two main types
of bio-detection according to the bio-recognition mechanism. Bio-catalysis refers to the
process of using enzymes or biological organisms (whole cells, organelles, tissues, etc.) as
catalysts for chemical transformation, while bio-affinity-based sensor uses bio-receptor to
bind with the target analyte [5]. Based on different transduction pathways, biosensors can
be classified as electrochemical, optical, and calorimetric biosensors.
In fact, advancements in nanobiotechnology can be largely attributed to new dis-
coveries and progress in the nanomaterials field [6]. Nanomaterials can be defined as
https://www.mdpi.com/journal/metals
Metals 2023, 13, 792 2 of 31

materials possessing, one external dimension measuring 1–100 nm at minimum. The

definition given by the European Commission demonstrates that the particle size of at
least half of the particles in the number size distribution must measure 100 nm or below.
The main characteristics of nanomaterials resulting from nanoscale dimensions can be
summarized as follows: high surface-to-volume ratio, quantum size effect, small-size effect,
surface and interface effects, quantum tunnel effect, and enhanced biological and chemical
activity [1,7,8].
This review mainly summarizes the advances in nano-biosensors based on noble
metal and semiconductor materials. Semiconductor nanomaterials include metallic oxides,
TMDs, MOFs, and MMONPs. Noble metal and semiconductor materials possess unique
optical, electrical, and biological properties, which have attracted significant attention
due to their potential use in many applications, such as bio-imaging, biological sensors,
and drug delivery [9–11]. The development and applications of nano-biosensors are of
great significance for timely prevention, accurate diagnosis, and effective treatments of
various diseases. The roles of noble metal and semiconductor nanomaterials in biosensors
mainly include increasing the changes in refractive index, accelerating electron transfer,
and improving the catalytic performance between chemiluminescence and substrates, thus
helping the accurate and even ultra-sensitive detection of neurotransmitters and specific
markers for diseases such as cancer and Alzheimer’s disease [12,13]. Gold NPs, silver NPs,
and platinum NPs are the most representative and popular noble metal NPs with good
biocompatibility, abundant surface modification properties, and unique optical properties,
i.e., Surface plasmon Resonance (SPR) and surface-enhanced Raman scatting (SERS), which
display unique properties in biomedical detection [14,15]. Metal oxides have a wide range
of applications in the biomedical fields. The methods used to synthesize metal oxide
nanomaterials are chemical, physical, and biosynthetic, such as chemical vapor deposition
(CVD), sol-gel, hydrothermal, and green deposition methods [16,17]. Since the beginning
of research on biosensors in 1954, metal oxides have been important candidates for sensor
applications. Titanium dioxide and zinc oxide as representative metal oxides have been
emphatically introduced due to their wide application in biosensors [18]. MMONPs are a
special type of nanomaterials, possessing superparamagnetism, biocompatibility, and low
toxicity, that can be well applied in the field of biomedicine [19,20]. Additionally, the current
usage and development of Fe3 O4 and Fe-based binary mixed metal oxides are introduced
in detail, and we stress on the summary of the drawbacks and limitations overcame
by MMONPs in biomedical applications. Apart from metal oxides, 2D transition metal
dichalcogenides (TMDs), in this review, i.e., MoS2 and WS2 , have received widespread
attention due to their graphene-like layered structure [21,22]. The use of MOFs and MOFs-
based nanomaterials in biomedical applications has been greatly explored owing to their
precision tunability, high surface areas, and high loading capacities, and they are highly
expected to be substitutes for conventional enzymes in enzymatic reactions, providing a
new direction for design and applications in biomedical fields [23,24].

2. Noble Metal Nanoparticles

2.1. Gold Nanoparticles
Gold nanoparticles (AuNPs) have good biocompatibility, abundant surface modifica-
tion properties, and unique optical properties, which are related to the surfactant, shape,
size, and structure of the nanoparticles [14]. AuNPs can be modified in covalent and non-
covalent ways [25]. Covalent modification is generally performed by sodium borohydride
reduction and ligand substitution. The surface of the nanoparticles can be easily chemi-
cally modified with functional group-containing ligands such as thiols, phosphines, and
amines [26]. For example, reducing chloroauric acid with silyl mercaptan as a protecting
agent in ethanol solution or encapsulating gold nanoparticles with thiopolyethylene glycol
may help the application in various fields of nucleic acids, proteins, and immunoassays.
The high surface free energy of gold nanoparticles allows them to adsorb surrounding
molecules through non-covalent interactions, reducing the surface free energy of surface
Metals 2023, 13, 792 3 of 31

ligand functional groups, thus allowing some other parts to attach, such as proteins, nucleic
acids, and antibodies to improve their properties [27]. Depending on their characteristics,
they can be used in various biomedical fields, such as medical testing, imaging and therapy,
photochemotherapy, photodynamic therapy, and photothermal therapy. For example, in
Tasneem’s research, they immobilized the Human epidermal growth factor receptor 2 on
the screen-printed electrode surface by electrostatic adsorption and modified with gold
nanoparticles (~20 nm in diameter) to support aptamer immobilization [28]. It took only
5 min binding time to receive a response and showed a log-linear response in a wide
concentration range.
Gold nanoparticles with surface plasmon resonance (SPR) phenomena are used in
the field of nucleic acid construction and analysis of protein detection [15]. SPR refers to
the resonance phenomenon that may occur when light forms an extinction wave into the
light sparse medium when the total reflection phenomenon occurs on the prism and metal
film surface, and a certain plasma wave exists in the medium when the two waves meet
based on the premise of energy conservation. They can convert the biological recognition
reflection into optical or electrical signals, so they have been combined with DNA, RNA, and
amino acids, which is very effective in the detection of nucleic acids and proteins [29–31].
Additionally, the detection method has many advantages, such as simplicity of operation,
good anti-oxidation, and biocompatibility. A number of colorimetric sensors have been
developed given that the shortening of the distance between AuNPs caused by the plasma
coupling of the surface between particles makes significant color changes in different
aggregation states and can be applied for visual inspection [32,33]. In a recent study, the
stochastic DNA dual-walkers for ultrafast colorimetric bacteria detection method was
proposed. The proposed method can detect bacteria sensitively and specifically within
15 min owing to its ultrafast reaction kinetics and color change mechanism, displaying a
linear response ranging from 100 to 105 CFU/mL with a limit of detection of 1 CFU/mL [34].
The sensitivity of SPR biosensors is proportional to the overlapping integral of the
modal electromagnetic field with the ambient medium [35]. As a result, appropriate surface
treatment in improving the performance of these sensors merits. Assembling low refractive
index materials (AuNPs) on the surface of high refractive index dielectric film materials
(graphene oxide, TiO2 , Al2 O3 , and other organic materials) plays an important part in
improving the sensitivity, resolution, and specificity of biosensors in detection [36,37]. As
shown in Figure 1, Zhu and coworkers developed a bio-nanonetwork by pyridinium por-
phyrin mediated calixarene-functionalized AuNPs composites (Apt/PyP-pSC4-AuNPs) act-
ing as an SPR signal amplification tag for the sensitive and rapid Brain Natriuretic Peptide
(BNP) assay [31], acting as a quantitative plasma biomarker in detecting the existence and
severity of heart failure. A wide linear concentration range (1–10,000 pg/mL (R2 = 0.9852))
and low limit of detection (0.3 pg/mL) were obtained. However, the enhanced sensitivity
of biosensors may bring about the problem of lack of reliability due to vulnerability from
spectral signal contaminations or other analytes. Therefore, some researchers were trying
to solve this problem with other optical phenomena. Surface-enhanced Raman scattering
(SERS) is a phenomenon in which the Raman signal of adsorbed molecules is enhanced
due to the enhancement of the electromagnetic field when molecules are adsorbed on
metal surfaces, which can be utilized to make the bio-detection process more sensitive and
easier. Recently, Song and coworkers proposed a novel SPR/SERS dual-mode plasmonic
biosensor based on a catalytic hairpin assembly (CHA)-induced AuNPs network aimed at
both high sensitivity and reliable detection of cancer-related miRNA-652 [38]. As depicted
in Figure 2, the proposed biosensor is composed of capture DNA-functionalized AuNPs
(Probe 1), H1 and 4-mercaptobenzoic acid (4-MBA) co-modified AuNPs (Probe 2), and
6-carboxyl-Xrhodamine (ROX)-labeled H2 (fuel strands). Then, the networks composed
of Probe 1–Probe 2 were formed via the target-triggered CHA reactions, thus resulting
in a color change in dark-field microscopy (DFM) images and an enhanced SERS effect.
Additionally, the SPR sensing mode can be achieved by extracting the integral optical
density of dark-field color in the DFM images.
 Then, the networks composed of Probe 1–Probe 2 were formed via the target-trigger
CHA reactions, thus resulting in a color change in dark-field microscopy (DFM) imag
Metals2023,
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13,792 an enhanced SERS effect. Additionally, the SPR sensing mode can be
REVIEW ofachieved
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extracting the integral optical density of dark-field color in the DFM images.

Then, the networks composed of Probe 1–Probe 2 were formed via the target-triggered
CHA reactions, thus resulting in a color change in dark-field microscopy (DFM) images
and an enhanced SERS effect. Additionally, the SPR sensing mode can be achieved by
extracting the integral optical density of dark-field color in the DFM images.

Figure 1. A schematic diagram of the bionanonetworks based on organic compounds and inorga
Figure 1. A schematic diagram of the bionanonetworks based on organic compounds and inorganic
nanoparticles asschematic
Figure 1. A
nanoparticles an SPR
as an SPRsignal
diagramamplification strategy
of the bionanonetworks
signal amplification strategy for BNP
based
for BNP detection
on organic
detection (Reprinted
compounds
(Reprinted with permiss
and inorganic
with permission
nanoparticles
from Ref. [32]. as an SPR2016,
Copyright signal Microchimica
amplification strategy
Acta).for BNP detection (Reprinted with permission
from Ref. [31]. Copyright 2016, Microchimica Acta).
from Ref. [32]. Copyright 2016, Microchimica Acta).

Figure2.2. Schematic
Figure Schematicdiagram
diagramofofSPR/SERS
SPR/SERS dual-mode
dual-mode plasmonic
plasmonic biosensor
biosensor based
based on
on CHA-induced
CHA-induced
AuNP network for the detection of miRNA-652. (a) Preparation of the Probe
AuNP network for the detection of miRNA-652. (a) Preparation of the Probe 1 and 1 and Probe 2. (b)
Probe 2.
SPR/SERS dual-mode sensing strategy based on the CHA-induced AuNP network (Reprinted
(b) SPR/SERS dual-mode sensing strategy based on the CHA-induced AuNP network (Reprinted with
permission from Ref. [39]. Copyright 2021, Elsevier).
with permission from Ref. [38]. Copyright 2021, Elsevier).
Figure 2. Schematic diagram of SPR/SERS dual-mode plasmonic biosensor based on CHA-induc
AuNP network for the detection of miRNA-652. (a) Preparation of the Probe 1 and Probe 2.
SPR/SERS dual-mode sensing strategy based on the CHA-induced AuNP network (Reprinted w
permission from Ref. [39]. Copyright 2021, Elsevier).
Metals 2023, 13, 792 5 of 31

At present, gold nanomaterials-modified biosensors have been widely used in bio-

analysis, environmental monitoring, medical diagnosis, and other fields. In Table 1, we
show some examples of the application of AuNPs. We need to make continuous efforts to
explore and optimize this technique to solve various problems encountered in practical
applications. First, the preparation methods of gold nanoparticles are usually small batches
or laboratory level, so more large-scale preparation methods need to be explored. This
is critical for translating AuNPs biosensors technology into realistic clinical applications.
Second, the sensitivity, specificity, and response speed of AuNPs biosensors need to be
further optimized to meet the requirements of more stringent and complex biomedical
detection. Last, gold nanomaterials themselves may have toxic effects on the human body,
so a comprehensive and in-depth evaluation of their biocompatibility and related safety
studies should be carried out when using AuNPs biosensors.

2.2. Silver Nanoparticles

Silver nanoparticles (NPs) are currently popular metal nanomaterials with wide ap-
plications in the biomedical field, including diagnostics [39], imaging [40], and drug de-
livery [41]. AgNPs are usually synthesized by reducing silver salts and adding polyvinyl
pyrrolidone (PVP) or citrate to improve the stability of AgNPs, thus benefiting their applica-
tions in biosensors [42]. AgNPs possess a large specific surface area, good catalytic activity,
and high conductivity. Moreover, AgNPs have the optical property of surface plasmon
resonance (SPR), which is helpful for Raman signal enhancement. The SPR of AgNPs can
produce electromagnetic field enhancement, thus benefiting biosensors detection by the
surface-enhanced Raman scatting (SERS) phenomenon [43]. Biosensors using AgNPs are
often used to detect glucose, cholesterol, dopamine, DNA and other substances via using
fluorescence, colorimetry, electrochemistry, and Raman spectroscopy.
Glucose detection is usually performed by oxidizing glucose to gluconic acid and hy-
drogen peroxide (H2 O2 ) and then calculating the glucose concentration by detecting the
amount of generated H2 O2 or the changed pH caused by gluconic acid. Prabha Sound-
haraj et al. synthesized a silica and silver (SiO2 -Ag) colloidal nanoparticles to detect
glucose [44]. During detection, the sample solution and SiO2 -Ag colloidal nanoparticles
were mixed and excited at 260 nm, and the fluorescence spectrum at 325 nm was recorded.
The fluorescence quenching during the detection process is shown in Figure 3. When the
excited SiO2 -Ag colloidal nanoparticles released fluorescence, part of the energy was
absorbed by biomolecules and then reduced the released fluorescence intensity. There-
fore, they can obtain the glucose concentration by reducing the fluorescence intensity.
The biosensor can efficiently detect glucose in human urine and serum, and eliminate
the interference of other biomolecules, which can meet clinical needs. In addition to
this direct detection method using SiO2 -Ag colloidal nanoparticles, methods for the
indirect detection of glucose have been developed. Wu et al. successfully established
a colorimetric biosensor to detect glucose in blood [45]. They deposited AgNPs on the
surface of MIL-101 (Fe) to form a peroxidase mimic. In the detection process, glucose
was oxidized to H2 O2 with glucose oxidase (GOx). Then they used AgNPs@MIL-101
(Fe) and H2 O2 to oxidize the colorless substance 3,30 ,5,50 -Tetramethylbenzidine (TMB),
turning it into blue product oxTMB. Finally, the concentration of glucose was calculated
by the change in absorbance of the product detected by UV-vis spectroscopy. The detec-
tion limit of the biosensor is 0.23 µM with a satisfying sensitivity in detecting glucose.
Compared with the direct detection method, the indirect detection method can detect
glucose more sensitively, and it can reduce the interference of other substances. However,
the biological enzymes used are greatly affected by the environment, which can be a new
area to explore for researchers.
2023, 13,Metals
x FOR PEER
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13, 792 6 of 31 6

Metals 2023, 13, x FOR PEER REVIEW 6 of 31

FigureFigure
3. Schematic
Figure diagram
3.3.Schematic
Schematic diagramfor
diagram forfluorescence
for quenching
fluorescence quenching
fluorescence quenching SiOin
in SiO
in SiO
22-Ag
-Ag 2-Ag colloidal
colloidal
colloidal nanoparticles
nanoparticles
nanoparticles with
with the
the wi
addition of biomolecules
addition
addition of (Reprinted
ofbiomolecules
biomolecules(Reprinted with
(Reprintedwith
with permission
permission
permission fromfrom
from Ref.
Ref. [44].
Ref. [45]. [45]. Copyright
Copyright
Copyright 2021, Elsevier
2021, Elsevier).
2021, Elsevier).

Most biosensors for cholesterol detection are combined with cholesterol oxidase
Most biosensors for cholesterol detection are combined with cholesterol oxidase
Most biosensors for
breakcholesterol detection are, and
combined with cholesterol ox
(ChOx). ChOx
(ChOx). ChOx can canbreak down
downcholesterol
cholesterolinto
intoH2H O22,Oand
2 thenthen
the concentration
the concentration of cho-
of
(ChOx). ChOxcancan
lesterol
cholesterol bebe
can break
obtaineddown
obtained cholesterol
bybydetecting
detecting the into H2O2, and
the concentration
concentration of
of Hthen
H22O the
Wu concentration
O22.. Wu et al. used
et al. used of
lesterol can be obtained
AgNPs@MIL-101
AgNPs@MIL-101 (Fe), which
(Fe), byisisdetecting
which used
usedasasthe the
theperoxidaseconcentration
peroxidase and substrate
and substrate ofSERS
of of H 2O 2.[46].
[47].
SERS Wu
As As et al.
de-
AgNPs@MIL-101
picted in Figure
depicted in
(Fe),
Figure 4,
which
4, they
they first
is used cholesterol
first oxidized
oxidized
as the peroxidase
cholesterol to H22O22with
to H O
and
with
substrate
ChOx,
ChOx, and thenof
and then
SERS [47]. A
colorless
colorless
leucomalachite green
leucomalachite green (LMG)
(LMG) with
with nono Raman
Raman activity
activity waswas oxidized
oxidized to to malachite
malachite green
green
picted(MG)
in Figure 4,combined
they first oxidized cholesterol to H 2O 2 with ChOx, and then colo
(MG) with the combined action of H22O22 and AgNPs@MIL-101 (Fe). Finally, they obtained
with the action of H O and AgNPs@MIL-101 (Fe). Finally, they obtained
leucomalachite
the greenof
the concentration
concentration of(LMG)
cholesterol
cholesterolwithfromno
from theRaman
the enhanced
enhanced activity was The
Ramansignal.
Raman signal. oxidized
The tolimit
detection
detection malachite
limit
of g
(MG) with
of the combined
AgNPs@MIL-101
AgNPs@MIL-101 action
(Fe)-based
(Fe)-based ofbiosensor
SERS
SERS Hbiosensor
2O2 and AgNPs@MIL-101
is
is 0.36 0.36
μM,µM, which
which (Fe).
enables
enables Finally,de-
ultra-sensitive
ultra-sensitive they obta
detection of cholesterol.
tection of cholesterol.
the concentration of cholesterol from the enhanced Raman signal. The detection lim
AgNPs@MIL-101 (Fe)-based SERS biosensor is 0.36 μM, which enables ultra-sensitiv
tection of cholesterol.

Figure 4.4. Illustration

Figure Illustrationofofthe
theAgNPs@MIL-101
AgNPs@MIL-101 (Fe)-based SERS
(Fe)-based biosensor
SERS to detect
biosensor cholesterol
to detect (Re-
cholesterol
printed with permission from Ref. [47]. Copyright 2022, Elsevier).
(Reprinted with permission from Ref. [46]. Copyright 2022, Elsevier).

Dopamine is a well-known neurotransmitter. The low content of dopamine in the

human body may lead to Alzheimer’s disease, depression and other diseases, while the
high concentration of dopamine may also lead to hypertension, nerve overexcitation, and
Figure other problems [48].
4. Illustration Therefore,
of the accurate and(Fe)-based
AgNPs@MIL-101 non-toxic detection of dopamine
SERS biosensor is an im-
to detect cholestero
portant research direction. Isa Anshori et al. reported a sensitive
printed with permission from Ref. [47]. Copyright 2022, Elsevier). biosensor that detected
dopamine in human urine [49]. As Figure 5 shows, they synthesized functionalized multi-
Metals 2023, 13, 792 7 of 31

Dopamine is a well-known neurotransmitter. The low content of dopamine in the

human body may lead to Alzheimer’s disease, depression and other diseases, while the high
concentration of dopamine may also lead to hypertension, nerve overexcitation, and other
problems [47]. Therefore, accurate and non-toxic detection of dopamine is an important
Metals 2023, 13, x FOR PEER REVIEW 7 of 31
research direction. Isa Anshori et al. reported a sensitive biosensor that detected dopamine
in human urine [48]. As Figure 5 shows, they synthesized functionalized multi-walled
carbon nanotubes (f-MWCNT) and AgNPs as biosensing materials modified on glassy
carbon electrodes
glassy carbon to detect
electrodes the concentration
to detect of dopamine
the concentration basedbased
of dopamine on differential pulse
on differential
voltammetry (DPV). The biosensor has good stability and high sensitivity with
pulse voltammetry (DPV). The biosensor has good stability and high sensitivity with a a minimum
detection
minimumlimit of 0.28limit
detection mM,ofwhich is farwhich
0.28 mM, loweristhan the normal
far lower dopamine
than the normal concentration
dopamine con-in
human urine and can be used in routine detection.
centration in human urine and can be used in routine detection.

Figure 5. Schematic illustration of the (f-MWCNT/AgNP) nanocomposites-modified electrode fab-

Figure 5. Schematic illustration of the (f-MWCNT/AgNP) nanocomposites-modified electrode
rication process (Reprinted with permission from Ref. [49]. Copyright 2021, Nanocomposites).
fabrication process (Reprinted with permission from Ref. [48]. Copyright 2021, Nanocomposites).
DNA detection
DNA detection hashas recently
recently become
become aa veryvery popular
popularresearch
researchdirection.
direction.During
Duringgene
gene
expression, DNA is transcribed and translated into proteins, which have
expression, DNA is transcribed and translated into proteins, which have different functions different func-
tionsshapes.
and and shapes. The process
The process of genes
of genes controlling
controlling traitstraits is mainly
is mainly divided
divided intointo
twotwo ways:
ways: one
one is by controlling the shapes of the proteins, and the other is by
is by controlling the shapes of the proteins, and the other is by synthesizing enzymes synthesizing enzymes
to control
to control metabolic
metabolic processes.
processes. Therefore,
Therefore,we wecancanstudy
studythetheprocess
processofofsome
somediseases
diseasesby by
detecting DNA,
detecting DNA, helping
helpingthe theprocess
processofofprevention
prevention andandefficient treatment.
efficient treatment.Kais Daoudi
Kais Daoudi et
al.al.
et synthesized
synthesized AgNPs/SiNPs
AgNPs/SiNPs hybrid
hybrid arrays thatthat
arrays can can
detect DNA
detect sensitively
DNA [50].[49].
sensitively The bi-
The
osensor utilized the SERS phenomenon to detect DNA, based on
biosensor utilized the SERS phenomenon to detect DNA, based on the fact that different the fact that different
Ramanpeaks
Raman peaks on on the Raman
the Raman spectrum spectrum
represent represent
different different kindsThe
kinds of DNA. ofAgNPs/SiNPs
DNA. The
AgNPs/SiNPs biosensor not only displays good stability and reproducibility,
biosensor not only displays good stability and reproducibility, but also performs but also ultra-
per-
forms ultra-sensitive detection ability of DNA with a satisfying
sensitive detection ability of DNA with a satisfying detection limit of 1.52 pg/L. detection limit of 1.52
pg/L.As far as the current research is concerned, biosensors using AgNPs are often used for
As far asofthe
the detection current
daily research
indicators, such is concerned, biosensorscholesterol
as glucose detection, using AgNPs are often
detection used
displayed
for the detection of daily indicators, such as glucose detection, cholesterol
in Table 1, and most of them can reduce the originally expensive detection costs. Moreover, detection dis-
played in Table 1, and most of them can reduce the originally expensive
other study committed to detecting some early signs of serious diseases helps a lot in detection costs.
Moreover,due
diagnosis other study
to the committed
sensitivity to detecting
in detecting some early
abnormal signs of serious diseases helps
indicators.
a lot in diagnosis due to the sensitivity in detecting abnormal indicators.

2.3. Platinum Nanoparticles

Platinum nanoparticles (NPs), which possess excellent biocompatibility, high specific
surface area, and excellent electrocatalytic performance, have been a hot metal nano-
material. Generally, PtNPs are synthesized with H2PtCl6 as the raw material, ethylene gly-
col as the solvent, NaOH as the reducing agent, and polyethylene pyrrolidone (PVP) as
Metals 2023, 13, 792 8 of 31

2.3. Platinum Nanoparticles

Platinum nanoparticles (NPs), which possess excellent biocompatibility, high specific
surface area, and excellent electrocatalytic performance, have been a hot metal nanomaterial.
Generally, PtNPs are synthesized with H2 PtCl6 as the raw material, ethylene glycol as
the solvent, NaOH as the reducing agent, and polyethylene pyrrolidone (PVP) as the
stabilizer [50]. In view of the strong strength of precious metals such as gold and silver
in biomedicine, people have also begun to study the applications of PtNPs in various
fields. In the field of treatment, compared with AuNPs and AgNPs, PtNPs have stronger
cytotoxicity [51]. Therefore, PtNPs are often used to treat cancer. At present, PtNPs have
been used in the targeted treatment of liver cancer [52]. In addition to treatment, PtNPs
also have many applications in biosensors. In the field of biosensors, most biosensors use
PtNPs to detect target analytes by electrochemical methods. PtNPs are a kind of special
metal nanoparticles with strong electrocatalytic activity for H2 O2 . During the detection
process, certain enzymes combined with PtNPs can oxidize the target analyte to H2 O2 and
other substances, and then PtNPs can promote the decomposition process of H2 O2 . Finally,
we can calculate the concentration of the target analyte by the current resulting from the
decomposition of H2 O2 . In this way, more sensitive and convenient detection of target
analytes can be achieved, and interference of most interfering substances can be prevented.
With the increasing number of patients with Alzheimer’s disease, an increasing num-
ber of studies have focused on the diagnosis and treatment of Alzheimer’s disease. Acetyl-
choline is an excitatory neurotransmitter that plays an important role in signal transmission
between neurons, so the decrease of acetylcholine content in the human body may lead to
Alzheimer’s disease. Therefore, detecting the content of acetylcholine in the human body
has become one of the diagnostic methods. N. Chauhan et al. constructed a biosensor using
dual-enzyme to detect acetylcholine [53]. As shown in Figure 6, they co-immobilized acetyl-
cholinesterase and choline oxidase on PtNPs and metallic organic frameworks to modify
Au electrode. During the detection process, acetylcholine was first oxidized to choline
by acetylcholinesterase, and then choline was oxidized to H2 O2 and other substances by
choline oxidase. Finally, H2 O2 was decomposed on the surface of the gold electrode. The
current generated during this process is linearly dependent on the concentration of acetyl-
choline. This biosensor helps a lot in the area of diagnosis and treatment of Alzheimer’s
disease.
Apart from this, Parkinson’s disease, which is a neurodegenerative disease similar
to Alzheimer’s disease, is related to the content of dopamine [54]. Dopamine, as an indis-
pensable part of the human brain nervous system, controls human mood and movement.
When the level of dopamine in the human brain decreases, he will be depressed and his
motor ability will decrease. Therefore, the detection of dopamine has also become an
important research direction. Jing Li et al. developed a non-enzyme biosensor for the
real-time detection of dopamine [55]. They first combined PtNPs onto f-MWCNT, and then
modified them on the screen-printed electrode (SPE). Finally, they successfully assembled a
convenient and sensitive biosensor. At the same time, the strong biocompatibility of PtNPs
enables the biosensor to avoid interference from other substances.
However, there are few studies on biosensors using PtNPs based on optical methods,
but optical methods are still a convenient and fast detection method that cannot be ignored.
Khan et al. reported a label-free electrochemical luminescence (ECL) biosensor [56]. The
PtNPs were deposited on the graphene oxide sheets and modified with luminol to produce
a strong ECL signal, and then the antibody of prostate-specific antigen (PSA) was attached
to the surface of PtNPs. They obtained a linear relationship between PSA content and
ECL reduction. The biosensor uses ECL to achieve the ultra-sensitive detection of PSA,
which has great clinical potential. As mentioned above, the optical method is indeed a
sensitive and convenient way to detect target analytes, which has lots of areas to develop
in biosensor using PtNPs.
 choline by acetylcholinesterase, and then choline was oxidized to H2O2 and other
stances by choline oxidase. Finally, H2O2 was decomposed on the surface of the gold
trode. The current generated during this process is linearly dependent on the conce
tion
Metals of13, acetylcholine.
2023, 792 This biosensor helps a lot in the area of diagnosis and
9 of treatme
31

Alzheimer’s disease.

Figure 6. Schematic Figure

illustration ofillustration
6. Schematic the AChE-ChO/PtNPs/MOF nano-composite
of the AChE-ChO/PtNPs/MOF nano-composite onto the onto
Au elec-the Au
trode and subsequent recognition of Ach (Reprinted with permission from Ref. [54]. Copyright
trode and subsequent recognition of Ach (Reprinted with permission from Ref. [53]. Copyright 2019,
Elsevier).
Elsevier).
In recent years, most biosensors have used PtNPs to detect target analytes via electro-
chemical methods. Subsequent research on PtNPs may continuously improve the detection
efficiency and sensitivity on the basis of electrochemistry. In Table 1, we list recent appli-
cations of PtNPs in biosensors. Apart from this, most biosensors using PtNPs are used
to detect conventional analytes. There is a lack of research on the detection of specific
biomolecules, which appear only when humans have a serious disease. This may be a
blank area to be filled by future research.
Metals 2023, 13, 792 10 of 31

Table 1. Metallic nanomaterials biosensors for biomedical applications.

Nanomaterial Detection Method LOD Linear Range Analyte Ref.

CdS-Au nanorod arrays ECL 0.6 ppb 1.0–12 ppb PSA [57]
Colorimetric
AuNP-based 3D track 1 CFU/mL 1–105 CFU/mL Staphylococcus aureus [34]
method
GO/AgNPs LSV 0.33 ppt 5–2 × 104 ppt PSA [58]
AgNPs modified gold
LSV 0.1 pM 0.1–100 pM p53 [59]
electrode
Colorimetric
AgNPs and ChOx 0.04 mM 0.1–1.5 mM cholesterol [60]
method
Ag/MoS2 CV and DPV 0.2 µM 0.2–50 µM dopamine [61]
0.46 µM 0.25–1.1 µM dopamine
GNR/AgNPs LSPR [62]
1.2 µM 1–75 µM glutathione
CNF-AgNPs UV-vis - 5–35 µM glucose [63]
AgNPs/CNF SWV 0.39 nM 0.1–10 nM bisphenol A [64]
GONRs/Ag@AuNPs CV 100 aM 100 aM−1 × 106 aM HPV-16 [65]
GC/PtNPs- Amperometric
0.88 µM 10–100 µM L-glutamic acid [66]
MWCNTs/PPy/GlUtOx measurement
UOx/BSA/BLG-
CA 0.8 µM 0.02–0.5 mM uric acid [67]
MWCNTs-PtNPs
Zn-MOF-74-rGO-
LSV 1.8 × 10−3 mM 0.006–6 mM glucose [68]
PtNPs-GOx
2.57 mM 5–3200 mM glucose
LSG/PBSE/PtNPs CV [69]
1.8 × 10−5 µM 5–480 mM uric acid
Amperometric
SOx/Naf/Pt/MTP/GCE 0.4 µM 1–71 µM sarcosine [70]
measurement

3. Metallic Oxide
3.1. TiO2
High surface-to-volume ratio and excellent biocompatibility of TiO2 make it easier to
fix with biometric elements such as TiO2 electrochemical enzyme biosensor. TiO2 NPs have
a strong ability to immobilize enzymes by forming chemical bonds with amino groups
and carboxyl groups of enzymes, thus fixing enzymes on the surface of TiO2 or inside
the nanostructure [71]. According to recent studies, glucose oxidase (GOx), d-amino acid
oxidase (DAAO) [72], thrombin [73], and dehydrogenase enzymes [74] can be easily fixed
by TiO2 , thus enhancing the ability of biosensors to analyze target analytes. Bhawna Batra
et al. proposed a method to immobilize cholesterol oxidase on TiO2 NPs and adsorb
them to a modified pencil graphite electrode to establish an amperometric biosensor to
detect cholesterol in the blood. Experiments displayed that the enzyme sensor responded
relatively quickly (2 s) with a wide linear range (3–10 mM), reproducibility, and strong
stability (4 months at 4 ◦ C) [75].
To date, researchers have extensively synthesized and reported a variety of nanomate-
rials, among which nano-hybrids have received widespread attention, and nanomaterials
are combined by hydrogen bonding, van der Waals forces, and electrostatic forces to obtain
hybrid materials aimed at enhancing properties benefiting for biomedical detection such as
electrical conductivity, stability and sensitivity [76,77]. In this review, discussions of TiO2
nanocomposite biosensors have been divided into TiO2 -organic sensors and TiO2 -inorganic
sensors.

3.1.1. TiO2 -Organic Nanocomposite

Most of the organic compounds of titanium dioxide composite are conductive poly-
mers, such as polyaniline, polypyrrole, and polythiophene. These organic materials are
associated with TiO2 for the effective diagnosis of biosensors. Table 2 lists the organic mate-
rials mixed with TiO2 . The composite of conductive polymer with TiO2 greatly changes the
electron transfer efficiency and shortens the reaction time. Hongin Jeong et al. synthesized
Metals 2023, 13, 792 11 of 31

high-purity TiO2 NPs in a hot plasma, deposited them directly on the matrix, and then
electrodeposited the conductive polymer chitosan-polypyrrole (CS-PPY) to construct a
non-enzymatic glucose sensor. As shown in Figure 7, FTO (fluorine-doped tin oxide-coated
glass slide) fixed with TiO2 NPs was added to the prepared reaction solution. A three-
electrode cell system was used to deposit the CS-PPY conductive polymer film on the
TiO2 layer with potentials ranging from −1 to +1.2 V (vs. Ag/AgCl) with a scan rate of
50 mV s−1 [78]. In addition, to overcome the limitations of traditional infectious disease de-
tection and achieve rapid, accurate, and low-cost detection of COVID-19, MA Sadique et al.
developed an electrochemical immunosensor based on chitosan-functionalized titanium
dioxide nanoparticles (TiO2 -CS nanocomposites) to detect severe acute respiratory syn-
dromecoronavirus2 (SARS-CoV-2). It can be seen from the electrochemical characterization
that the GCE/TiO2 -CS/Antigen/BSA electrochemical probe was successfully prepared for
the recognition of SARS-CoV-2 antibody. The sensor showed excellent performance with a
limit of detection of 3.42 ag mL−1 and a linear range from 50 ag mL−1 to 1 ng mL−1 [79].

Table 2. Summary of organic materials hybridized with TiO2 for biosensor applications.

Hybrid Material Detection Method Analyte LOD Ref.

TiO2 -CS DPV SARS-CoV-2 3.42 ag mL−1 [79]
MIPs-TiO2 -rGO CV and DPV and EIS TZR 0.21 µg/L [80]
PANI@TiO2 UV Xn 0.1 µM [81]
UA 0.2 nM
TiO2 /TiCT-NUF DPV [82]
Metals 2023, 13, x FOR PEER REVIEW DA 0.18 nM 11 of 31
LDH/Au-EVIMC-TiNTs-PANI ITO CV and EIS Lactate 1.65 × 10−7 M [83]

Figure 7.7. Schematic

Figure Schematic diagram
diagram of
of (a)
(a) aa three-electrode
three-electrode measuring
measuring system
system and
and (b)
(b) the
the preparing
preparing CS-
CS-
Py/TiO 2 nanocomposite films on FTO (Reprinted with permission from Ref. [79]. Copyright 2021,
Py/TiO2 nanocomposite films on FTO (Reprinted with permission from Ref. [78]. Copyright 2021,
Biosensors (Basel)).
Biosensors (Basel)).

3.1.2. TiO
3.1.2. TiO22-Inorganic
-Inorganic Nanocomposite
Nanocomposite
Au, Pt,
Au, Pt, Mn,
Mn, Cu
Cu and
and other
other noble
noble metals
metals and
and TiO
TiO22 composite
composite nanomaterials
nanomaterials havehave been
been
widelyused
widely usedinin biosensors
biosensors toto reduce
reduce the the recombination
recombination rate
rate ofof electrons
electrons and
and holes,
holes, enhanc-
enhanc-
ing the
ing the quantum
quantum yield
yield and
and conductivity
conductivity serving
serving for
for the
the expected
expected detection
detection sensitivity
sensitivity [85].
[84].
Table33summarizes
Table summarizesdifferent
differentnanostructures
nanostructuresof ofTiO
TiO22and
and their
their applications
applications in in biosensing
biosensing
in recent
in recent years.
years. Jiao
JiaoYang
Yangetetal.al.assembled
assembled gold nanorods
gold nanorods (AuNRs)
(AuNRs) thatthat
grow TiO2TiO
grow at both
2 at
endsends
both on the
onsurface of fluoride
the surface tin oxide
of fluoride (FTO)(FTO)
tin oxide electrodes
electrodesby hydrophobic
by hydrophobicactionaction
to formto
an optical
form microRNA-21
an optical microRNA-21biosensor modified
biosensor with carbon
modified with carbondots (CDs) as photosensitizers
dots (CDs) as photosen-
and dumbbell-like
sitizers heterostructures
and dumbbell-like (AuNRs(AuNRs
heterostructures @ end-TiO 2). Hairpin
@ end-TiO 2 ). probes
Hairpin(HPs) are(HPs)
probes fixed
on the electrode surface by Au-S bonds, then HPs were binded to miRNA to trigger dou-
are fixed on the electrode surface by Au-S bonds, then HPs were binded to miRNA to
ble-stranded specific nucleases in order to shear their complementary parts. The sheared
trigger double-stranded specific nucleases in order to shear their complementary parts.
HPs expose sequences complementary to the photosensitive probe cDNA and trap the
photosensitive probes to the electrode surface to increase the photocurrent, and the detec-
tion limit is 96 aM in the linear range of 0.1 fM~100 pM [86].
Graphene has been widely used in biosensors due to its unique physical properties,
 Metals 2023, 13, 792 12 of 31

The sheared HPs expose sequences complementary to the photosensitive probe cDNA and
trap the photosensitive probes to the electrode surface to increase the photocurrent, and
the detection limit is 96 aM in the linear range of 0.1 fM~100 pM [85].
Graphene has been widely used in biosensors due to its unique physical prop-
erties, high specific surface area and excellent electrical conductivity. Recently, TiO2 -
graphene biosensors have attracted widespread attention. Qi Yan Siewet et al. used
graphene/titanium dioxide (G/TiO2 ) nanocomposites modified screen-printed electrode
carbon electrodes to construct an electrochemical immunosensor for the detection of dengue
virus (DENV) IgG antibodies. Using dengue envelope domain III (EDIII) protein as the
antigen probe, the bilayer structure of G/TiO2 provides an excellent matrix for the fixation
of EDIII and directly promotes the transfer of electrons. This electrochemical immunosensor
exhibits high sensitivity for IgG detection with a detection limit of 5.2 ng/mL in the linear
range of 2.81 ng/mL to 62 µg/mL [86]. Figure 8 displays the step-by-step assembly of
the mentioned immune sensor. They first prepared functionalized PSE nanocomposites
to modify the electrodes. Subsequently, 5 µL of a diluted solution of EDIII was deposited
on each electrode and incubated at room temperature. Finally, 5 µL of diluted antibody
OR PEER REVIEW 12 of 31
solution was incubated on the working electrode for detection of target antibodies (DENV
1–4 IgG antibodies).

Figure 8. Schematic diagram

Figure for the
8. Schematic development
diagram of G/TiO2of
for the development /PSE-modified electrochemical
G/TiO2 /PSE-modified im-im-
electrochemical
munosensor for dengue detection
munosensor (Reprinted
for dengue with(Reprinted
detection permission
withfrom Ref. [87].
permission fromCopyright 2021, Else-
Ref. [86]. Copyright 2021,
vier). Elsevier).

Siraprapa Boobphahom et al. reported a new TiO2 sol/graphene-Lox electrochemi-

Table 3. Shows some TiO2-inorganics used in biosensor analysis.
cal sensor, which was decorated by 3D porous Ni foam coated with TiO2 sol/graphene
nanocomposites. Compared to the un-modified Ni foam electrode, the modification of
Hybrid Material Detection Method Analyte LOD Ref.
TiO2 sol/graphene greatly improves the sensitivity of the sensor to hydrogen peroxide.
Pt/TiO2 In addition, its stability
PEC is also enhanced,
ADA 0.019 UL
and it can effectively
−1 [89] in the
avoid interference
GQDs-TiO2 NTs PEC and glucose. Under
presence of dopamine DEHP 0.1 ng/L
optimal conditions, [90]of lactic
the linear range
acid is 50~10 mM and the detection limit is 19 µM [87].
AuNPs/g-C3N4@TiO2 PEC DNA 2.2 aM [91]
TiO2-NGO/Au@Pd CV HE4 13.33 fM [92]
Au-VG/TiO2 CV CA125 0.0001 mU∙mL−1 [93]
Metals 2023, 13, 792 13 of 31

Table 3. Shows some TiO2 -inorganics used in biosensor analysis.

Hybrid Material Detection Method Analyte LOD Ref.

Pt/TiO2 PEC ADA 0.019UL−1 [88]
GQDs-TiO2 NTs PEC DEHP 0.1 ng/L [89]
AuNPs/g-C3 N4 @TiO2 PEC DNA 2.2 aM [90]
TiO2 -NGO/Au@Pd CV HE4 13.33 fM [91]
Au-VG/TiO2 CV CA125 0.0001 mU·mL−1 [92]

3.2. ZnO
ZnO nanostructures (NSMs) due to their unique structure, in the field of biomedical
sensing attract abundant attentions. With the development of nanotechnology, ZnO crystals
can already synthesize approximately 10 types of ZnO NSMs in the field of growth, such as
nanowires [93], nanorods [94], nanoparticles [95], quantum dots [96] and thin films [97]. The
NSM and properties of ZnO crystals directly determine the immobilization of the detection
substance. Additionally, the biometric elements can be divided into: some lower molecular
weight molecules: uric acid, urea; nucleic acids: DNA, RNA; protein: immunoglobulin,
BSA; cells: cancer cells, bacteria, viruses. This section focuses on biosensors for the detection
of infectious diseases, small molecules and early cancer detection. Table 4 summarizes the
nanostructures of ZnO and their applications in biosensing in recent years. Figure 9 shows
SEM images of several nanostructures of ZnO.
The 1-D nanometer geometry has received much attention because it can guide charge
carriers during transmission such as nanorods and nanofibers. The 1-D nanometer has
been widely used in biosensors for the detection of infectious diseases and small molecules.
Ling Zhu et al. developed a new photoelectrochemical (PEC) immunodetection method to
detect prostate-specific antigen (PSA), which uses the ion exchange reaction between silver
ions and ZnO/CdS nanorods on the photosensitive electrode to generate ZnO/CdS/Ag2 S
nanohybrids, thus generating a strong photocurrent. PEC immunodetection has good
reproducibility and high specificity, and the detection limit is 0.018 ng within the specified
detection range of 0.05~50 ng mL−1 , which provides new perspectives on the detection
of other disease markers [98]. Fernanda L. Migliorini et al. proposed a biosensor for
the detection of urea, fabricated using polymeric electrospun nanofibers of polyamide
6 (PA6) and polypyrrole (PPY) deposited on a fluorine doped tin oxide (FTO) electrode.
Moreover, ZnO was used to modify the electrode. The FTO/PA6/PPY/ZnO/urease
modified electrode showed good performance with immobilized urease and high sensitivity
in the concentration range of 0.1~250 mg dL−1 with a detection limit of 0.011 mg dL−1 [99].
Early cancer diagnosis has always been a problem to be solved, however, available
diagnostic approaches cannot achieve both low cost and high analytical performance. To
address this, Thevendran Ramesh et al. developed an improved nano-biosensor based on
an interdigitated electrode (IDE) for biorecognition of Human Papillomavirus-16 (HPV-16)
infected cervical cancer cells by electrochemical impedance spectroscopy. The IDE was
coated with gold-doped zinc oxide nanorods and HPV-16 viral DNA bioreceptors. Due
to the improved sensitivity and biocompatibility of the designed nanohybrid film, Au
decorated ZnO-Nanorod biosensors showed good detection of the HPV-16 E6 oncogene
with a sensitivity as low as 1 fM [100].
Although ZnO nano-biosensors have been well developed in biosensing recently,
there are still many problems worth deeply studying. First, how to achieve efficient and
stable preparation of P-type ZnO nanomaterials is still a bottleneck problem. This requires
better control of defect self-compensation and improved solubility of acceptor dopant in
ZnO and understands the mechanism of p-type doping in ZnO. Second, how to further
improve the response and sensitivity of the sensor is still worth studying. Last, sensor
detection and identification are not the ultimate goal, and how to use the unique properties
of nanomaterials such as photoelectric characteristics, photodynamics and other treatments
of diseases, is worth further research.

Metals 2023, 13, 792
an interdigitated electrode (IDE) for biorecognition of Human Papilloma
16) infected cervical cancer cells by electrochemical impedance spectrosco
coated with gold-doped zinc oxide nanorods and HPV-16 viral DNA bior
the improved sensitivity and biocompatibility of the designed nanohybrid
rated ZnO-Nanorod biosensors showed good detection of the14HPV-16of 31 E6
a sensitivity as low as 1 fM [101].

Figure
Figure 9. SEM 9. images
SEM images of (a)(Reprinted
of (a) nanorods nanorods (Reprinted
with withRef.
permission from permission from
[94]. Copyright Ref. [95]
2018,
Elsevier); (b) nanobelts (Reprinted with permission from Ref. [102]. Copyrigh
Elsevier); (b) nanobelts (Reprinted with permission from Ref. [101]. Copyright 2017, Elsevier); FESEM

FESEM image of (c) nanosheets (Reprinted with permission from Ref. [103]. Cop
image of (c) nanosheets (Reprinted with permission from Ref. [102]. Copyright 2018, Elsevier);
FESEM images of deposited (d) ZnO NWs (Reprinted with permission from Ref. [103]. Copyright
vier);
2018, FESEM images of deposited (d) ZnO NWs (Reprinted with permission from
Elsevier).
yright 2018, Elsevier).
Table 4. Recent findings on ZnO nanostructures for the detection of biomolecules.
Table 4. Recent findings on ZnO nanostructures for the detection of biomolecules
Nanomaterial Structure Detection Method LOD Linear Range Analyte Ref.

Nanomaterial
Co3 O4 -ZnO Structure
nanorod CVDetection
and EIS Method
0.03 µM LODµM
0.05–50 Linear
aspartic acid Range
[104] An
NCDs@CuO/ZnO nanoflowers PEC 1.81 × 10−7 nM 10−6 –7.5 × 10−1 nM DNA [105]
Co3O 4-ZnO
ZnO/CNO nanorod
nano-onion CVCV and EIS - 0.03 μM
0.1–15 mM 0.05–50 μM
glucose [106] aspa
15 zM
–7.5 × 10[108]
MWCNT-ZnO nanofibers CV and EIS 5.368 zM 10–1 × 10 atrazine [107]
NCDs@CuO/ZnO
ZnO/MXene nanoflowers
nanoflakes CV PEC 17 µM 1.81 50–700
× 10 µM−7 nM 10glucose
−6 −1 nM D
ZnO/CNO
ZnO nanorods nano-onion
nanorod Amperometry CV 1 µM -- 0.1–15 mM
glucose [109] gl
Zn0.5 Cd0.5 nanoparticle PEC 0.22 pg/mL 1.0–10,000 pg/mL PSA [110]
MWCNT -ZnO
IGZO nanofibers
nanosheet FETCV and EIS0.0066 ng/mL 5.368 zM
0.01–1000 ng/mL 10 –1 × 1015[111]
cTnI zM atr
50–700 μM
CV, DPV and
ZnO/MXene
ZnO-g-Ru-C3 N4 nanoflakes
nanorods CV 3.5 × 10−6 mM
chronoamperometry 17 μM
2–28 mM glucose [112] gl
ZnO/ZnIn2 S4 nanorods PEC 0.03 ng/mL 0.1–100 ng/mL AFP [113]
Chit-ZnONP nanoparticles CV and EIS 1.34 fM 4.08 fM BCR/ABL [114]
Metals 2023, 13, 792 15 of 31

4. Magnetic Metal Oxide Nanoparticles

4.1. Magnetic Iron Oxide Nanoparticles
With the continuous development of nanotechnology, magnetic iron oxide nanoparti-
cles (MIONPs) have also begun to attract attention. MIONPs generally refer to Fe3 O4 and
γ-Fe2 O3 , which can be synthesized by coprecipitation and hydrothermal synthesis [115].
Normally, we hope MIONPs to combine with other substances to prevent them from
coalescing due to magnetism and oxidizing by oxygen because of their strong surface activ-
ity [116]. In the process of modification, not only can the original properties of MIONPs
be maintained, but other functions can also be added by using the modifier. They have
the advantages of flexible structure, small size, low toxicity, easy synthesis, similar activity
to biological enzymes, superparamagnetism and biocompatibility. Thus, they have broad
prospects in biosensors [117].
Electrochemical biosensor is a very common sensor, which has the advantages of high
sensitivity, simple operation, stable operation and strong selectivity. Thus, MIONPs are
often combined with electrochemical detection methods to attain satisfying catalytic activity,
superparamagnetism and biocompatibility to achieve the detection of different analytes.
Lincai Peng et al. reported a glucose biosensor modified with chitosan, β-cyclodextrin and
MWCNTs on spherical Fe3 O4 [118]. Unlike using GOx to detect glucose, they established
a direct electron transfer (DET) between the enzyme and the electrode. Normally, DET is
difficult to be established because the redox center of the enzyme is located in the center
of the enzyme, but the addition of Fe3 O4 can promote the electron transfer between the
enzyme and the electrode, thus helping to establish DET. The biosensor can achieve ultra-
sensitive detection of glucose concentrations ranging from 40 µM to 1.04 mM with excellent
reproducibility and stability.
MIONPs are also used in optical biosensors due to their small size effect and optical
characteristics such as SPR, which can be well combined with optical detection methods.
The surface that is easy to modify and the magnetic properties of MIONPs also facilitate
the detection. The main methods used in optical biosensors are colorimetry, fluorescence
detection, SPR technology and SERS phenomenon. Xiaoyu Qi et al. assembled a biosensor
based on the SERS phenomenon with Teicoplanin (Tcp) functionalized gold coated Fe3 O4 as
a capture probe and oligonucleotide (Apt) functionalized silver coated gold nanoparticles
as a signal probe [119]. Tcp can recognize gram-positive bacteria and Apt can specifically
capture Staphylococcus aureus. Therefore, as a gram-positive bacterium, Staphylococcus
aureus can be easily detected by the biosensor. During the detection process, when the
capture probe and signal probe are connected with pieces of Staphylococcus aureus, a
sandwich structure is formed, which can largely improve the Raman signal. This biosensor
can be used to detect other analytes by changing the capture probe and signal probe as
well.
The enzyme activity of MIONPs can be applied to construct nano-enzyme biosensors.
However, because it is impossible to detect signals only by enzyme activity, nano-enzyme
biosensors are often combined with electrochemical and optical methods. Yudum Tepeli
Buyuksunetci et al. developed a colorimetric sensor for detecting SARS-CoV-2 based on
γ-Fe2 O3 as a peroxidase [120]. Due to the existence of the S-protein on the surface of
SARS-CoV-2, it can interact with angiotensin-converting enzyme 2 (ACE2). During the
test, γ-Fe2 O3 first oxidized colorless TMB to blue oxTMB, and then ACE2 and the test
sample were added. If there is S-protein in the sample, the solution will become colorless,
otherwise it will not change. This biosensor realizes the rapid and accurate detection of
SARS-CoV-2, and can be used to make a kit for routine detection.
A variety of detection methods have enriched the application of MIONPs in biosensors.
In addition to the detection of conventional analytes, biosensors of MIONPs can carry out
ultra-sensitive detection of specific biological molecules of major diseases such as cancer,
providing convenience for the diagnosis of cancer. Preeyanut Butmee et al. reported a
biosensor for the detection of carcinoembryonic antigen [121]. Carcinoembryonic antigen
(CEA) is one of the most important biomarkers in clinical cancer, and it is associated with a
Metals 2023, 13, 792 16 of 31

variety of cancers. Core-shell Fe3 O4 @Au was used to immobilize CEA antibody and MnO2
modified graphene nanosheets were used to enhance the electrocatalytic activity. Finally,
they modified the composite material onto the screen-printed carbon electrode. During
detection, CEA was first bound to the antibody on the electrode surface. They can obtain
the concentration of CEA by comparing the signal response in the [Fe(CN)6 ]3−/4− redox
process before and after interaction with CEA. Fe3 O4 @Au unique magnetism can be good
at adsorbing CEA antibody to achieve sensitive detection of CEA.
As far as the current research is concerned, MIONPs are mostly used in electrochemical
biosensors and nano-enzyme biosensors, while optical biosensors are less studied. However,
convenient and fast optical detection methods still have great development space. Table 5
displays some biosensors using MIONPs, which can be used as a reference for research
achievements in recent years. In the future, there may be more research on different shapes
of MIONPs. Moreover, the unique properties of MIONPs could also be useful in detecting
specific biomolecules for major diseases.

Table 5. Magnetic metal oxide nanoparticles biosensors for biomedical applications.

Nanomaterial Detection Method LOD Linear Range Analyte Ref.

CDs-Fe3 O4 @PDA fluorescence method 7.6 × 104 nM 0.5–100 nM miRNA-167 [122]
Fe3 O4 nanoring ULF-NMR 10 ppb - calreticulin [123]
Fe3 O4 /ITO CV 4.3 × 10−14 M 10−5 –10−14 M methotrexate [124]
CH-Fe3 O4 NPs CV 0.4 ppm 4–1200 ppm urea/glucose [125]
Urease-CH-Fe3 O4 NPs CA - 0.1–80 mM urea [126]
0.10 µM 1–150 µM GSH
Fe3 O4 /Au NPs SERS [127]
0.08 µM 1–100 µM cholesterol
Polydopamine@Fe3 O4 DPASV 0.11 nM 0.5–400 nM diclofenac [128]
γ-Fe2 O3 /CeO2 -PDI fluorescence method 0.45 µM 0.5–5 µM Vitamin C [129]

4.2. Magnetic Transition Metal Ferrites (MFe2 O4 , M = Co, Ni, etc.)

CoFe2 O4 nanomaterials, as a representative member of magnetic transition metal fer-
rites, have a sharp stone type crystal structure. Owing to a large magneto-optical deflection
angle in the visible light region, stable chemical properties, mild saturation magnetiza-
tion field and large coercivity making CoFe2 O4 fascinating materials [130,131]. Moreover,
benefiting from high coercivity property, CoFe2 O4 nanomaterials displayed improved cell
separation properties without influencing the iron oxides properties. Compared with the
undesirable low purity cell separation between hemoglobin and the iron atoms in Fe3 O4 ,
CoFe2 O4 nanomaterials are hoped to overcome the defects in Fe3 O4 via strong Co-Fe
interactions [132]. Additionally, due to their high saturation magnetization strength and
magnetic anisotropy, CoFe2 O4 nanomaterials are highly expected to be used in magnetic
resonance imaging, magnetothermal therapy and other medical fields. Proper coating and
modification on the surface of CoFe2 O4 nanomaterials can increase their biocompatibility.
However, for NiFe2 O4 and MgFe2 O4 nanomaterials, though relevant researches in verifying
the biomedical activity and antibacterial activity have been performed, studies using them
in biodetection are still a blank area that needs to be explored [133,134].
The advantages of utilizing magnetic nanomaterials in biosensing include but are not
limited to a high surface-to-volume ratio benefiting the detection limit due to more binding
sites for cells, dynamic interactions owing to the magnetic nanomaterials improving the
capability of binding cells and a decline in the possibility of cell solution pollution via
magnetic separation, in Vajhadin’s study, i.e., decreasing the electrode biofouling with blood
matrix and even impeding false positive responses via cell separation. In Vajhadin’s work,
they demonstrated CoFe2 O4 @Ag magnetic nanohybrids combined with the HB5 aptamer
using a Mxene-based cytosensor for the electrochemical detection of HER2-positive cancer
cells, where the HB5 aptamer possessing electrostatic interactions with HER-2 positive cells
was immobilized on the MXene layers (2 nm thickness and 1.5 µm lateral size), as depicted
in Figure 10 [135]. Then, HER-2 positive circulating tumor cells were sensitively and
tamer using a Mxene-based cytosensor for the electrochemical detection of HER2-positive
cancer cells, where the HB5 aptamer possessing electrostatic interactions with HER-2 pos-
itive cells was immobilized on the MXene layers (2 nm thickness and 1.5 μm lateral size),
as depicted in Figure 10 [136]. Then, HER-2 positive circulating tumor cells were sensi-
tively and efficiently detected via cell isolation instead of cell capture using CoFe2O4@Ag
Metals 2023, 13, 792 17 of 31

magnetic nanohybrids combined with the HB5 aptamer, and a rather wide detection lin-
ear range of 102–106 cells/mL and low
efficiently detected viadetection
cell isolationlimit
instead(47 cells/mL)
of cell wereCoFe
capture using attained.
2 O4 @Ag magnetic
In Xu’s work, near-infrared (NIR) fluorescent quantum dots (QDs), i.e.,linear
nanohybrids combined with the HB5 aptamer, and a rather wide detection Ag2SrangeQDs of
102–106 cells/mL and low detection limit (47 cells/mL) were attained.
doped with CoFe2O4 nanomaterials
In Xu’s work,were proposed
near-infrared (NIR) as a new method
fluorescent quantum dotsto detect and
(QDs), i.e., Agimage
2 S QDs
Cry1Ab, which is widely dopedknown as 2aOmember
with CoFe 4 of
nanomaterials Bacillus
were thuringiensis
proposed as a new in
methodgenetically
to detect andmod-
image
ified crops [137]. In vitro, the enhanced fluorescence intensity consistent with the Lang-
Cry1Ab, which is widely known as a member of Bacillus thuringiensis in genetically
modified crops [136]. In vitro, the enhanced fluorescence intensity consistent with the
muir binding isothermLangmuir
equation in the
binding range
isotherm of 0–200
equation in theng/mL
range ofof Cry1Ab
0–200 ng/mL proteins with a
of Cry1Ab proteins
low detection limit of with
0.2 ang/mL. In vivo
low detection imaging
limit of 0.2 ng/mL. was benefited
In vivo imaging wasfrom the extended
benefited fluo-
from the extended
rescence wavelength to the second NIR. The innovation breakthrough lies in this study
fluorescence wavelength to the second NIR. The innovation breakthrough lies in this
study lies in the available technique for the sensitive direct visual detection method
lies in the available technique
of Cry1Ab forboththe sensitive
in vitro and vivo, direct visual detection
thus providing methodforofbiomedical
potential prospects Cry1Ab
both in vitro and vivo, thus providing potential prospects for biomedical applications.
applications.

Figure 10. Schematic illustration of an MXene-based

Figure 10. Schematic illustration of an cytosensor for the detection
MXene-based cytosensor of SK-BR-3
for the detection of SK-BR-3cells:
cells:
(a) Magnetic cell isolation
(a)using
MagneticCoFe 2O4@Ag-HB5,
cell isolation using CoFe(b)O
2 4 Electrochemical
@Ag-HB5, (b) cell detection
Electrochemical cell on
detection a
on function-
a functional-
alized MXene-based surface (Reprintedsurface
ized MXene-based with(Reprinted
permission from Ref.from
with permission [138].
Ref. Copyright
[137]. Copyright 2022,
2022,Elsevier).
Elsevier).

5. Metallic Sulfide
5.1. MoS2
With the rapid development of nanotechnology, 2D transition metal dichalcogenides
have received widespread attention, including compounds that can form stable two-
dimensional structures, including metals, semiconductors, and superconductors. As a
graphene-like layered structure, it has a wide range of research prospects in biomedical
fields because of its unique bandgap structure and photoelectric properties, as depicted in
Figure 11. Among them, nanosheets are one of the materials with the best-known opto-
electronic performance of two-dimensional semiconductors. Due to its atomic-level thin
planar structure, large surface area, rather low band gap (1.8 eV), good biocompatibility
and excellent catalytic performance, MoS2 has higher sensitivity than graphene and has
been widely used in biosensors.
Metals 2023, 13, 792 18 of 31

In the past 5 years, the research team has developed a number of new biosensors with
good biometric capabilities based on MoS2 (Table 5). Siyuan Wu et al. developed a new
PEC biosensor with MoS2 nanosheets for sensitive glucose detection. With the help of
C3 N4 sacrificial template, ultra-thin MoS2 nanosheets with high PEC performance were
generated by thermal decomposition to form a three-dimensional porous skeleton. The
three-dimensional porous structure has a uniform porous distribution and a large surface
area, which is conducive to the fixation of glucose oxidase. As a photocatalytic material,
ultrathin MoS2 nanosheets have good photocatalytic activity against glucose in neutral
buffer, and their detection limit is 0.61 nM, which is much lower than the detection limit of
similar structures previously reported [138].
However, enzymes may fall off during fixation and are affected by ambient tempera-
ture and pH. Therefore, researchers began to use noble metals, metal oxides and alloys, etc.,
as catalytic materials instead of biological enzymes immobilized on the electrode surface.
The surface defects of MoS2 nanosheets affect their electrocatalytic properties, so the devel-
opment of new biosensors should be combined with a variety of high-quality materials,
which is difficult to meet with a single material. MoS2 nanosheets have a high degree of
anisotropy and unique crystal structure and can be easily functionalized by modifying
their surface with chemical and physical methods, showing good biocompatibility and
providing a basis for the development of composite materials [139]. For example, some
researchers found that the synergistic effect of MoS2 nanosheets and Au nanoparticles is the
fundamental reason for promoting the enhancement of electrocatalytic activity. Li, F. et al.
used MoS2 /Au NPs as substrate-modified naked glassy carbon electrodes to construct
novel ultrasensitive sandwich-type electrochemical immunosensors, and cuprous oxide
decorated with titanium dioxide octahedral composites composite (Cu2 O@TiO2 -NH2 ) were
prepared to load platinum-copper nanoparticles (Pt-Cu NPs). Under optimal conditions,
the immunosensor is in the linear range of 0.1~100 ng/mL, and the minimum detection
limit is 0.024 pg/mL [137].
Recently, biosensors based on MoS2 nanosheets for early cancer diagnosis have at-
tracted much attention. Karaman, C. et al. used AuNPs modified molybdenum disulfide
and reduced graphene oxide (AuNPs@MoS2 /rGO) as the electrode platform and CoFe2 O4
@Ag nanometers as the signal amplification to construct an electrochemical nanostruc-
tures (NSE) immune sensor for small cell lung cancer(SCLC) detection and early cancer
diagnosis. AuNPs@MoS2 /rGO captures anti-NSE secondary antibody, and conjugation
on anti-NSE secondary antibody was successfully achieved by esterification with a detec-
tion minimum detection limit of 3.00 fg mL−1 [140]. Song, Y. et al. fixed molybdenum
disulfide-based graphitic phase carbon nitride (MoS2 /g-C3 N4 ) on Pt-CuNPs and synthe-
sized MoS2 /g-C3 N4 -PtCu in visible light with a 5-fold lower electrode impedance than
under dark conditions, improving the detection ability of carcinoembryonic antigen (CEA)
with a detection limit of 33 fg mL−1 [141].
Due to its good biocompatibility, high specific surface area, high switching ratio, and
good catalytic activity, 2D MoS2 is widely regarded as an important material for biosensors
to convert biological signals into electricity or optics, solving some bottlenecks in medicine,
such as the detection of cancer cells. Table 6 summarizes the recent applications of MoS2 in
biosensing. However, there are still many problems in the preparation of 2D MoS2 . First, it
is difficult to synthesize 2D MoS2 with a layered structure with good dispersion properties
and uniform thickness. Second, the potential drawbacks of its biocompatibility also limit
its application in detection and analysis. Therefore, it is important to find suitable methods
for the synthesis and functionalization of 2D MoS2 . As a result, researchers can change the
structure of MoS2 nanomaterials and their functionalization in the future. Due to the large
modulus of elasticity of 2D MoS2 , it has broad application prospects for flexible wearable
biosensors.
 persion properties and uniform thickness. Second, the potential drawbacks of its biocom-
patibility also limit its application in detection and analysis. Therefore, it is important to
find suitable methods for the synthesis and functionalization of 2D MoS2. As a result, re-
searchers can change the structure of MoS2 nanomaterials and their functionalization in
the13,
Metals 2023, future.
792 Due to the large modulus of elasticity of 2D MoS2, it has broad application19 of 31
prospects for flexible wearable biosensors.

Figure 11. (a) The structure of (a)

Figure 11. a single-layered
The structure of aMoS 2 or WS2. MoS
single-layered The2 Mo or2 . W
or WS Theatoms
Mo or are in black
W atoms are inand
black and
the sulfur atoms are inthe
yellow. (b) The
sulfur atoms are structure of The
in yellow. (b) GOstructure
showing of rich oxygenated
GO showing groups: the
rich oxygenated carbon
groups: the carbon
atoms in black, oxygen in red,
atoms andoxygen
in black, hydrogenin red,inand
grey (Reprinted
hydrogen in greywith permission
(Reprinted from Ref.
with permission [143].
from Ref. [142].
Copyright 2021, Elsevier).
Copyright 2021, Elsevier).

Table 6. Biosensors based

Table on MoS2 NPs.
6. Biosensors based on MoS2 NPs.

Hybrid Material Detection Method Analyte LOD Ref.

Hybrid Material Detection Method Analyte LOD Ref.
AuNPs@MoS2 @Ti3 C2 Tx SWV NSCLC 0.03 pg mL−1 [142]
AuNPs@MoS2@Ti3C2TMoS
x SWV
2 -graphene PEC NSCLC 0.03 pg mL
glucose
−1
- [143] [143]
MoS2-graphene MoS2 @Cu2 O-Ag PEC ECL glucose cTnI - 2.90 fg mL[144]
−1 [144]
Au/MoS2 -PAA DPV LPS −
29 ag mL 1 [145]
MoS2@Cu2O-Ag ECL cTnI 2.90 fg mL−1 [145]
Au/MoS2-PAA DPV LPS 29 ag mL−1 [146]
5.2. WS2
Recently, WS2 nanomaterials such as WS2 nanotubes, nanoparticles, quantum dots,
5.2. WS2
and WS2 -based nanocomposites have been used in medical and biological science re-
Recently, WS2 search
nanomaterials
[146,147]. WSsuch as WS
2 acting as 2a nanotubes,
member of TMDs nanoparticles,
has attractedquantum dots,due to
wide attention
and WS2-based nanocomposites have two-dimensional
the similar excellent been used in medical layered and biologicalanalogous
nanomaterials science research
to graphene, as
[147,148]. WS2 acting as a member of TMDs has attracted wide attention due to the similar
shown in Figure 10. Monolayer WS2 (1.69 eV) is a straight-gap semiconductor material
with a high carrier migration rate [148]. Additionally, due to the presence of heavy atom
excellent two-dimensional layered nanomaterials
W, the spin-orbit coupling effect (SOC) analogous to graphene,
in the WS as shown in Fig-
2 structure brings about an obvious
ure 10. Monolayer WS 2 (1.69
valence eV)
band is a straight-gap
energy level split, andsemiconductor materialvalue
the valence band splitting with a high
(426 meV)car-
is approx-
rier migration rate imately
[149]. Additionally,
three times the due to band
valence the presence of heavy
splitting value of MoSatom
2 (150W, the
meV), spin-
thus making
orbit coupling effect (SOC) in the WS2 structure brings about an obvious valence band
its valley hall effect more obvious [149]. TMDs nanosheets can be easily synthesized
at scale and dispersed directly in aqueous solutions without surfactants or oxidation
energy level split, and the valence band splitting value (426 meV) is approximately three
treatments, thus preventing the denaturation of proteins and unexpected structural
times the valence band
changessplitting value of MoS
in semiconductors 2 (150
[150]. meV), thusthiophenolic
Additionally, making itscompounds
valley hallcaneffect
be added
more obvious [150].toTMDs nanosheets
the surface can be easily
of WS2 nanosheets synthesized
by a simple at scale
self-assembly andThese
process. dispersed
discoveries
directly in aqueous solutions withoutprospects
indicate promising surfactants or oxidation
in biomedical treatments,
detection. thus preventing
WS2 nanomaterials have been
the denaturation of proteins and unexpected structural changes in semiconductors [151].
successfully used to observe DNA hybridization, enzymes and proteins, as well as in
biosensors and nanomedicine such as environmental pollution and medical diagnos-
Additionally, thiophenolic
tics [147].compounds
Simple DNA can be added toaptamers
oligonucleotides, the surface of WS2 nanosheets
and thiolated DNA combined by with
a simple self-assembly
WS2 and process. These
MoS2 have beendiscoveries indicate promising
reported for DNA-based prospects
sensing applications. Theinmain
bio-reason
medical detection. WS 2 nanomaterials
for the adsorption of DNA have been
bases by successfully
TMDs is the van used to observe
der Waals DNA
force. Lu hy-
and coworkers
bridization, enzymes and proteins, as well as in biosensors and nanomedicine such as and
reported the comparison of MoS 2 , WS 2 and graphene oxide for DNA adsorption
sensing [21]. They demonstrated that MoS2 , WS2 and GO can all adsorb single-stranded
DNA while repelling double-stranded DNA, which may be beneficial for electrochemical
or fluorescent sensors for biomedical applications. Zhang fabricated electrodes with WS2
nanosheets and graphite microfibers via in situ synthesis of WS2 nanosheets on the sur-
face of graphite microfibers to realize high sensitivity and selectivity for the detection of
 Metals 2023, 13, 792 20 of 31

adenine and guanine [151]. Additionally, the proposed hybrid WS2 nanosheet combined
with graphite microfiber electrode has the potential to be applied in harsh environments
and even in vivo, providing a new vision for biomedical applications. Similarly, as
shown in Figure 12, Xi and coworkers proposed a highly sensitive and selective strategy
for MicroRNA detection based on WS2 nanosheet-mediated fluorescence quenching and
duplex-specific nuclease signal amplification, wherein, a DNA/RNA heteroduplex was
formed by hybridizing target miRNA with ssDNA [152]. It is worth noting that Xi’s
strategy displayed a detection limit of 300 fM and can even differentiate single-base from
miRNA family members [152].
In addition to relying on the single-stranded DNA as probe biomolecules, Sun and
coworkers demonstrated that WS2 and MoS2 can absorb Arg amino acids and especially
for Arg-rich peptides [22]. Depending on the adsorption ability, they designed a novel
WS2 and MoS2 -based platform using peptides as probe biomolecules for the detection
of collagen. Selective adsorption of a fluorescent Arg-rich probe peptide was observed
using WS2 and MoS2 nanosheets, making the fluorescence quenching of the dye. The
highly specific WS2 -based platforms to target collagen peptides can be employed in
quantitative detection for complex biological fluids and have promising prospects in
biomedical applications.
Due to its good biocompatibility, high specific surface area, high switching ratio and
good catalytic activity, metallic sulfide is widely regarded as an important material for
biosensors to convert biological signals into electricity or optics, solving some bottlenecks
in medicine, such as the detection of cancer cells. However, there are still many problems
in the preparation of metallic sulfide. First, it is difficult to synthesize a layered structure of
metallic sulfide with good dispersion properties and uniform thickness. Second, the poten-
tial drawbacks of its biocompatibility also limit its application in detection and analysis.
Therefore, it is important to find suitable methods for the synthesis and functionalization
of metallic sulfide. Researchers can change the structure of metallic sulfide and their func-
R REVIEW 20 of 31
tionalization in the future. Due to the large modulus of elasticity of metallic sulfide, it has
broad application prospects for flexible wearable biosensors.

Figure 12. Schematic Illustration of the miRNA

Figure 12. Schematic IllustrationAssay BasedAssay
of the miRNA on WS 2 Nanosheet
Based Mediated
on WS2 Nanosheet Fluores-
Mediated Fluores-
cence Quenching and Duplex-Specific
cence Quenching and Nuclease Signal
Duplex-Specific Amplification
Nuclease (Reprinted
Signal Amplification withwith
(Reprinted permission
permission
from Ref. [154]. Copyright
from2014, Analytical
Ref. [153]. CopyrightChemistry).
2014, Analytical Chemistry).

6. MOFs
Metal-organic frameworks (MOFs) are porous crystalline materials, composed of
metal ions or metal clusters (transition metals and lanthanides) coordinated with organic
ligands (carboxylates, phosphonates, imidazole, and phenolates), forming a one-, two-, or
Metals 2023, 13, 792 21 of 31

6. MOFs
Metal-organic frameworks (MOFs) are porous crystalline materials, composed of
metal ions or metal clusters (transition metals and lanthanides) coordinated with organic
ligands (carboxylates, phosphonates, imidazole, and phenolates), forming a one-, two-,
or three-dimensional (1D, 2D, or 3D) extended coordination network [24]. It is worth
noting that the pore size, shape, and surface area of MOFs can be adjusted via changing
suitable organic linkers, combinations of metals and organic ligands, and synthesis reaction
conditions. This adjustment allows MOFs to bind with various bioactive molecules for
biomedical sensing and detection, providing great potential in biomedical applications
due to the easy synthesis, functionalization, and good biocompatibility [154]. Table 7
summarizes the recent applications of MOFs in biosensing. Luminescent metal organic
framework materials (LMOFs) have attracted great interest recently as a member of MOFs.
Wang proposed a ratiometric fluorescent probe for the detection of dopamine and reduced
glutathione using a member of the LMOFs called UiO-66-NH2 MOF [155]. UiO-66-NH2
MOF possessing a fluorescence emission wavelength of 450 nm was synthesized by using a
hydrothermal process. Dopamine and reduced glutathione can be simultaneously detected
by comparing the ratiometric fluorescence intensity because dopamine can be oxidized to
polyethyleneimine solution to form a copolymer, i.e., PDA-PEI, which quenches the fluores-
cence of UiO-66-NH2 MOF and increases at 530 nm. The ratiometric fluorescent method has
a satisfying detection limit, 0.68 µM and 0.57 µM for dopamine and reduced glutathione,
respectively. Limin Zhou et al. proposed a sensitive ECL immunosensing method. They
used Cu-doped terbium MOF as ECL emitter to detect CYFRA21-1. An immunosensor
was prepared by immobilizing the capture antibody on a Pd nanoparticle-modified Ni-Co
layered double hydroxide (Pd-ZIF-67@LDH) nanocartridge, which exhibited strong electro-
catalytic activity against the reduction of S2 O8 2− , thereby amplifying the ECL signal. The
linear range of this method is 0.01–100 ng/mL, and the detection limit is 2.6 pg/mL [156].
The SERS effect, as discussed in Section 2.1, could greatly amplify the ordinary Raman
scattering signal due to the enhancement of the electromagnetic field on the sample surface
or near the surface in the excitation region on the surface or sol of some specially prepared
metal conductors or sols. Therefore, many researchers have combined MOFs with SERS
technology to further improve biosensing performance [153]. In Fu’s research, an ultra-
sensitive and multiplex detection strategy of volatile organic compounds (VOCs) using an
SERS-active MIL-100 (Fe) sensory array was proposed, where the SERS-active substrate
was composed of Fe clusters and 1,3,5-benzenetricarboxylic acid with deposited concen-
trated AuNPs onto the substrate [157]. This strategy has the ability to detect the gaseous
indicators of lung cancer with a ppM detection limit and promising prospects for early lung
cancer diagnosis in vivo. Similarly, Huang and coworkers demonstrated a noninvasive
diagnosis of gastric cancer using a tubular SERS sensor based on breath analysis [130]. A
silver particle core modified with a uniform zeolitic imidazolate framework-67 (ZIF-67)
shell was modified with 4-ATP. It was then introduced into a glass capillary, where the
end holes were functionalized to act as air inlets and outlets, as well as flow channels and
detection chambers for capturing target molecules as shown in Figure 13. The improvement
of gas enrichment with the coating of the ZIF-67 layer was tested by pumping fluorescent
gas molecules encapsulated with Ag@ZIF-67/4-ATP and Ag/4-ATP. In Figure 13d–f, a
brighter red intensity was displayed and calculated, indicating that the ZIF-67 layer has a
greater gas absorption capacity benefiting from the nanoporous MOFs structure. As de-
picted in Figure 14, a barcode output diagnosis performed with a smartphone is shown in
Figure 13a,b based on the model established with SERS spectra of 57 gastric cancer patients
and 61 healthy subjects. The proposed method paves a broad way for the noninvasive
detection of gastric cancer and other diseases.
 pumping fluorescent gas molecules encapsulated with Ag@ZIF-67/4-ATP and Ag/4
In Figure 13d–f, a brighter red intensity was displayed and calculated, indicating th
ZIF-67 layer has a greater gas absorption capacity benefiting from the nanoporous
structure. As depicted in Figure 14, a barcode output diagnosis performed w
smartphone is shown in Figure 13a,b based on the model established with SERS s
Metals 2023, 13, 792 22 of 31
of 57 gastric cancer patients and 61 healthy subjects. The proposed method paves a
way for the noninvasive detection of gastric cancer and other diseases.

Figure 13. Tubular Figure

SERS 13.
gasTubular
sensor. SERS
(a) SEMgasimage
sensor.
of(a)
theSEM image of the
cross-section cross-section
of the of the
capillary tube capillary tube
loaded
with Ag@ZIF-67/4-ATP powder and (b) high magnification
with Ag@ZIF-67/4-ATP powder and (b) high magnification SEM image of the particle clusters.SEM image of the particle clust
Schematic diagram of the sensing device with the glass capillary
(c) Schematic diagram of the sensing device with the glass capillary loaded with Ag@ZIF-67/4-ATP loaded with Ag@ZIF-67
nanoparticles and fixed in a resin channel, which was connected with two tubes at the end
nanoparticles and fixed in a resin channel, which was connected with two tubes at the ends of the
capillary. (d,e) Fluorescence microscopy images for the capillary filled with (d) Ag@ZIF-67
capillary. (d,e) Fluorescence microscopy images for the capillary filled with (d) Ag@ZIF-67/4-ATP
and (e) Ag/4-ATP nanoparticles upon the absorption of fluorescent gas molecules. (f) Relativ
and (e) Ag/4-ATP nanoparticles
rescent intensity upon
obtainedthe from
absorption of fluorescent
the above fluorescencegas molecules.
images (f) Relative
(d,e) processed by ImageJ t
theobtained
fluorescent intensity difference in absorbed
from the abovefluorescent
fluorescence gas molecules
images between the
(d,e) processed by tube sensor
ImageJ filled with A
to show
67/4-ATP fluorescent
the difference in absorbed and AgNPs/4-ATP nanoparticles,
gas molecules between respectively (Reprinted
the tube sensor filledwith
withpermission
Ag@ZIF- from Re
Metals 2023, 13, x FOR PEER REVIEW Copyright 2022,
67/4-ATP and AgNPs/4-ATP American respectively
nanoparticles, Chemical Society).
(Reprinted with permission from Ref. 22[134].
of 31
Copyright 2022, American Chemical Society).

Figure 14. Breath analysis based on SERS sensor. (a) Schematic diagram of SERS sensor-based diag-
Figure 14. Breath analysis based on SERS sensor. (a) Schematic diagram of SERS sensor-based
nostic workflow. (b) Typical SERS spectrum of breath sample obtained from (i) a gastric cancer pa-
diagnostic workflow. (b) Typical SERS spectrum of breath sample obtained from (i) a gastric cancer
tient and (ii) a healthy volunteer, and the barcodes were converted from the corresponding spectra
patient and (ii)
(Reprinted a healthy
with volunteer,
permission and [135].
from Ref. the barcodes were2022,
Copyright converted fromChemical
American the corresponding
Society). spectra
(Reprinted with permission from Ref. [134]. Copyright 2022, American Chemical Society).
Table 7. MOFs biosensors for biomedical applications.

Nanomaterial Detection Method LOD Linear Range Analyte Ref.

Colorimetry
Cu-MOF 0.04 ng/mL 0.1–50 ng/mL CRP [159]
or fluorometry
Dy-MOF ECL 0.3 fg/mL 1.0–1.0 × 109 fg/mL kanamycin [160]
Metals 2023, 13, 792 23 of 31

Table 7. MOFs biosensors for biomedical applications.

Nanomaterial Detection Method LOD Linear Range Analyte Ref.

Colorimetry
Cu-MOF 0.04 ng/mL 0.1–50 ng/mL CRP [158]
or fluorometry
Dy-MOF ECL 0.3 fg/mL 1.0–1.0 ×109 fg/mL kanamycin [159]
Zn-MOFs-NPs PL 0.145 fg/mL 0.1–2.0 × 104 fg/mL PSA [160]
Cu QD-SH-SiO2 @Cu-MOF SWV - 0.2–34285.0 µM piroxicam [161]
J-aggregate K-ptc MOF ECL 7.4 10−3 ng/mL 10–50 ng/mL SCLC [162]
Cu2+ @Zr-MOF@TiO2 NRs PEC 8.6 pg/mL - cTnI [163]
2.8 nM 10–120 nM Parathion
Mn/Fe-MIL(53) MOF colorimetry [164]
0.95 nM 5–50 nM chlorpyrifos

7. Emerging Trends and Future Prospects

With the rapid development of nanotechnology, nanoparticles have been widely used
in biomedical fields such as medical imaging, disease treatment, drug transportation, and
biosensors. Due to the excellent electrochemical and optical properties of noble metal and
semiconductor nanomaterials, this review focuses on electrochemical and optical biosen-
sors. The combination of biosensors with noble metal and semiconductor nanomaterials
can achieve sensitive and accurate detection of target analytes, improving the sensitivity
and selectivity of detection and reduce the response time of signals by doping and mod-
ifying different substances with noble metal and semiconductor nanomaterials. Based
on the phenomena of plasma resonance and surface Raman spectroscopy enhancement,
researchers can also continue to develop many optical biosensors with higher accuracy.
The gradual maturation of noble metal and semiconductor nanomaterials provides
new insight for research on electrochemical sensors. In the future, with the progress of
synthesis technology of nanomaterials and the discovery of new metal-based nanomaterials,
the following are the research directions worth exploring for biosensors: (1) Set out to
develop sensors that are simple, convenient, and can respond quickly in natural conditions.
(2) Taking advantage of the properties of noble metal and semiconductor nanomaterials
(surface effect, small size, macroscopic tunneling effect) to build micron-sized sensors
suitable for intracellular use. In addition, attention can also be paid to constructing a
bionic interface, which is conducive to the study of neural activity. (3) Biosensors can be
used to detect life-threatening diseases in the heart, brain, kidneys, and other critical parts
of the body. Therefore, the development of flexible wearable electrochemical biosensors
has broad prospects. Due to the presence of interference in human body fluids (such as
glucose, lactic acid, and metal ions), the specific detection of target substances is particularly
critical. By combining with other high-quality materials, noble metal and semiconductor
nanomaterials can realize the specific recognition of the detection substance and reduce the
detection limit.

8. Conclusions
With the rapid development of nanotechnology, nanoparticles have been widely used
in biomedical fields such as medical imaging, disease treatment, drug transportation, and
biosensors. This review focuses on electrochemical and optical biosensors achieving sen-
sitive and accurate detection of target analytes based on excellent electrochemical and
optical properties of noble metal and semiconductor nanomaterials. In fact, numerous
research teams have devoted themselves to the study of noble metal and semiconductor
nanomaterials and their synthetic method for the specific detection of electrochemical
biosensors. In earlier studies, metallic nanomaterials such as gold, silver, and platinum as
well as metal oxides such as TiO2 and ZnO have been widely explored due to their high
surface-to-volume ratio, high conductivity, excellent catalytic activity and biocompatibility.
Recently, optical properties such as SPR and SERS of noble metal nanomaterials have been
widely used, and the electromagnetic field of metal nanomaterials was enhanced after
Metals 2023, 13, 792 24 of 31

absorbing photons, thus improving the sensitivity of biosensors by increasing the Raman
signal of absorbed molecules. The composite of various metal and metal compounds, such
as alloys and metal or metal oxide composites, has attracted widespread attention because
of its synergistic effect and excellent electrocatalytic activity. Conductive polymer and
metal compound composites are also used for the modification of electrode surfaces due to
their high selectivity and biocompatibility. Additionally, with the vigorous development of
nanotechnology, TMDs are also well known as a graphene-like layered structure, which
has high carrier mobility compared to graphene. TMDs nanosheets are more sensitive than
graphene, and can be directly dispersed in aqueous solutions without surfactants or oxida-
tion treatment. At the same time, functionalized MOFs show great potential in biosensing
because they can bind various bioactive substances by changing organic connectomes and
thus changing their pore size, shape and surface area. Compared to other materials used in
biosensors, magnetic metal oxide nanoparticles have strong biocompatibility and minimal
biological toxicity, which can not only avoid causing immune reactions in the human body,
but also have no toxic effects on the living body. Therefore, it is possible to further develop
highly sensitive in vivo biosensors.
Although novel electrochemical biosensors have been improved in various parameters
such as linear detection range, detection limit, and stability, there are still many problems
and challenges. The biocompatibility and stability of noble metal and semiconductor
nanomaterials need to be improved, for example, MOFs-based drug delivery systems still
have potential toxicity in clinical applications. The research is still in the laboratory, and the
actual promotion of the user side has not yet been carried out. In addition, the development
of biosensor technology requires the close cooperation of many researchers to achieve
continuous innovation and common progress through mutual communication.

Author Contributions: Conceptualization, G.Z.; methodology, G.Z. and X.Z.; investigation, L.F., S.S.,
H.L., S.C., J.W. and R.H.; writing—original draft preparation, L.F., S.S., H.L. and R.H.; writing—
review and editing, L.F., G.Z. and X.Z.; supervision, G.Z.; project administration, G.Z. All authors
have read and agreed to the published version of the manuscript.
Funding: The authors acknowledge the support provided by the Natural Science Foundation of
Jiangsu Province (No. BK20200546), the National Natural Science Foundation of China (No. 32001411),
the Fundamental Research Funds for the Central Universities (No. KYLH2022001) and the National
Natural Science Foundation of China (32271977).
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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