Polymer Testing 115 (2022) 107746

Contents lists available at ScienceDirect

Polymer Testing
journal homepage: www.elsevier.com/locate/polytest

Application of fluorescent nano-biosensor for the detection of cancer

bio-macromolecular markers
Nan Ouyang a, 1, Lei Hong a, b, 1, Yuanshuai Zhou c, Jingzhong Zhang c, Shaheryar Shafi a,
Jinlin Pan a, Rongchuan Zhao a, Ying Yang d, **, Wenya Hou e, *
a
School of Biomedical Engineering, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
b
Suzhou Science & Technology Town Hospital, Suzhou, 215153, China
c
Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, 215163, China
d
The People’s Hospital of Suzhou New District, Suzhou, China
e
Shenzhen University General Hospital, Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen University School of Medicine, Shenzhen,
Guangdong, 518060, China

A R T I C L E I N F O A B S T R A C T

Keywords: Fluorescent sensors developed based on nano-materials have penetrated into cancer medical sensing research
Cancer due to their unique properties, such as high sensitivity, high specificity. The number of cancer patients has
Nano-materials continued to rise in recent years, and the limitations of traditional cancer diagnosis methods can no longer meet
Cancer bio-macromolecular markers
the demand for accurate early cancer screening. Accurate identification of cancer bio-macromolecular markers
Fluorescent nano-biosensors
can significantly improve early diagnosis and follow-up treatment. To this end, we provide an overview of the
properties and uses of different nano-materials and detail the principles and functions of fluorescent nano-
biosensor detection for different cancer bio-macromolecular markers. In addition, the prospects and chal­
lenges of translating this convenient and visual diagnostic method into the clinical application are discussed.

1. Introduction bio-macromolecular markers. A wide variety of biosensors have been

Cancer is abnormal cell division or uncontrolled growth in response
to various tumorigenic factors. Cancer is a leading cause of death
worldwide, causing 10 million deaths in 2020 [1]. Despite the rapid
development of modern cancer treatment technology, the survival rate
of patients is still low. Early diagnosis improves cancer outcomes, and
early detection can significantly reduce cancer-related mortality [2,3].
Currently, sample biopsy, tumor imaging, and cancer
bio-macromolecular markers detection are the most common methods
for cancer diagnostic [4–11]. However, current imaging and sample
biopsies exist that are limited to identifying significant tissue areas with
cancerous lesions. Cancer bio-macromolecular markers are molecules
that change significantly during the cancer process (e.g., cancer
cell-specific proteins, intracellular nucleic acids, enzymes and hor­
mones). Therefore, precise and sensitive identification of cancer cells is
essential for the early diagnosis of cancers [12]. Recently, with the de­
mand for low-cost, rapid, and sensitive detection of cancer
developed based on different signaling methods, such as electrochemical
[13], fluorescence [14], surface-enhanced Raman scattering (SERS)
[15], surface plasmon resonance (SPR) [16]. Nanomaterial-based
biosensor technology relies on nano-materials with high specific sur­
face area, biocompatibility function, high stability, and other charac­
teristics, showing high sensitivity, rapid response, accurate
identification, etc., which is widely used in biomarker sensing research
[17,18].
The fluorescent nano-biosensor takes the nano-material as a new
biosensing medium and uses the fluorescence signal as a detection
element to detect biomarkers. Cancer bio-macromolecular markers can
be proteins, glucose or nucleic acids secreted by the body or cancer cells
in cancer development [19–23]. Recently, many novel nano-materials
such as gold nano-particles (AuNPs), magnetic nano-particles, metal
nano-particles, quantum dots (QDs) and carbon nano-tubes (CTNs) have
been used for cancer bio-macromolecular markers detection [24–26].
Fluorescence-based nano-biosensors have many advantages in the

* Corresponding author.
** Corresponding author.
E-mail addresses: ou1020@mail.ustc.edu.cn, becsy123@163.com (N. Ouyang), huayu342@foxmail.com (Y. Yang), wenya.hou@szu.edu.cn (W. Hou).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.polymertesting.2022.107746
Received 13 April 2022; Received in revised form 8 August 2022; Accepted 12 August 2022
Available online 18 August 2022
0142-9418/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
N. Ouyang et al. Polymer Testing 115 (2022) 107746

Table 1
Comparison of biosensing properties of various nano-materials.
Materia Advantage Shortcoming Application References

Gold/Silver Nano- Variable optical properties, strong electrical High production cost, and low stability of Biosensing, Bioimaging [36,37]
particles conductivity, outstanding biocompatibility, biofunctionalized particles
silica nano-particles Large specific surface area, good biocompatibility, lack of autofluorescence Drug Delivery, and Biosensing [38]
high stability
CDs and GQDs High chemical stability, good electrical conductivity limited analytical options Bioimaging, Biosensing, and [39,40]
Genetic Diagnosis
Metal oxide nano- High catalytic efficiency, strong signal amplification, Toxic, poor analytical selectivity, poor Biosensing, Biomedical [41]
materials low cost biocompatibility Diagnosis and Therapy
Fluorescent Copper High efficiency, powerful molecular detection, low Fragile photostability, easy to oxidize, low Biosensing and Fluorescent [42,43]
Nano-materials biological toxicity biological tolerance Probes

detection of cancer bio-macromolecular markers (such as rapid response

time and providing visual identification). In this review, we will sum­
marize the recent advances in fluorescent nano-biosensors targeting
Cancer bio-macromolecular markers. Due to the different features of
cancer bio-macromolecular markers such as PH, stability, concentration,
and the biological properties of nano-materials, detection strategies of
various fluorescent nano-biosensors will be discussed in the following
sections. Different fluorescent nano-biosensors are highlighted in
sensitivity, stability, linear detection range, and detection limit. The
challenges and prospects of applying fluorescent nano-sensors will also
be discussed in this review.
2. Comparison of the potential of different nano-materials for
biosensing
Since the beginning of nanotechnology, nano-materials have
received much attention in biology and medical research, including the
use of nano-materials for cancer bio-macromolecular markers detection.
In general, the size of biomolecules (DNA or proteins) is usually in the
range of 2 – 100 nanometers, and biomolecules and nano-materials have
similar sizes. Furthermore, a critical advantage of nano-particles for
cancer detection is due to the high specific surface area of nano-
materials, which allows them to carry a wide range of biomolecules
with targeting and detection functions [27]. Stimulated by the demand
for early tumor diagnosis, various nano-particles with sensing potential
have been developed. As shown in Table 1, metal nano-particles, rep­
resented by gold or silver have the advantages of variable size, optical
properties and strong conductivity, among which the representative
silver nanoclusters are widely used in biosensing, and the photo­
luminescence mechanism of silver nanoclusters is the coupling of sur­
face plasmon and emitter [28]. At the same time, Silica nano-particles
have promising applications in the biomedical field owing to their large
specific surface area and high stability properties. Furthermore, multi­
functional silica nano-particles have been used in medical bioimaging
and drug-targeted delivery studies [20]. In the past few years,
carbon-based nano-materials have become the most widely used bio­
materials due to their unique optical, electronic, mechanical and
chemical properties [21]. For example, carbon dots (CDs), which are
quasi-spherical oxygen-containing carbon nanoparticles with a particle
size of less than 10 nm, which PL mechanisms are now generally
accepted: carbon core state luminescence from conjugated π-domain
with quantum confinement effect, surface state luminescence from the
interaction of surface groups and carbon core and crosslink enhanced
emission effect, etc. [29,30]. Besides, graphene quantum dots (GQDs)
are also car-bon-based nanoscale particles, which are emissive graphene
nanosheets and less than 100 nm, and the main PL mechanisms of GQDs
include the quantum confinement effect of conjugated π-domains, the
surface/edge states of GQDs, and the synergistic effect of these two
factors [31]. They exhibit the similar outstanding properties, including
low toxicity, biocompatibility, photostability, water solubility, and
simplicity of preparation. However, carbon-based quantum dots’ low
quantum yield (QY) limits their pertinency [32,33]. Fluorescent copper
Table 2
Characteristics of an ideal fluorescent nano-biosensor.
Parameter Required characteristics
Sensitivity Low detection limit (LOD) < 104 cfu mL- 1 or <10 nm
Specificity Correctly distinguish between normal cells and cancer cells
Response time Quick Response Detection
Stability Stable in complex testing environments
Biocompatibility Does not affect and adapts to the detection environment
nano-materials (CuNMs), including copper nano-particles (CuNPs) and
copper nanoclusters (CuNCs), are widely used in biosensing and fluo­
rescent probe research owing to their abundant raw materials, easy
synthesis, low cost, and excellent biocompatibility. But the disadvan­
tages of CuNCs are short photostability and poor biotolerance [34]. In
recent years, 2D transition metal oxides materials attracted more and
more attention, which have many unique advantages, such as high
thermal stability and strong oxidation ability. 2D transition metal oxides
materials have been widely used in the fields of electronics, energy
technology, biosensing and biomedical diagnosis and treatment [35].
Therefore, nano-materials have been developed for early cancer diag­
nosis studies due to their good biosensing properties.
3. Fluorescent nano-biosensors developed for a variety of cancer
bio-macromolecular markers
Early diagnosis of precancerous lesions can allow early cancer
detection, reduce cancer mortality, and raise the chance of cure [12,44].
Nanotechnology offers high selectivity and sensitivity in cancer diag­
nosis, and enables the simultaneous measurement of multiple targets.
Quantum dots (QDs) [45], gold nano-particles (AuNPs) [46] and poly­
mer dots (PDs) are three standard nano-particle probes used to diagnose
cancer. Interestingly, recent studies have shown that nano-materials
combined with fluorescence sensing can accurately identify and target
cancer bio-macromolecular markers [47]. As shown in Table 2, bio­
sensors combining fluorescence and nanotechnology have various
properties, such as high stability, high specificity, strong sensitivity, fast
response speed and good biocompatibility.
3.1. Protein detection
The FDA has approved many proteins for cancer detection, including
CEA (carcinoembryonic protein), PSA (prostate cancer), CA-125
(ovarian cancer) and others [48,49]. Furthermore, intracellular
reducing substances (IRS) have been used as a new indicator to differ­
entiate cancer cells/normal cells [50]. In humans, GSH (a kind of IRS)
concentration is about four times higher in cancer cells than in normal
cells [51,52]. Therefore, the accurate and specific identification of
“signals” released by cancer cells is significant for cancer patients’ early
diagnosis and treatment.

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Fig. 1. Schematic diagram of PDAN@AgNC based fluorescent nano-biosensor for detection of CAE and AFP.
It is adapted from Ref. [57] with permission to reproduce from RSC.

Fig. 2. Schematic illustration of the paper assay device (PAD): CEA is recognized by the modified MSN, and a specific reaction occurs resulting in the release of
glucose, and GOD then decomposes the glucose to produce hydrogen peroxide which quenches the QDs fluorescence emission.
It is adapted from Ref. [59] with permission to reproduce from ACS.

3.1.1. CEA detection
CEA is a 180 kDa glycoprotein, which is considered as a cancer
marker for multiple cancers, such as breast cancer, lung cancer, colon
cancer and ovarian cancer. Thus, CEA is considered a valid indicator for
assessing response to cancer treatment [53–56]. Chen et al. designed a
specific aptamer to detect CEA by binding to dsDNA-templated copper
nano-particles (CuNPs) [57]. When the aptamer recognizes CEA, it
prevents dsDNA from binding to Cu2+, which could quench the strong
fluorescence emission of double-stranded DNA template copper
nano-particles. This sensor is susceptible to CEA detection, and the limit
of detection (LOD) is 0.0065 ng mL− 1. In addition, jiang et al. proposed
an innovative device based on a polydopamine nanosphere@silver
nanocluster (PDAN@AgNC) system for the accurate detection of CEA.
Briefly, in the presence of CEA, AgNCs is released from the PDAN surface
as a complex, resulting in the recovery of previously quenched fluores­
cence (Fig. 1). In addition, the device could also detect α-fetoprotei­
n-AFP (a liver cancer marker), and the detection limits for AFP and CEA
were 2.4 nM and 5.6 nM, respectively [58]. This multi-target detection
technique shows great potential for the detection of cancer markers in
human serum samples.
A study by Qiu et al. successfully developed an all-in-one paper-
based analysis de vice (PAD) to detect CEA [59]. The assay was carried
out in a centrifuge tube using glucose-loaded mesoporous silica nano­
containers (MSNs) with a CEA aptamer and a “Quantum
Dot-Enzyme-Impregnated Paper” attached to the lid. After adding CEA,
the analyte reacted specifically with aptamers immobilized on MSN, and
then glucose was released. The immobilized Glucose oxidase (GOD)
oxidized the released glucose on paper to produce hydrogen peroxide,
which could quench the fluorescence of CdTe/CdSe QDs. The PAD-based
sensing system sensitively discriminates target CEA from other bio­
markers or proteins, and this device provides sensitive detection of CEA
over a linear range of 0.05–20 ng mL− 1 with detection limits as low as
6.7 pg mL− 1 (Fig. 2).
3.1.2. PSA detection
In prostate cancer progression, accurate assessment of prostate-
specific antigen (PSA) levels is beneficial for cancer diagnosis [60].
Early detection of prostate cancer can effectively improve a patient’s
chance of cure [61]. Therefore, Huang et al. designed a fluorescent
biosensor(Metal-organic frameworks(MOF)@ gold nano-particles

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Fig. 3. (A) Synthesis method of MOF@AuNP@GO; (B) Schematic diagram of MOF@AuNP@GO fluorescent nano-sensor for detecting target proteins.
It is adapted from Ref. [62] with permission to reproduce from Theranostics.

(AuNP)@ graphene oxide(GO))based on a nanohybrid system [62]. The

designed nanohybrid exhibited an enhanced ssDNA binding affinity and
fluorescence quenching ability, and it used specific dye-labeled aptamer
probes to recognize prostate-specific antigens (Fig. 3). This nano-sensor
can sensitively measure PSA with a detection limit of 0.01 ng mL− 1,
which can quickly and sensitively measure cancer bio-macromolecular
markers. In another rapid detection research, Choi et al. proposed a
novel fluorescent nano-sensor based on “fluorescein isothiocyanate
(FITC)/peptide bound gold (Au) nano-particle complex (FPAN)", and it
relied on specific enzyme digestion reactions to detect PSA [63]. This
simple process of constructing the FPAN probe was superior to other
sensing systems because it reduced the possibility of probe defects in the
sensing process and diagnoses prostate cancer by measuring the fluo­
rescence signal. It could detect PSA concentrations ranging from 10 pM
to 100 nM.
Up to 30% of patients with prostate cancer have metastatic recur­
rence after treatment, so urokinase fibrinogen activator (uPA) as a
marker for metastatic prostate cancer, its effective diagnosis is particu­
larly important [64]. By using the unique fluorescent properties of
single-walled carbon nanotubes (SWCNTs), Williams et al. developed a
quantitative fluorescent nano-sensor to detect uPA in serum samples
[65]. The nano-sensor complexes were synthesized from single-walled
carbon nanotubes encapsulated with single-stranded DNA (TAT) 6
coupled with monoclonal anti-uPA antibodies (Fig. 4). The sensor could
quantitatively detect uPA concentrations in human blood products with
a detection limit of up to 50 nm.

3.1.3. GSH detection

Cancer cells have higher levels of reactive oxygen species and
therefore have higher concentrations of reducing substances to
Fig. 4. Synthesis scheme of Anti-uPA-DNA-SWCNT complexes.
neutralize reactive oxygen species, of which reducing glutathione (GSH)
It is adapted from Ref. [65] with permission to reproduce from ACS.
is one of the most abundant intracellular reducing substances, and GSH
is upregulated in many cancers such as gastric, colorectal and breast
cancers [66,67]. In order to perform cancer cell identification easily, Li

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N. Ouyang et al.
Fig. 5. Synthesis scheme of GQDs-MnO2 nanocomposites and the principle of GSH-stimulated fluorescence turn-on.
It is adapted from Ref. [69] with permission to reproduce from Elsevier.
Fig. 6. Schematic diagram of targeting TrxR identification and detection.
It is adapted from Ref. [74] with permission to reproduce from ACS.
et al. proposed a facile fluorescent biosensor based on silicon
nano-particles (SiNP) [68]. Chelating Fe3+ ions quenched the fluores­
cence of SiNPs, and after redox reactions with reducing species, the
nano-sensors showed sensitive fluorescence recovery. The sensor relied
on efficient cellular uptake and could detect IRSs by fluorescence im­
aging. The LOD was evaluated to be 352 nM and 16.7 μM. Under the
demand for high-precision identification of cancer cells, Wang et al.
constructed two novel sensors for intracellular GSH detection using
composite nano-materials composed of MnO2 and GQDs and
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Polymer Testing 115 (2022) 107746
CPs@AgNPs [69,70]. The introduction of glutathione (GSH) decom­
posed MnO2 and caused the fluorescence recovery of GQDs. Therefore,
GSH overexpressed in cancer cells could be accurately identified, and an
acceptable linear detection range for GSH was 0.07–70 μM and the LOD
was 48 nM (Fig. 5). However, a study by Wong et al. fabricated a novel
fluorescent sensing platform based on BSA/AuNCs. Which showed
excellent sensing performance for GSH detection after its functionali­
zation with graphene oxide and folic acid [71]. And the specific per­
formance as follows: its sensitive and extremetly rapid detection of GSH
N. Ouyang et al. Polymer Testing 115 (2022) 107746

Fig. 7. (A)The schematic of FRET-based MMP-2 detection method using QDs–peptide–dye nano-assembly; (B) Schematic diagram of the synthesis and detection
principle of QD-FRET nano-sensor.
It is adapted from Refs. [76,77] with permission to reproduce from Elsevier and ACS.

and with a detection limit down to 0.1 μM.
3.1.4. TrxR detection
High expression of thioredoxin reductase (TrxR) has been observed
in many cancers (e.g. colorectal cancer, lung cancer, prostate cancer).
TrxR is an attractive pharmacological target for tumor radiosensitization
[72,73]. Sidhu et al. proposed a ratiometric fluorescent nano-sensor,
“Biotin-CDs-Naphthalimide” to target TrxR in cancer cells [74]. The
schematic (Fig. 6) shows that Nano-sensors could precisely enter cancer
cells via biotin receptor-mediated endocytosis. Because of the fluores­
cence resonance energy transfer (FRET) between carbon dots (CDs) and
naphthalimide, the fluorescence of the sensor was turned on once the

Fig. 8. Schematic design and activation mechanism of a fluorescence quenching biosensor based on sol-gel matrix film wrapped with Au nano-particles.
It is adapted from Ref. [79] with permission to reproduce from ACS.

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Fig. 9. Schematic diagram of GQD-PEG-aptamer/MoS2-based FRET biosensor to detect EpCAM protein.

It is adapted from Ref. [82] with permission to reproduce from Elsevier.

Fig. 10. (A)Schematic diagram of synthesis of AgNCs (DNA/AgNCs) fluorescent probe sensor with DNA template; (B) Schematic diagram of fluorescent complex
nanoprobe to detect BRCA1 gene deletion.
It is adapted from Ref. [86]with permission to reproduce from Elsevier.

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N. Ouyang et al.
Fig. 11. Schematic diagram of logic gates based on AgNCs and HCR to recognize miRNA-21 and telomerase.
It is adapted from Ref. [88] with permission to reproduce from RSC.
overexpression of thioredoxin reductase (TrxR) was detected in cancer
cells, and this device could sensitively detect TrxR at concentrations
down to 7.2 × 10− 8 M.
3.1.5. MMP-2 detection
Matrix metalloproteinase 2 (MMP-2) is a protease associated with
tumor invasion and metastasis [75]. Li et al. constructed a novel fluo­
rescent sensing system utilizing the combination of quantum dots and
organic dyes to detect MMP-2 in vivo and in vitro [76]. When these probes
are exposed to MMP-2, the selective cleavage of the peptide result in the
recovery of fluorescence from QDs, by using the produced
540QD–peptide–RB and 720QD–peptide–MPA probes, and the detection
limit is reduced to 0.25 nM (Fig. 7A). In addition, Ochs et al. proposed a
quantum dot-based fluorescent nano-sensor using the exact FRET
mechanism, and the device was used to detect matrix metalloproteinases
(MT1-MMP) on cell membranes [77]. As shown in the figure (Fig. 7B),
the sensor could recognize activated MT1-MMP in cancer cells, and the
specific cleavage reaction interrupted the FRET between Cy3 peptide
and QD. Thus, the fluorescence emission of QD was restored. Their
studies can sensitively detect MMP-2 in vitro and in vivo, providing a
diagnostic strategy for accurately identifying cancer cells.
3.1.6. CA-125 detection
Cancer antigen 125 (CA-125) is an essential and significant
biomarker in ovarian malignancies [78]. Mona et al. designed a simple
fluorescence-quenched biosensor based on a gold-coated to detect
oncomarker CA-125 [79]. The fabricated sensor consisted of a nano-gold
thin film doped into a sol-gel matrix. The quantification of CA-125 was
based on the quenching ability of this fluorescence signal, with a
sensitivity of 97.35%, a specificity of 94.29%, and the LOD was 1.45 U
mL− 1. In particular, the developed biosensor could successfully
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Polymer Testing 115 (2022) 107746
differentiate patient samples(Fig. 8).
3.1.7. EpCAM detection
The epithelial cell adhesion molecule (EpCAM) is a well-known
marker which is highly expressed in multiple cancers and implies a
poor prognosis [80]. Tao et al. designed an EpCAM antibody-dependent
device to detect EpCAM overexpression in colon cancer cells [81], which
presented imaging of colon cancer cells by combining anti-EpCAM an­
tibodies with Rubpy-encapsulated core-shell silica nano-particles, and
showed distribution and abundance of EpCAM in cell membranes. In
another meaningful work, Shi et al. reported a new GQD-PEG-Apta­
mer/MoS2 based FRET assay for the detection of EpCAM protein with
GQD and MoS2 nanosheets as a donor and quencher, respectively [82].
The sensing platform immobilized the GQD-labeled EpCAM aptamer on
the MoS2 surface. Once EpCAM exists, it could bind with the EpCAM
aptamer properties so that the EpCAM aptamer could be detached from
the MoS2 nanosheet, which eventually led to the recovery of the fluo­
rescence intensity (Fig. 9). By monitoring the change in fluorescence
signal, the target EpCAM protein could be detected sensitively and
selectively with a linear detection range from 3 nM to 54 nM, and the
LOD was as low as 450 pM.
3.2. Nucleic acid detection
3.2.1. Genetic testing of BRCA1
Breast cancer susceptibility gene 1(BRCA1) is a tumor suppressor,
and mutations in the BRCA1 gene predispose to breast and ovarian
cancer, and it can be a target for breast cancer prevention and treatment
[83,84]. Borghei et al. developed a label-free detection strategy for
significant deletion mutation in the BRCA1 gene [85]. According to the
principle of DNA-induced hybridization, the DNA-silver nanocluster
N. Ouyang et al.
Fig. 12. (A) Synthesis and fluorescence emission principle of DNA/AgNCs; (B) Fluorescence detection strategy of miRNA-378.
It is adapted from Ref. [92] with permission to reproduce from Elsevier.
(NC) fluorescent probe could recognize the mutation DNA fragment of
the BRCA1 target gene, resulting in higher fluorescence. Using this
nano-biosensor, the significant deletion mutation in the BRCA1 gene
could be detected with a LOD of 6.4 × 10 − 11 M (Fig. 10). Subsequently,
another new FRET biosensor based on the interaction of DNA and CdTe
quantum dots was developed [86]. Hybridization between deletional
BRCA1 targets and probed restores nanocluster and quantum dot fluo­
rescence emission. This method was sensitive to detecting the deletion of
the BRCA1 target gene, and its linear detection range was 0.5pM–1 nM
(Fig. 10B).
3.2.2. MiRNA testing
MiRNAs are short RNA sequences that regulate gene expression.
MiRNA-21 is upregulated in almost all solid tumors of epithelial cell
origin, and most of its reported targets are tumor suppressors [87].
MiRNA-21 is an essential biomarker for early prediction and tumor
metastasis, and its accurate detection often provides the best chance for
a cure [88]. Morteza et al. developed a fluorescent biosensor based on
DNA-AuNCs nano-materials, which was used to detect of miRNA-21 in
human plasma samples, and the LOD of this method was 0.7 pM [89].
Gong et al. designed a multifunctional nanocomposite based on gold
nanorods (AuNR) for miRNA-21 detection and cancer therapy [88].
Briefly, the device used functional DNA strands to modify the early
synthesized AuNRs, and carried doxorubicin (DOX) and folic acid. Once
microRNA-21 was detected to bind to double-stranded DNA, it would
trigger drug release and cause fluorescence recovery. It also showed
high selectivity for the microRNA-21 assay with a LOD of 2.1 nM. Driven
by the need for multifunctional analysis, Jiang et al. proposed a novel
fluorescent nano-sensor based on “DNA-templated silver nanoclusters
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Polymer Testing 115 (2022) 107746
(AgNCs)”, a device that relies on fluorescent logic gates for signal
switching to directly reflect information about intracellular miRNA-21
and telomerase (a ribonucleoprotein complex upregulated in most
human cancers) [90]. Briefly, in the presence of miRNA-21 and telo­
merase, disruption of the logic gate of this sensor device released DNA
leading to the resumption of fluorescence from graphene oxide
(GO)-quenched AgNCs, and the LOD for miRNA-21 was 2.8 pM (Fig. 11).
This device provides a simple, fast and reliable method for miRNA-21
and telomerase related research and diagnosis. These types of fluores­
cent nanobiosensors are of great significance in human disease diagnosis
and anti-tumor therapy.
MiRNA-378 in serum can be used as a new potential non-invasive
biomarker in gastric cancer detection [91]. Liu et al. developed a sus­
ceptible method for microRNA-378 detection, using DNA-templated
silver nanoclusters as label-free fluorescent probes [92].
MicroRNA-378 bonded to the cDNA complementary sequence that
triggers rolling circle amplification, thus realizing the “fluorescence
enhancement” phenomenon (Fig. 12). This sensor has low cost, high
specificity, and a detection limit of 1.07 fM in vitro serum samples.
3.3. Tumor-derived exosomes detection
Exosomes are a class of small membrane vesicles of small molecular
complexes that are commonly released into the tumor microenviron­
ment and can also be detected in body fluids. There is evidence that
exosomes promote tumorigenesis by regulating angiogenesis, immunity.
Exosomes are viewed as a non-invasive biomarker for early clinical
cancer diagnosis [93,94]. Driven by the need for real-time in vitro cancer
diagnosis, Li et al. developed a homogenous magneto-fluorescent
N. Ouyang et al. Polymer Testing 115 (2022) 107746

Fig. 13. Schematic diagram of the hMFEX nano-sensor. (a) Tumor-derived exosomes are captured by magnetic beads with specific antibodies to form a magnetic
bead-exosome-adaptor complex. (b) Captured exosomes are detected by aptamer-triggered DNA three-way junctions cyclic assembly strategy along with TPE-TA and
the GO-based “turn-on” fluorescent system.
It is adapted from Ref. [95] with permission to reproduce from ACS.

exosome (hMFEX) nano-sensor for rapid and sensitive detection of
tumor-derived exosomes [95]. This hMFEX nano-sensor used specific
antibodies to recognize and bind to exosomes, followed by an
aptamer-triggered DNA three-way junctions cyclic assembly strategy to
turn on the quenched fluorescence of the tert-amine tetraphenylethylene
(TPE-TA) and GO complexes (Fig. 13). This device detects exosomes of
tumor origin with high specificity, and the limit of detection is 6.56 ×
104 particles/μL. In addition, Wang et al. constructed a
surface-enhanced Raman spectroscopy (SERS) sensor using highly sen­
sitive gold nanorods (AuNR) material [96]. Three specific aptamers
modified on the surface of AuNRs were able to capture breast cancer
cell-derived exosomes into the sensing array, which will exhibit an
enhanced SERS signal. This sensor device is highly sensitive and ho­
mogeneous, enabling a wide detection range (1.0 × 104–5.0 × 106
particles/mL) and low detection limit (5.3 × 103 particles/mL). The
development of these types of highly sensitive fluorescent nano-sensors

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N. Ouyang et al.
Fig. 14. (A) Synthesis and detection strategy of AgNPs@GQDs-GOD fluorescent nano-sensor; (B) Schematic diagram of constructing a dual-function nano platform
for detection and treatment.
It is adapted from Ref. [99] with permission to reproduce from Elsevier.
has excellent prospects for clinical applications, enabling real-time
diagnosis of early cancer-derived exosomes.
3.4. Glucose detection
Cancer cells have a higher glucose uptake rate than normal cells
[97]. Glucose is also an essential biomarker for cancer diagnosis [21,
98]. Targeting and identifying highly expressed glucose in cancer cells
can facilitate early diagnosis and promote the development of precision
therapy. Therefore, Hai et al. developed a dual-mode glucose fluorescent
biosensor based on AgNPs@GQDs-GOD nano-materials for cancer cell
identification [99]. This novel sensor targets cancer cell detection
combined with targeted therapy. Due to high glucose levels in the tumor
microenvironment, the nanocomposites undergo glucose-related redox
reactions, ultimately leading to fluorescence recovery of GQDs. This
device could be susceptible to identifying cancer cells with high glucose
concentrations, and the detection range of glucose levels was from 10
μM to 4 mM, and its LOD was 4.78 μM. Furthermore, it could also induce
cancer cell apoptosis in combination with starvation-like therapy, metal
ion therapy, and Tannic acid (TA) (Fig. 14A and B). In another report on
the diagnosis and treatment of cancer cells, Chen et al. developed a
smart nanoprobe that can accurately identify cancer cells with high
glucose levels, and under NIR laser irradiation adjuvant therapy, it could
kill cancer cells well [100]. Therefore, these two sensors are promising
for potential practical diagnostic and therapeutic applications.
4. Conclusions and future prospects
For decades, the total number of cancer patients and mortality rates
have continued to increase, despite some successes in treating cancer
patients, and partially is due to the slow progress of new technologies for
early cancer diagnosis. This review describes recent researches on
fluorescence sensing of cancer bio-macromolecular markers using nano-
materials. It summarizes the development of fluorescent biosensors
based on different nano-materials (including gold/silver/silica nano-
11
Polymer Testing 115 (2022) 107746
particles, carbon dots, quantum dots, etc.) and also describes the prop­
erties, functions and fabrication methods of fluorescent nanobiosensors
for the detection of different cancer bio-macromolecular markers.
Currently, most fluorescent nanobiosensors are investigated for in vitro
cancer marker detection (e.g., blood and urine tests) and do not yet meet
the needs for in vivo biosensing and combination of drugs for targeted
therapy. In addition, cancer cell-based biomarkers often involve multi­
ple complex physiological processes. Therefore, another major chal­
lenge is the need to design multi-targeted and more accurate fluorescent
nano-sensors to identify cancer cells with high complexity.
On the other hand, the optical imaging quality of most short-wave
emitting nanomaterials is far from adequate for high-quality in vivo
fluorescence sensing, while long-wave emission is ideal for applications
such as in vivo bioimaging, photothermal and photodynamic therapies
[101]. Currently, there are a number of research teams working on the
emission red shift of nanomaterials (such as carbon dots). By choosing
appropriate C source or reaction medium, changing reaction conditions
or other treatments, high fluorescence CDs with long wavelength
emission can be obtained [102], however, its quantum yield (QY) needs
to be improved. Therefore, suitable precursors, innovative synthesis
methods and appropriate purification methods or modeling with the
help of machine learning should be sought for the synthesis of CDs with
more desirable properties (e.g. deep tissue penetration, low photo­
damage and high-resolution fluorescence imaging properties). Facilitate
the emission red shift and high QY of nanomaterials such as CDs, which
will greatly promote the development of in vivo fluorescence sensing
[103–105]. At the same time, it is also worth paying attention to the
photoluminescence (PL) mechanisms of some of the most promising
nano-materials, such as carbon dots, Due to the structural and compo­
sitional diversity and complexity of CDs, their photoluminescence
mechanism is still controversial and is likely to be highly dependent on
particle size, surface functional groups, degree of graphitization, het­
eroatom doping, etc., and these photoluminescence origins should be
understood in depth, which will be important for the synthesis of
nano-materials with high biocompatibility, ultra-high resolution sensing
N. Ouyang et al.
as well as imaging and application for early diagnosis of cancer bio­
molecules in complex in vivo environments.
In fact, for now, most of the fluorescent nano-sensors for accurate
detection of cancer bio-macromolecular markers are still in the experi­
mental stage, and the need for rigorous validation hampers the appli­
cation of biosensor-based models to clinical application. There is a need
to consider better targeting effects, sensitivity, detection cost, and real-
time efficiency. Finally, we note that fluorescent nano-biosensors can
precisely target and detect nucleic acid molecules. Which may have
potential applications for the diagnosis of cancers that viral infections
may induce (e.g. hepatitis C virus (HCV) induced liver cancer, human
papillomavirus (HPV) induced cervical cancer, etc.) or nucleic acid
molecules of the new coronavirus.
Author contributions
Writing - original draft, data curation, Nan Ouyang; data collection
and curation, Lei Hong; investigation, review, Yuanshuai Zhou; re­
sources, supervision, Jinzhong Zhang and Ying Yang; writing – review,
Shaheryar Shafi; investigation, Software, Jinlin Pan and Rongchuan
Zhao; writing - review & editing, Wenya Hou.
Funding
This research was funded by the National Natural Science Founda­
tion of China (Grant No. 32101039), Natural science foundation of
Guangdong province of China (2022A1515011208), the Natural Science
Foundation of Tianjin (Grant No. 17JCYBJC43400), and the Major
Innovative Research Team of Suzhou (Grant No. ZXT2019007).
Institutional review board statement
Not applicable.
Informed consent statement
Not applicable.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
Data will be made available on request.
Acknowledgments
Thanks to Dr. Jiang for Figs. 1 and 11 citation permission.
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