J Mater Sci

Review
REVIEW

Fluorescent carbon dots are the new quantum dots:

an overview of their potential in emerging technologies
and nanosafety
Melis Ozge Alas1, Fehmi Burak Alkas2, Ayca Aktas Sukuroglu3, Rukan Genc Alturk1,*, and
Dilek Battal2,4,*

1
Department of Chemical Engineering, Faculty of Engineering, Mersin University, Mersin, Turkey
2
Department of Toxicology, Faculty of Pharmacy, Near East University, Nicosia, Cyprus
3
Department of Toxicology, Faculty of Pharmacy, Gazi University, Ankara, Turkey
4
Department of Toxicology, Faculty of Pharmacy, Mersin University, Mersin, Turkey

Received: 28 April 2020 ABSTRACT

Accepted: 5 July 2020
Ó Springer Science+Business
Media, LLC, part of Springer
Nature 2020
Carbon dots (CDs) have become a potential material for biosensing, drug
delivery, and bioimaging because of their strong fluorescence, for which they
are referred to as fluorescent carbon dots. CDs have drawn significant attention
as a new class of carbonaceous nanomaterials with accelerating applications in
varying different technologies. This attention is mainly based on a multitude of
appealing properties of CDs, such as high hydrophilicity, biodegradability,
biocompatibility, chemical stability, and ease of surface modification, together
with their unique optic properties. In this review, CDs were classified and
evaluated based on the difference in precursors and preparation methods. The
synthetic methods of CDs were summarized, and their luminescence mecha-
nism was analyzed. The applications of CDs in biosensing, drug delivery,
energy, and bioimaging were also discussed. The issues and challenges of CDs
were analyzed for their further development, with specific emphasis on the
toxicity profiles or lack thereof, especially that of cytotoxicity and long-term
genotoxicity developed secondary to nanotoxic effects, of carbon dot-based
systems. Additional research in toxicity is sure to lead to improved baseline
nanosafety statistics for CDs and will be a crucial determinant in the adoption of
CDs into many fields across all scientific disciplines, as well as indirectly assist
in the development of more efficient and cost-effective technologies. Sugges-
tions for the development of the concepts contemplated herein were also pro-
vided, along with additional insight into the controversy concerning the
phenomenon of emission and the upconverted photoluminescence.

Address correspondence to E-mail: rgenc@mersin.edu.tr; dilekbattal@mersin.edu.tr

https://doi.org/10.1007/s10853-020-05054-y
 J Mater Sci

Abbreviations CDs/PEI/NB Conjugated CDs with

CDs Carbon dots polyethyleneimine (PEI) and Nile
CDots Carbon dots blue (NB)
CQDs Carbon dots Hg Mercury
PL Photoluminescence NB Nile blue
QDs Semi-metal-based quantum dots TPF Two-photon fluorescence
LED Light-emitting diode Cu2? Copper
COOH Carboxyl group S2- Sulfide
OH Hydroxyl group PEI@CDs Polymeric ethylene imine
SWCNT Single-walled carbon nanotubes functionalized photoluminescent
MWCNT Multi-walled carbon nanotubes carbon dots
PEG Polyethylene glycol BrO3 Bromate
PPEI-EI Polypropyleneethyleneimine-co- Au@CQDs Gold nanoparticles @ carbon
ethylenimine quantum dots nanocomposites
NMR Nuclear magnetic resonance PVA Polyvinyl alcohol
AFM Atomic force microscopy PCDs Phosphorus-containing carbon dots
TEM Transmission electron microscope L929 Murine fibroblast cell line
FT-IR Fourier-transform infrared Gd Gadolinium
spectroscopy Gd@CQDs Gd3? doped magneto-fluorescent
XRD X-ray diffraction carbon dots
UV Ultraviolet FA-Gd@CQDs CDs conjugated with folic acid
HOMO Highest occupied molecule orbital MCF-7 Breast cancer cell
LUMO Lowest unoccupied molecular MDA-MB-231 Breast cancer cell
orbital BT-549 Human breast cancer cell
CNTs Carbon nanotubes E@CDs Element-doped carbon dots
DSSC Dye-sensitized solar cells SH-SY5Y Labeled neuronal cells
PSC Perovskite solar cells DOX Doxorubicin
QDSC Quantum dot solar cells ROS Reactive oxygen
OSC Organic solar cells Spd-CQDs Spermidine-coated fluorescent
TiO2 Titanium dioxide carbon quantum dots
CD–RhB–TiO2 CD-doped dye/semiconductor MDR Non-multidrug-resistant bacteria
complex system MRSA Methicillin-resistant S. aureus
Jsc Short circuit current density E. coli Escherichia coli
Voc Open circuit voltage S. aureus Staphylococcus aureus
V Volt B. subtilis Bacillus subtilis
PCE Power conversion efficiency P. aeruginous Pseudomonas aeruginosa
FF Fill factor AMP Ampicillin
N719 Ruthenium dye AREC Ampicillin-resistant Escherichia coli
PEG-m-CQDs Polyethylene glycol-modified KREC Kanamycin-resistant Escherichia coli
carbon quantum dots NPs Nanoparticles
ETL Electron transfer layer HepG2 Human hepatocellular carcinoma
HTL Hole transfer layer cells
HTM Hole transfer material MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-
SnO2 Tin(IV) oxide diphenyltetrazolium bromide
SCs Supercapacitors MCF-10A Healthy mammary epithelial cells
GO Graphene oxide FL83B Liver cells
rGO Reduced graphene oxide CDs-PEG Polyethylene glycol-modified
MnO2 Manganese dioxide carbon dots
PPy Polypyrrole CD-Pri Pristine carbon dots
PANI Polyaniline
J Mater Sci

CDs-PEI Polyethyleneimine-coated carbon based nanomaterials. They have come to the fore in
dots the use of biomedical, sensor, light-emitting diode
NIH/3T3 Mouse fibroblasts (LED), photocatalytic, and photocatalytic devices due
Al-CDs Aluminum-doped carbon nanodots to their optical properties [3–7].
TNFa Tumor necrosis factor-a CDs first have been discovered accidentally during
IL1 Interleukin-1b the purification of single-walled carbon nanotubes by
hMSCs Human mesenchymal stem cells electrophoresis in 2004 by Xu et al. [8]. As shown in
CNBs Carbon nanobeads Fig. 1, the structure of a typical CD is a spherical-like
Pb2? Palladium core, which is formed by stacking multiple pieces of
Cd2? Cadmium graphene fragments regularly or irregularly. Besides,
B16F10 Cellosaurus cell line CDs contain oxygen-rich functional groups scattered
RAW264.7 Murine macrophages on the surface, such as carboxyl (–COOH) and
HEK-293 Human embryonic kidney cell hydroxyl (–OH) groups, which ensure high aqueous
LDH Lactate dehydrogenase solubility, high biological activity, and good conju-
PEI Polyethyleneimine) gated with various inorganic and organic substances
BPEI Branched poly-(ethylenimine) [9–11] In 2006, Sun et al. reported achieved high-
PAA Poly(acrylic acid) quantum yield luminescent CDs using a chemical
APTMS (3-Aminopropyl) trimethoxysilane surface passivation agent [12]. Since then, several
AT II Alveolar type II cells studies have been conducted by researchers to
DCFH-DA Dichloro-dihydro-fluorescein understand the origin of the photophysical behavior
diacetate assay of CD, to develop different synthesis methods, to
NBT Nitroblue tetrazolium assay modify their surfaces, and to use them in advanced
p53 The P53 gene applications [13–16]. These particles typically feature
TNF3 The TNF3 gene some form of surface passivation through chemical
CDKNIA The CDKNIA gene modification. Most CDs exhibit robust fluorescence
NFKBIA The NFKBIA gene and/or phosphorescence due to quantum effects.
AgNP Silver nanoparticle Another result of these dominating quantum effects
CuO NP Copper oxide nanoparticle is that CDs are highly photostable and chemically
TiO2 NP Titanium oxide nanoparticle resilient [17]. For these reasons, CDs attracted much
Ni NP Nickel nanoparticle attention in the areas of bioimaging, biosensing, and
CAL-27 Oral adenosquamous carcinoma cell drug delivery over the last decade [18–25]. CDs have
several significant advantages compared to other
nanoparticles. Carbon is a very abundant element,
making CDs cheaper and easier to produce.
Introduction In contrast to most nanoparticles, which are semi-
conductive, CDs are conductive, which simplifies
their chemistry and electrical behavior. CD’ toxicity is
Fluorescent carbon dots (denoted as CDs, CDots, or also generally lower than other nanoparticle toxici-
CQDs), also called carbon quantum dots, are a new ties, especially metal nanoparticles. Environmental
type of carbon-based zero-dimensional consisting of analyses of CDs found them to be environmentally
quasi-spherical and discrete nanoparticles with non-persistent, obviating the need for concerns of
dimensions less than 10 nm in diameter [1, 2]. CDs bioaccumulation [26].
exhibit unique properties such as high-water solu- The goals and content of the study were mainly
bility, chemical inertness, high fluorescence quantum aimed at a determination and evaluation of the
yield, photo-bleaching resistance, wavelength-de- nanosafety aspect of CDs, with particular emphasis
pendent photoluminescence (PL) behavior, broad on long-term toxic effects such as cytotoxicity and
Stokes shift, low toxicity, and biocompatibility. In genotoxicity. Such safety concerns must be alleviated
many studies with these properties, CDs have been or, at the very least, soothed to allow for a strong
presented as alternatives to heavy metal-based impetus for adoption. To date, the nanosafety aspect
quantum dots (QDs), organic dyes, and other carbon- of CDs is still being developed, with articles such as

Figure 1 A Picture of different fractions of fluorescent carbon under UV light (365 nm), B TEM image of tubular carbon, and C TEM
image of purified carbon nanotubes and D morphological structure of CDs. Reprinted with permission from [8, 10, 11].
those discussed and referenced in this article being
published regularly. Thus, the safety margins for CD
toxicity have been improving regularly, a summary
of which is one of the goals this review seeks to
accomplish.
The concept of nanosafety has been in develop-
ment for as long as nanomaterials themselves. The
primary concern is that due to the minuscule size of
CDs, they cannot be expected to correlate in physic-
ochemical characteristics to macro-sized materials.
On the scales at which one expects to find CDs, the
diameter of the CD is comparable to the de Broglie
wavelength for the electron (* 1.2 nm for electron
energies of * 1 eV); thus, the inherent wave-like
nature of the electron becomes apparent. In addition,
the exciton Bohr radius increases to beyond the
physical size of the nanoparticle itself, resulting in a
divergence of the behavior of CDs from macro-sized
J Mater Sci
materials due to quantum electrodynamic (QED)
corrections to classical electromagnetism. Thus, the
toxicity profiles of bulk materials cannot be reliably
extrapolated to nanomaterials in general and CDs in
particular, necessitating custom-tailored toxicity tests
to address nanosafety concerns. Ideally, the behavior
of a nanoparticle in general, and a CD, in particular,
can be definitively calculated within reasonable
accuracy on a purely quantum mechanical basis by
the development of a Dirac-form bispinor wave-
function; however, to the knowledge of the authors,
no such attempt has been previously made. The
nanosafety concerns concerning nanoparticles, in
general, can thus be satisfied by the development of
custom-tailored assay methodologies explicitly
developed to produce data aimed at addressing these
concerns.
J Mater Sci
This mini-view was provided to update the present
status of CD research, to ensure the dissemination of
up-to-date information about the toxicity effects of
this soon-to-be-functional material in biomedical
applications as well as potentially highlight the
shortcomings of the data already produced. It also
aims to inspire new research to increase the potential
of these interesting materials, in addition to under-
scoring the remarkable physicochemical properties
boasted by CDs.
Synthesis, properties, and characterization
of carbon dots
Synthetic strategies
In the past few years, many easy synthetic strategies
have been advanced to obtain CDs with different
physical and chemical properties. In reported studies,
researchers have shown that parameters such as
carbon source, synthesis method, and surface passi-
vation agent used during synthesis modify the pho-
toluminescence properties by modifying the
properties of the surface of CDs [12, 16, 27]. Synthesis
methods of the fluorescent CDs are summarized
under two main headings ‘‘top-down’’ and ‘‘bottom-
up approaches,’’ as shown in Fig. 2. In the top-down
approach, CDs are synthesized by arc-discharge,
laser ablation, electrochemical oxidation methods
Figure 2 Methods used in the
synthesis of carbon nanodots.
from starting materials such as graphite dust or sin-
gle and multi-walled carbon nanotubes (SWCNT–
MWKNT) and are generally carried out under
physical or chemical conditions. Microwave pyroly-
sis, ultrasonic synthesis, and hydrother-
mal/solvothermal methods are applied to the
bottom-up approach. In this approach, CDs are syn-
thesized from macromolecular precursors containing
surface passivation agents, biomass, and materials
with carbon sources such as glucose, fructose (Fig. 3).
Recently, microwave, thermal, and hydrothermal
synthesis methods have been preferred due to their
advantages such as being environmentally friendly
and economically cheaper, the synthesis reaction
occurring in a shorter time, the size of the synthesized
particles being smaller and having a higher quantum
yield [16, 28, 29]. Some synthesis methods of CDs in
the literature and the physical properties of the syn-
thesized particles are given in Table 1.
Synthesis of carbon dots from natural
sources
CDs are synthesized from inorganic materials con-
taining carbon sources such as graphene, carbon
black, wax, and organic materials such as polymers,
plant extracts, food, and food waste. Recently,
organic materials are more preferred as the carbon
source in terms of economically cheap, easy avail-
ability, and green chemistry synthesis than inorganic
 J Mater Sci

Figure 3 A Emission effect

of surface passivated CDs with
PEG1500N at band-pass filters
of different wavelengths.
Reprinted with permission
from [12], and B Emission
effect of surface passivated
CDs with different passivation
agents under 365 nm UV light.
Reprinted with permission
from [48].

Table 1 Some synthesis methods of CDs in the literature and the physical properties of the synthesized particles

Sources Method Fluorescence color Particle size (nm) References

Bread Ultrasonication Blue 27.5 ± 6.1 [30]

Jaggery Thermal Blue 20.3 ± 7.5 [30]
Sugar caramel Thermal Blue 4.3 ± 1.5 [30]
Waste food Ultrasonication Blue 4–6 [31]
Pomelo peel Hydrothermal Blue 2–4 [32]
Molasses Microwave Blue 5––7 [33]
Eggshell Calcination treatment Blue 2–6 [34]
Hair Pyrolysis treatment Blue 2.3 [35]
Sucrose Microwave Green 3–10 [36]
Chitosan Hydrothermal Blue 4–7 [27]
Graphite Laser ablation Blue 1–8 [37]
Citric acid Microwave pyrolysis Blue 2.2–3 [38]
Phosphoric acid Acidic oxidation Yellow–green 1–3, 2–4 [39]
Polyacrylic acid Pyrolysis White–blue 2–5.3 [6]
Phenylenediamine isomers (mPD, oPD, pPD) Solvothermal Blue–green–red 6, 8.2, 10 [40]
Carbon soot Thermal Green 2–6 [41]

materials. These carbon-containing natural sources
have been described as precursors in the synthesis of
CDs. CD synthesis was performed by the carboniza-
tion of these precursors [42–44]. These carbon-con-
taining organic sources have been described as
‘‘green’’ precursors in the synthesis of CDs, and in
most of the preparation methods, CD synthesis was
performed by the carbonization of these precursors.
CD synthesis from ‘‘green’’ precursors has advan-
tages of reducing chemical exposure, decrease waste,
producing cost-effective and eco-friendly, plenty of
biomass (Fig. 4). Over time, the surfaces of the CDs
were functionalized using organic and polymeric
macromolecular surface passivating agents (i.e.,
polyethylene glycol (PEG), polypropyle-
neethyleneimine-co-ethylenimine (PPEI-EI)) and CDs
synthesized CDs without surface passivation agent
the fluorescence quantum yield was found to be
higher [12, 45]. Photoluminescent properties and
fluorescence quantum yield of CDs synthesized with
surface passivation material were found to be chan-
ged (Fig. 3). To date, various green carbon precursors
J Mater Sci

Figure 4 Some of the natural resources used in the synthesis of carbon nanodots.

have been used to synthesize CDs with high-quan- inorganic, or polymeric surface passivating agents, it
tum yields using simple, cost-effective, environmen- has been observed that there are large amounts of –
tally friendly methods [46, 47]. OH and –COOH and –NH2 and other groups on the
surfaces of the particles [37, 50]. When we look at
Physical and chemical properties of carbon X-ray diffraction (XRD) and Raman studies, it is
dots generally found that CDs contain an amorphous-
nanocrystalline nucleus, often sp2 carbon and the
Structure properties cage spacing is consistent with graphite and tur-
bostratic carbon [53, 54]. XRD spectra of CDs usually
CDs are routinely characterized by various analytical
display a broad peak that can be attributed to highly
methods to determine the physical and chemical
irregular carbon atoms between 20° and 27°. Here,
properties of the particles, the crystal structure of the
the degree of graphitization becomes higher with the
carbon atoms, and the functional group type and
sharpness of the peak [48, 55, 56].
abundance on the particle surface. The nuclear
magnetic resonance (NMR) measurements taken by
Optical properties
Liu et al. showed that CDs consist of sp2 hybridized
with saturated sp3 carbon atoms and these are con-
Absorbance The UV–visible spectrum of CDs typi-
jugate systems [14]. In general, spherical or spherical
cally has a sharp absorption peak in the UV region
shaped particles having dimensions in the range of
(240–320 nm), with a tail extending to the visible
1–67 nm are reported, depending on the conditions
region. Due to differences in HOMO–LUMO energy
of synthesis and the products of the CD, and these
levels after surface passivation or/and functional-
dimensions are shown by atomic force microscopy
ization and heteroatom doping of CDs, absorption
(AFM) and transmission electron microscope (TEM)
band maxima shifts to red [45, 57]. The absorption
images [49–52]. As a result of Fourier-transform
peaks appearing of the CDs between 230 and 270 nm
infrared spectroscopy (FT-IR) analyzes for CDs
and 300–330 nm is due to the p–p* electronic transi-
functionalized surfaces using various organic,
tion of the C=C bonds, and the n–p* transition of the

C=O bonds, respectively [48, 58]. Green fluorescence
CDs synthesized from lemon salt exhibited a spec-
trum of absorption extending to the visible range
with peaks assigned to the p–p* transition at 245 and
270 nm and n–p* electron transition at C=O bonds at
335 nm [55].
Photoluminescence The color-emitting photolumi-
nescence feature (PL) is one of the unique properties
of the CD. In the last decade, rational strategies have
been developed, and surface modification has been
carried out by conjugating various passivation agents
to the surface of the CDs to clarify the factors affect-
ing the fluorescent mechanism of CDs. As a result, it
is possible to edit the color emission when the CDs
are prepared in a controlled manner. However, there
is only one known fact that the PL characteristic of
the CDs is dependent on the excitation wavelength
(kex) of the emission wavelength and intensity [59].
Recent studies have shown that the PL property of
CDs decreases, as in QDs, due to the decrease in the
energy gap caused by the increase in the particle size.
PL behavior has been attributed to surface properties
such as carbon excitons, emissive traps, aromatic
conjugate structures, free zigzag region, heteroatom
doping, and functional groups [60–62]. Sun et al.
Reported that after the passivation of CD’s surface
with polymeric materials such as poly(propionyl
ethylenimine-co-ethylenimine) (PPEI-EI) and poly-
ethylene glycol (PEG), they stabilized existing surface
defects and exhibited strong fluorescence emissions
both in solution and in the solid form [12]. Alaş and
Genç showed that the photoluminescence of CDs
could be chemically controlled by surface functional
groups. They found that fluorescence intensity and
the color was associated with particle surface func-
tional groups (i.e., carboxyl, alkyl, hydroxyl) by pro-
viding particle surface passivation with various
biocompatible macromolecules (i.e., polyethylene
glycol, polyvinyl alcohol, chitosan) [48]. Although
there is a lot of research on CDs in the literature, the
information about the origin of CD’ PL is still a
matter of debate and needs further research.
Up-conversion photoluminescence Additionally, to the
down-conversion fluorescent emissions of the CDs, it
has also been observed up-conversion fluorescence
emission optical behavior where fluorescence emis-
sion wavelength is shorter than the used excitation
wavelength. This optical phenomenon makes CDs
J Mater Sci
more attractive for in vivo bioimaging with improved
photon tissue penetration, reduced background aut-
ofluorescence, and low photon-induced toxicity at
longer wavelengths in the NIR region. Sun et al.
obtained S, N doped CDs exhibiting up-conversion
photoluminescence from hair fiber. They reported
that with the control of the atomic composition, the S,
N doped CDs change the down-conversion and up-
conversion PL properties. The emission wavelengths
showed redshift by increasing excitation wavelengths
from 600 to 900 nm [63]. Cui et al. synthesized green
fluorescence CDs using ammonium citrate, ammonia,
and water and used them directly to imaging living
human HeLa cancer cells without surface alteration.
CDs stimulated at different long wavelengths appear
with a maximum upconverted fluorescence intensity
under 850 nm excitation [64].
Applications of carbon dots
CDs have been applied to different areas such as
solar cells, supercapacitors, optronic, and sensors due
to their outstanding electronic and optical properties
such as electron acceptor and donor, wavelength-
dependent emission, and broad absorption spectra.
Also, the superior biological and optical properties of
CDs, such as low toxicity, excellent biocompatibility,
bright fluorescence, and high resistance to photo-
bleaching, make them potential materials in
bioimaging, biosensor, and drug delivery systems.
Physical properties and application areas of CDs
synthesized from different green natural sources in
the literature are given in Table 2 and Fig. 5. Here,
we will present the specific applications using CDs as
follows.
Energy applications
Solar cell
Solar cells convert directly into electricity using
sunlight, one of the cleanest, safest, and sustainable
energy sources among renewable energy sources. In
order to capture photon energy and increase effi-
ciency, environmentally friendly (‘‘green’’ materials)
and inexpensive materials are vital in the new gen-
eration fabrication of solar cells. In a solar cell system,
electrons and holes in the donor materials are pro-
duced by photo-excitation and are separated by the
J Mater Sci

Table 2 The synthesis and applications of CD from different green carbon sources in the literature

Nature source Method Fluorescence color Particle size (nm) Application References

Mango Thermal Blue–green–orange 5 ± 15 Bioimaging [4]

Orange juice
Potato Hydrothermal Green * 2.5 Bioimaging [44]
Hydrothermal Blue 0.2–2.2 Cell imaging [42]
Lignin Hydrothermal Blue 2–10 Bioimaging [125]
Ginger Hydrothermal Blue 4.3 ± 0.8 Inhibition of tumor [126]
Peanut shell Ultrasonic filtration Blue 0.4–2.4 Cell imaging [127]
Winter melon Hydrothermal Blue 4.5–5.2 Bioimaging [128]
Silkworm chrysalis Thermal Blue 12 ± 27 Cell imaging [129]
Sweet pepper Carbonization Blue 3±7 Detection of hypochlorite [130]
Butter oil Thermal Blue 4–10 Reducing agent [131]
Citric acid Hydrothermal Blue * 4.8 Solar cells [68]
Potato starch Hydrothermal Blue *3 LED [132]
Aloe vera Thermal Blue * 6–8 Antimicrobial activity [133]
Waste paper Hydrothermal Blue 3–7 Bio-labeling [134]
Coriander leaves Hydrothermal Blue 1.5–3.15 Bioimaging [135]
Citric acid Microwave Blue 2–10 Fingerprint detection [136]
Lemon salt Thermal Green 11 ± 0.9 Supercapacitor [55]
Cola Thermal Green 12.85 ± 1.3 Supercapacitor [56]
Blue 42.2 ± 5.6
Red 11.73 ± 1.5

Figure 5 Schematic diagram concerning the synthesis method, properties, and applications of CDs.

acceptor along the junction. An excellent donor on the application of carbon nanostructures (such as
material should have a high absorption coefficient graphene, CNTs, fullerene, and CDs) to solar cells
and tunable bandgap for the solar spectrum. Studies have been reported for the development of new

generation solar cells [65–67]. CDs become an alter-
native material for the fabrication of solar cells due to
their excellent properties such as broad absorption
spectra and high absorption coefficients, wavelength-
dependent emission, electron acceptor and donor
behavior, photo-induced charge transfer, inexpen-
sive, and low toxicity [68–70]. To date, due to their
charming properties and green nature material, there
are many studies that CDs use as inexpensive sensi-
tizer replacements in dye-sensitized solar cells
(DSSCs) or as photoactive material, electrolyte, or
counter electrode dopants in other solar cells (e.g.,
perovskite solar cells (PSC), quantum dot solar cells
(QDSC), organic solar cells (OSC) [71–74].
CDs have attracted researchers’ attention as pho-
tosensitizers in solar cells. Ma and co-workers (2013)
developed a CD-doped dye/semiconductor complex
system (CD–RhB–TiO2) for the production of high-
efficiency photoelectric conversion systems. In this
system, CDs functioned as an electron transfer
intermediary, showing that RhB molecules are
attached to the TiO2 surface, and it showed seven
times more photoelectric conversion efficiency than
traditional dye-sensitized semiconductor systems
[75]. The literature on CDs as a solar-cell material is
still limited, although the recent outcomes strongly
encouraged further research into the application of
CDs in photovoltaic device development. CDs caught
the attention of researchers as potential sensitizers in
the photoanode in DSCCs. Mirtchev et al. (2012) first
used CDs in place of Ruthenium dye, which is a
sensitizer that performs well in DSSCs, and produced
a CD sensitive TiO2 solar cell. As a result, CD sensi-
tive TiO2 solar cell exhibits Jsc as 0.53 mA cm-2, Voc
as 0.38 V, fill factor of 0.64, and power conversion
efficiency of 0.13% [76]. Zhang and co-workers (2013)
have fabricated devices with like configuration by
using nitrogen-doped CDs. It has been observed that
efficiency increases from 0.03 to 0.13% with the
nitrogen additive and improves device performance.
Up to now, CDs have been used as sensitizers, co-
sensitizers, and counter electrodes for DSSCs [77].
Recently, DSSCs using dyes and CDs as co-sensitizers
have been produced, and high conversion efficiency
has been achieved. Zhu et al. (2017) designed a
hybridized DSSC prototype using N719 dye and
polyethylene glycol (PEG)-modified carbon quantum
dots (PEG-m-CQDs) as sensitizing photoanodes.
Compared to the DSSCs designed to date, this solar
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cell reached the highest efficiency, reaching 9.89%
[78].
OSCs are designed by combining CDs with other
typical interface materials as electrode interlayers,
and it has been reported to improve device perfor-
mance. In Zhang et al. (2015), CDs have used as ETL
material for OSCs and have been reported to perform
much better in CD-powered devices in terms of both
power conversion efficiency and life stability (Jsc as
10.25 mA cm-2, Voc as 0.609 V, fill factor of 0.548,
and power conversion efficiency of 3.42%) [79].
Zhang and co-workers (2016) have designed OSC by
adding CDs as the interface layer between the active
layer and the hole transport layer (HTL). They
showed that there was an improvement in hole
extraction in PCDTBT:PC71BM based solar cells and
that PCE increased from 5.93 to 7.22% due to the
improvement of Jsc and FF [80].
Nowadays, the use of CDs has started to increase
in PSCs with high efficiency. In particular, the effect
of CDs on various layers of PSCs has been investi-
gated. Paulo et al. (2016) reported the first study on
PSCs using CDs as a hole transfer material (HTM),
and they achieved a high power conversion efficiency
of up to 3% from this first PSC device designed. As a
result, it demonstrated that CDs are suitable as HTM
material to provide both effective hole transfer and
electron blocking capability from the perovskite layer
to the HTM layer [81]. As a result of reported studies,
Hui and co-workers (2019) reached the highest effi-
ciency of 22.7% in CD-doped PSCs by using RCD-
doped SnO2 composites as an electron transfer layer
(ETL). These results demonstrate that cheap and non-
toxic CDs are essential but perfect additives for pro-
ducing efficient ETLs with enhanced stability and
higher-performance PSCs [82].
Supercapacitor
In supercapacitors (SCs), CDs have been used as an
environmentally friendly electrode material to
expand the contact area between the electrode and
electrolyte and to facilitate electron transport and
ionic movement. When supercapacitors based on
carbon materials are hybridized with CDs, the elec-
trochemical performance of these supercapacitors has
been significantly improved due to the large specific
surface area of the CDs, which increases the accessi-
bility of charged ions and facilitate charge transport
and ionic motion during charge–discharge processes
J Mater Sci
[83]. For the application of CDs in SCs, Hoang et al.
have synthesized graphene–carbon dot (RGO/CD)
composites and investigated the electrochemical
performance of electrodes with GO–CD mass ratios.
The RGO/CD composite electrode exhibited excel-
lent specific capacitance and superior cycle stability,
and it has a higher capacitance of 278 F/g compared
to the RGO electrode [84]. Zhao et al. produced an
interconnected 3D network of reduced graphene
oxide (rGO/CDs) decorated with CDs and used them
as a non-binding electrode for the supercapacitor. As
a result, it demonstrated excellent long-term cycle
stability (ca. 92% capacitance retention after 20.000
charges/discharge cycles at a current density of 10
A/g) and maximum specific capacitance of 308 F/g
[85].
Moreover, the researchers reported that CDs
effectively improve their performance when added to
metal oxide-based electrode materials for superca-
pacitors. Lv and co-workers used the CD-induced
MnO2 nanowire as the electrode material. They
designed a supercapacitor with high specific capaci-
tance (340 F/g), excellent recyclability (80.1% capac-
ity retention over 10.000 cycles at 1 A/g), long cycle
life, and improved stability due to the enhanced
wettability between electrode and electrolyte by the
addition of CDs [86]. Prasath et al. have used CD-
MnO2 nanohybrid structures as an electrode in the
supercapacitor. The designed device indicated a
perfect electrochemical response with a high specific
capacitance of 189 F/g besides significant cycle sta-
bility (12.000 charge–discharge cycles at 0.14 A/g.
They attributed this result to the large surface area
and the presence of highly conductive CDs [87].
Conductive polymers (i.e., polyaniline and poly-
pyrrole) known as efficient pseudocapacitive mate-
rials combined with CDs, revealed stable specific
capacitance in supercapacitors. Genç et al., a-MnO2/
PPy hybrid nanorod decorated with CD have been
used as anode material, and they achieved a high
capacitance value of 17.3 lF/cm2. Capacitive prop-
erty of a-MnO2 nanorods and C8H16BImI and the
conductivity and ion donation ability of the CD have
indicated significantly superior capacitive and rate
performance in the designed hybrid SC compared to
the standard electrode–electrolyte combination [56].
Alaş and co-workers synthesized manganese(II)-
doped N-CD embedded PANI composite and used
both N-CD and composite as electrode material in
SC. As a result of the measurements, the N-CD
increased the efficiency of the PANI by providing a
larger surface area and reducing the resistance to
current flow, resulting in a relatively high specific
capacitance value of 595 F/g [55].
Sensor applications
CDs with facile surface functionalization, excitation
wavelength-dependent fluorescent behavior, and
narrow spectral bands have been used as a variety of
advanced fluorescent sensing platforms for specific
detection of chemical/biochemical materials, metal
ions, and pH. The principle of platforms where CDs
are used as fluorescence sensors is based on the flu-
orescence change after analyte detection [88–91].
In metal ions detection, Baç et al. prepared nitro-
gen-doped CDs for Hg2? detection in real samples
(tap, stream, and sea) with a detection limit of
1.41 lg/mL by making use of fluorescence quench-
ing through coordination among Hg2? and amino
groups of CDs [92]. Omer and co-workers have
demonstrated that CDs are suitable fluorescent
probes for high selectivity and sensitivity of Fe3?
through the fluorescence quenching mechanism. The
tests performed showed a linear response in the
0.1 lM to 0.9 lM Fe3? concentration range and limit
of detection 50 nM [93]. In anions detection, Sun et al.
have synthesized CDs/PEI/NB nanocomposite by
conjugating carrot-synthesized CDs with poly-
ethyleneimine (PEI) and Nile blue (NB) and used as a
ratiometric two-photon fluorescence (TPF) turn-on
probe for sulfide (S2-) detection. When Cu2? ions are
added, the fluorescence of CDs/PEI/NB is quenched,
but by adding S2-, the quenched fluorescence is
recovered by separating Cu2? from CD. The detection
system of this probe for the S2- concentration
between 0.1 and 8.0 lM is highly selective and has a
high sensitivity with a limit of detection 0.06 mM
[94]. Li and co-workers utilized polymeric ethylene
imine (PEI) functionalized photoluminescent carbon
dots (PEI@CDs) for the detection of BrO3- anions
with high sensitivity and selectivity through photo-
luminescence (PL)-based detection system. In this
BrO3- detection system, a quite low detection limit of
0.17 nM has been reached [95]. Baruah et al. designed
a simple system for the detection of biochemical
dopamine and ascorbic acid in an aqueous medium
using CDs synthesized by the green method. The
limits of detection were determined to be 33 lM and
98 lM for dopamine and ascorbic acid, respectively

[96]. Hu et al. used gold nanoparticles @ carbon
quantum dots nanocomposites (Au@CQDs) to visu-
ally determine the amount of melanin in milk. With
this sensor they designed, a calibration curve
(R2 = 0.9856), and fluorescence standard sequence
were set for melamine detection in the range of
1–10 lM. The limits of quantification and limit of
detection were found as 12 nM and 3.6 nM, respec-
tively [97]. Wang et al. have designed both fluores-
cence and visible dual-mode colorimetric/
fluorescence pH sensors with CDs. As the pH
increased (range 1–14), the fluorescence of both the
CD solution and the CD embedded pH test papers
changed from red to orange, then yellow [98]. Thus,
pH can be determined quickly by the fluorescence
and visible colorimetric changes with CD solution.
Ink for anti-counterfeiting and fingerprint detection
applications
Fluorescent dyes can be used for anti-counterfeiting
protection to prevent duplication of important doc-
uments (such as banknotes, tickets, certificates, and
various luxury items) and fingerprint detection in
forensic laboratories [99]. CDs are ideal materials to
be used in this application area due to their unusual
photoluminescence behavior, non-toxicity, and low-
cost synthesis [100, 101]. For instance, Li et al. syn-
thesized PVA nanocomposite with CDs with triple
mod emission, and this synthesized solution loaded
into a gel pen refill and used it as a direct ink for use
in counterfeiting. To illustrate the performance of this
ink, they wrote a Chinese character ‘‘heng’’ and an
English character ‘‘A’’ on the bill and invoice and saw
bright blue characters similar to the markers under
the 365 nm UV lamp [101]. Yang and co-workers
used xylose-derived CDs that display fluorescence
between green and blue emission in different pH
regions, as a fluorescent ink to produce QR code and
word information against optical counterfeiting. They
reported that with their high chemical stability and
fluorescence conversion, CDs are potential material
for optical applications against counterfeiting [102].
Moreover, unlike existing fingerprint powders,
Bahadur et al. used easy-to-synthesize, biocompati-
ble, and non-toxic CDs as a solid-state fluorescence
probe for fingerprint analysis using a simple mobile
phone camera. Since CDs are fluorescence-based
imaging probes, they have demonstrated that they
are suitable for the collection and analysis of
J Mater Sci
fingerprint data on ten different solid surfaces (i.e.,
paper, optical mouse, aluminum foil, metallic alloy,
porcelain) without contaminating the evidence at the
crime scene. Tang et al. used orange-emitting CDs to
detect latent fingerprints at high speed. Details of
latent fingerprints on the aged and various surfaces
were observed under UV after immersion in the CD
solution [103]. Wang et al. used strong fluorescence
solid-state CDs as fluorescent colorant reagents to
detect latent fingerprints. CD powder was sprinkled
on fingerprints on different surfaces, and CD powder
was carefully removed. Significant areas like back-
ending and bifurcation have been distinguished in
detail in the fingerprint patterns examined under UV
light [104].
CDs as fluorescent label in cell imaging
CDs with bright fluorescence, photobleach stability,
biocompatibility, and low toxicity are potential
materials for fluorescent imaging probes. Using
in vivo and in vitro cytotoxicity assays, CDs have
been reported to be non-toxic for cells with high
concentration levels as fluorescence labeling and
imaging agents [105, 106]. Therefore, there are many
reports in the literature where CDs are used for flu-
orescence labeling and imaging of cells [107, 108].
Wang et al. synthesized water-soluble phosphorus-
containing carbon dots (PCDs) with high green flu-
orescence using a one-step microwave-assisted
method. As a result of the MTT test, they saw that
these PCDs had low toxicity and used them as fluo-
rescence probes for cell labeling–imaging. While
PCD-labeled L929 cells imaged in vitro under 405 nm
excitation showed bright green light, there was not
shown fluorescence in the unlabeled control group
cells [109]. Yao and co-worker synthesized gadolin-
ium-doped magneto-fluorescent carbon dots
(Gd@CQDs) from the crab shell, and these CDs con-
jugated with folic acid (FA-Gd@CQDs) for targeted
cellular imaging of folate receptor-positive HeLa cells
and folate receptor-deficient HepG2 cells. The fluo-
rescence signal received in HeLa cells labeled with
FA-Gd@CQDs was more intense than HepG2 cells
labeled with FA-Gd@CQDs. Inhibition studies were
performed by adding free folic acid to the culture
medium before incubating the cells with FA-
Gd@CQDs. Cellular binding with free folic acid
occurred, and the HeLa cells labeled with FA-
Gd@CQDs showed weak intracellular fluorescence.
J Mater Sci
In addition, HeLa cells labeled with Gd@CQDs
exhibit a weak fluorescence emission, which indicates
that folic acid plays a significant role in effective
intracellular transmission via folate receptor-medi-
ated endocytosis [110]. Wang et al. used biocompat-
ible CDs synthesized from beer for imaging in breast
cancer cells. BCD-treated MCF-7, MDA-MB-231, and
BT-549 cells showed a fluorescence signal at 405 nm
excitation. However, control cells without BCD
showed almost no fluorescence signal. fluorescence
signals of BCD are collected in the cytoplasm, sug-
gesting the availability of BCDs for in vitro breast
cancer cell labeling [111]. Kumar et al. synthesized
carbon dots (E@CDs) doped with different elements
(B, N, and P) with a one-pot simple synthesis method
that displays to be sufficient for neuro-engineering
application and cell labeling. Labeled neuronal cells
(SH-SY5Y) with raw CD and E@CDs showed fluo-
rescence signals at confocal microscopy. These results
show that CDs and E@CDs can be used as ideal cell
imaging probes that are non-cytotoxic [112].
Drug delivery applications
CDs have been used in drug delivery systems to
increase drug solubility and drug half-life due to
their biocompatibility, low toxicity, good surface
activity, and improved cell uptake properties. For
example, Song et al. have developed a practical
approach for cancer cell screening and detection with
folic acid-modified CDs. With this proposed
approach, they indicated that there is a great poten-
tial for cancer diagnosis studies by showing the
applicability of cancer cells to distinguish them from
healthy cells [113]. Hettiarachchi et al. aimed to
deliver the chemotherapeutic drugs of epirubicin and
temozolomide with the triple (transferrin, epirubicin,
and temozolomide) conjugated CDs to the glioblas-
toma brain tumor cells with the help of transferrin
entering the cell through receptor-mediated endocy-
tosis. These triple conjugated CDs increased the
cytotoxicity of glioblastoma brain tumor cell lines
and were found to be a better therapeutic agent than
a single drug delivery method [114]. Kong et al. have
developed the CDs-DOX drug delivery system to
investigate the anti-tumor activity of CDs conjugated
DOX in cancer treatment. This system has shown a
high drug loading capacity and proper drug release.
Besides, in vitro results have shown that the CDs-
DOX complex has higher cellular uptake by cancer
cells and more effective inhibition capacity compared
to free DOX [115]. Jung et al. have synthesized multi-
functional zwitterionic carbon dots with citric acid as
carbon source and p-alanine as a passivating and
zwitterionic ligand for the nucleus-targeting drug
delivery system. The CD-based drug delivery system
created by electrostatic interactions of anticancer
drug doxorubicin (DOX) showed high anti-tumor
activity due to increased in vitro nuclear transport
and tumor accumulation in vivo. In addition, this
CD-based drug delivery system significantly
increased cytotoxicity in cancer, both in vitro and
in vivo [116].
CDs as antimicrobial agent
As a result of in vivo and in vitro experiments, CDs
are generally known as benign and non-toxic mate-
rials [117]. However, CDs have been reported to
exhibit strong photodynamic effects in cancer thera-
pies due to their ability to light-harvesting in a wide
spectral range from UV to IR [118, 119]. CDs inhibit
bacteria growth or kill bacteria by producing reactive
oxygen (ROS) species and fragmentation of genomic
DNA and cell structure [120, 121]. For example, Li
et al. tested the antimicrobial activity of spermidine-
coated fluorescent carbon quantum dots (Spd-CQDs)
on non-multidrug-resistant bacteria (MDR) such as
E. coli, S. aureus, B. subtilis, P. aeruginous, and MDR
bacteria such as methicillin-resistant S. aureus
(MRSA). Spd-CDs caused significant damage to the
bacterial membrane, exhibiting an effective antibac-
terial activity in both MDR and non-MDR bacteria.
They also performed an in vivo application to heal
MRSA-infected wounds in rats. Spd-CQDs have
shown that it can be used as antimicrobial and
wound-healing agents that provide better epithelial-
ization and the production of collagen fibers [122].
Song et al. have synthesized fluorescent CDs which
in vivo and in vitro low toxicity from cigarette smoke.
They examined the antimicrobial effect of these CDs
on E. coli, S. aureus, AREC, and KREC bacteria. They
reported that CDs exhibited broad-spectrum antimi-
crobial activity by disrupting the double helix struc-
ture of DNA and showed inhibitory effect at a
maximum concentration of 1000 lg/mL [123]. Jijie
et al. modified the surface of the amine-functional
CDs with antibacterial ampicillin (AMP) and pre-
sented a new perspective for antimicrobial photody-
namic therapy. Immunization of AMP to CD surface

(CDs-AMP) increased the stability and bactericidal
activity of CDs. Therefore, CDs-AMP has been very
effective in inactivating Escherichia coli growth by
producing middle amounts of reactive oxygen spe-
cies and impairment of cell membrane integrity
under visible light illumination [124].
Nanosafety aspect and toxicity assessment
studies of carbon dots
Nanosafety aspect of carbon dots
Risk assessment refers to the sum of the activities,
guidelines, and regulations aimed at the identifica-
tion, analysis, and quantification of current, possible,
and potential events and or exposures that may affect
in an adverse manner the individuals, flora and
fauna, assets, financial or otherwise and/or the
environment of an ecosystem. Thus, a proper risk
assessment provides the earliest and extremely
secure barrier against untoward exposures. A prop-
erly exercised systematic risk assessment is contin-
gent on an independent determination of both the
inherent hazard potential of the contaminant and a
thorough evaluation and analysis of actual exposure
levels (Fig. 6) [137]. In a typical exposure scenario
precipitated by the ordinary use of nanoparticle-
bearing consumer products, the exposure parameters
are best characterized by a relatively minor exposure
level and a low hazard potential inherent to these
nanoparticles. In comparison, nanomaterials with
higher hazard potential are delegated to professional
handling, where technical measures and purpose-
oriented procedures and techniques can be ade-
quately implemented and enforced to minimize, if
not outright eliminate, potentially dangerous
exposure.
Miniaturization of materials from macroscale to
nanoscale profoundly changes their physicochemical
characteristics. On the macroscale, the properties of a
material are well characterized by Maxwellian clas-
sical electromagnetism, with an expected Fermi–
Dirac distribution of electron states peaking around
the Fermi level(s) of that material. Thus, the electron
energy distribution of electrons in a macromaterial
can be described as a continuous Fermi–Dirac dis-
tribution of quantum states at the classical limit. This
continuous distribution breaks down as one approa-
ches the nanoscale, yielding to discrete energy levels
J Mater Sci
described by not classical electromagnetism, but first-
order and second-order quantization. On the scales at
which one expects to find CDs, the diameter of the
CD is comparable to the de Broglie wavelength for
the electron (* 1.2 nm for electron energies of * 1
eV); thus, the inherent wave-like nature of the elec-
tron becomes apparent. In addition, the exciton Bohr
radius increases to beyond the physical size of the
nanoparticle itself, resulting in a divergence of the
behavior of CDs from macro-sized materials due to
quantum electrodynamic (QED) corrections to clas-
sical electromagnetism. Thus, the toxicity profiles of
bulk materials cannot be reliably extrapolated to
nanomaterials in general and CDs in particular,
necessitating custom-tailored toxicity tests to address
nanosafety concerns. Ideally, the behavior of a
nanoparticle in general, and a CD, in particular, can
be definitively calculated within reasonable accuracy
on a purely quantum mechanical basis by the
development of a Dirac-form bispinor wavefunction,
however, to the knowledge of the authors, no such
attempt has been previously made. This divergence
in behavior between nanoscale materials and
macromaterials results in a large gap of knowledge
on the environmental characteristics of nanomateri-
als, such as the potential to impart unknown and
unpredicted effects upon biological systems apart
from the target. These effects, by their discreetness,
can be tremendously difficult to characterize or even
detect. Naturally produced nanomaterials and unin-
tentionally produced nanomaterials far outnumber
deliberately engineered and manufactured nanoma-
terials, but proceed through the ecosystem via shared
pathways, thus share a common base of action, and
thus, exposure scenarios [138, 139].
Nanosafety, or the safety of nanomaterials, is thus
supremely important in the development of bleed-
ing-edge nanotechnology. Among the large list of
factors that can determine the toxicity of nanoparti-
cles, size takes the lion’s share of studies. Quite a
large number of studies have laid particular empha-
sis on the effect of size on nanoparticle toxicity
[140–142]. Nanoparticle size has a profound effect on
the surface area, surface adsorption density, the
probability and effectiveness of cellular endocytosis/
exocytosis, pharmacokinetic parameters such as dis-
tribution, and may affect nanoparticle toxicity [143].
In addition to size, chemical constituency, shape,
chemical behavior, and functionalization of the sur-
face, the electrical charge retained at this surface, the
J Mater Sci
Figure 6 A The generally accepted principle assesses risk as
risk = hazard 9 exposure. B The workflow of in vitro testing. The
nanomaterials are dispersed in a physiological nutrient medium
that contains proteins and other macromolecules (coils) and low-
molar-mass components such as salts (dots). The nanomaterial
dosage and the route of administration, and the for-
mation of protein coronas also participate in the
determination of the toxicological profile of a
nanoparticle. Besides, ancillaries such as endocytosis,
leakage through plasma membranes, oxidative stress,
mitochondrial dysfunction, apoptosis, DNA damage,
necrotic death, metabolic products, and humoral
immune responses are also among the topics that are
on the discussion floor in nanosafety research. The
elucidation of these intracellular effects and their
mechanisms can aid in the design of safer nanoma-
terials. However, despite all of their advantages,
these in vitro studies still fall short of replicating the
biochemical and metabolic complexity and the pre-
dictive power of true in vivo tests. Such in vivo tests
produce information on whole-organism variables
such as distribution, metabolism, and excretion and
have been the topic of many studies on the matter.
Testbeds such as human cell lines employing human
endothelial cells or dermal fibroblasts, whole higher
animals such as rats, microorganisms such as bacte-
ria, aquatic organisms such as zebrafish and plants
are currently in utilization to determine the biological
surface changes by differential adsorption of some of these
components, correlated with changes in the state of agglomeration.
Only afterward, the interaction with a multitude of cell species is
studied by the (typically optical) readout of a large number of
markers and endpoints. Reprinted with permission from [138].
and environmental hazards of nanomaterials. Each
model can be custom tailored in specific configura-
tions to illuminate the behavior of nanoparticles in
realistic objects/systems with realistic scenarios and
assumptions. Combinations of these models allow for
a deeper understanding of nanoparticle toxicology in
biological or ecological settings [142, 144].
Nanosafety has long been growing as an impactful
issue in the global public safety consciousness. It
bears the potential to affect outcomes and repercus-
sions in societies and economies on a global scale. In
fact, it has been asserted that safety assurance of the
processes and used to manufacture and the tech-
nologies and products employing the use of these
nanoparticles will be integral to the successful
implementation of the use of these technologies,
materials, and products. The nurturing of a safety
culture that promotes the growth and development
of research on engineered nanomaterial safety will
thus be indispensable for the provision of tools and
methods over the next 10–20 years that allow high-
quality reliable research with high predictive power.
The analytical flow on the correlation between basic

and applied research and innovations is shown in
Fig. 7. This concept has been developed by the
NanoSafety Cluster (www.nanosafetycluster.eu/),
which incorporated all nanosafety research projects
and their scientists funded by the European Com-
mission Seventh Framework Programme (FP7) (htt
p://cordis.europa.eu/fp7/home_en.html) [145].
The evaluation of potential hazards of nanomate-
rials began in 1992 [138, 146–149] culminating in the
development of regulatory frameworks currently in
force, such as those in the EU, USA, and Canada
[150]. As the hazard potential of these nanomaterials
can stretch from virtually harmless to potent hazard,
the regulatory framework has morphed into case-by-
case risk assessment. Hazard potential and (internal)
exposure need to be merged into a testing strategy,
e.g., in the Registration, Evaluation, Authorization
and Restriction of Chemicals (REACH) Implementa-
tion Plan.
In order for nanomaterials to enter the global
markets as useful products will require not only a
quantitative determination of the aforementioned
physicochemical characteristics but also the factors
that can influence nanomaterial interactions with
biological structures and molecules such as proteins,
lipids, carbohydrates, and nucleic acids. Also, further
effects, if any, will need to be evaluated at the organ
and organism level in mammalian and environmen-
tally relevant species [145, 151]. Due to the afore-
mentioned physicochemical and safety hurdles,
Figure 7 Analytical flow on promoting the safety of engineered
nanomaterials and nanotechnologies (Redrawn from NanoSafety
Cluster (www.nanosafetycluster.eu/), which incorporated all
J Mater Sci
conventional testing strategies will fail with nano-
materials. These conventional approaches typically
employ rodent models, which are inherently prob-
lematic, especially in terms of financial, time, and
experimental thoroughness. Besides, due to rodents
being live animals, there will naturally exist issues
with the ethical ramifications of testing on animals
[152–155]. As the physicochemical landscape of
emerging nanomaterials is vast, rapid screening is
likely to be a major component of safety testing in the
early stages of development. Screening tests could
potentially employ lower organisms with reduced
ethical quandaries such as bacteria, nematodes, zeb-
rafish, fruit fly, and microorganisms, in combination
with improved protocols to accelerate the screening
process. These rapid tests, while not completely
replacing conventional testing, will rather supple-
ment them, allowing for effective decision-making in
an accelerated timeframe with greater safety margins.
Studies conducted on in vitro systems suggest that
nanomaterials can induce toxicity through a multi-
tude of mechanisms including particle breakdown
and release of contained toxic metals [141, 156–158]
and ROS production [159]. Some studies also indicate
that surface chemistry affects the in vitro toxicity
profile [160, 161]. Despite the presence of such stud-
ies, there exists a scarcity of animal-based toxicolog-
ical reports on nanomaterials. This may be
considered disturbing, as animal models are still
considered the best testbeds in the toxicological
nanosafety research projects and their scientists funded by the
European Commission Seventh Framework Programme (FP7) (h
ttp://cordis.europa.eu/fp7/home_en.html) [145].
J Mater Sci
profile generation for a novel agent, including
nanomaterials.
The sheer size of the landscape occupied by the
different characteristics assumed by nanoparticles in
general and CDs, in particular, unveils the enormity
of the cumulative avalanche of issues that await the
toxicologists bearing them: Not all nanomaterials are
alike and cannot be considered a homogeneous
spectrum of similar characteristics. Pharmacokinetic
and pharmacodynamic parameters, including toxic-
ity, of nanomaterials, are an amalgamation of many
different factors, including size, charge, concentra-
tion, outer coating bioactivity (capping material, and
functional groups), and oxidative, photolytic, and
mechanical stability. For example, some CDs have
been found to exert cytotoxic effects only after
oxidative and/or photolytic degradation of their core
coatings. Because CD dosage/exposure concentra-
tions reported in the literature vary in their units of
measurement, correlating dosage across current
nanosafety studies is a major undertaking by itself
[157]. Lastly, research on nanosafety and risk
assessment of CDs is still in a developing phase
despite thousands of studies that have already been
published on the subject, and several scientific open
questions exist.
Toxicity assessment studies of carbon dots
Many studies have attempted to elucidate the
mechanisms of nanoparticle toxicity and distinguish
between their bulk counterparts. The toxicity of
nanoparticles (NPs) is highly dependent on their
physicochemical characteristics. Full characterization
of nanomaterial includes determining the bulk
(shape, size, phase, electronic structure, and crys-
tallinity) and surface (surface area, the arrangement
of surface atoms, surface electronic structure, surface
composition, and functionality) properties of the NP.
Moreover, environmental factors (such as tempera-
ture, pH, ionic strength, salinity, organic matter) may
also affect NPs’ behavior and toxicity. Such concerns
of toxicity become especially prevalent when con-
sidering the possibility of long-term toxic effects with
stochastically unforeseeable outcomes such as cyto-
toxicity and genotoxicity.
In vitro and in vivo cytotoxicity assessment of carbon dots
Toxicity studies by various research groups have
shown that CDs have lower cytotoxicity compared to
heavy metal-based quantum dots due to their high
stability, hydrophilicity, and biocompatibility
[54, 162–164]. In 2009, Ray and colleagues exposed
HepG2 cells present in the human liver cell line to CD
solutions of 0.1–1 mg/mL synthesized from wax
culture for 24 h and determined the mean cell via-
bility by MTT assay, a colorimetric assay to assess cell
metabolic activity. When cells were exposed to con-
centrations lower than 0.5 mg/mL of CDs, cell via-
bility was observed to vary from 90 to 100% [54]. In
another study by Yang et al., two separate groups of
mice were treated with different concentrations of
CDs in solution (8 and 40 mg carbon core-equiva-
lent/kg body weight), and the activity of the mice
was monitored periodically. They found that the CDs
had low cytotoxicity (Fig. 8A) [165]. In 2012, Sahu
and colleagues synthesized CDs emitting green flu-
orescence from orange juice via the hydrothermal
method, which contains glucose, fructose, citric acid,
and ascorbic acid. They used these particles with
different morphological structures as bioimaging
agents [44]. Photoluminescent carbon dots were pre-
pared using the nitric acid oxidation method and
applied to the mousses and rats to systematic safety
evaluation via acute toxicity, subacute toxicity, and
genotoxicity experiments by Wang et al. (2013). At all
studied C-dot dosages in their study, no significant
toxic effect, i.e., no abnormality or lesion, was
observed in the major organs of the animals [166].
Recently, Yang et al. (2018) investigated the toxicity
and bio-distribution of green carbon dots after single
inhalation exposure in vivo. According to these
results, authors claimed that CDs caused mice death
at higher dosages and induced injury in the lung and
liver, including inflammation and necrosis after sin-
gle inhalation exposure at 5, 2, and 1 mg/kg dosages
of the CDs (Fig. 8A) [167].
Hsu et al. (2013) found that relative to catechin, the
CDs provide greater efficiency in the inhibition of
MCF-7 and MDA-MB-231 cancer cell growth, with
lower toxicity for the MCF-10A healthy cells [163]. Li
et al. (2014) showed that fluorescent carbon nanodots
(CDs; 4.3–0.8 nm) from fresh tender ginger juice
provide effective suppression of the growth of
human hepatocellular carcinoma cells (HepG2), with
low toxicity to healthy mammary epithelial cells

Figure 8 A a Illustration of the preparation procedure of green
fluorescent CDs, the formation of nanocomplexes with HA, and
bioimaging and drug delivery applications with H12 lung cancer
cells bright field and fluorescence images of a cells alone and
(MCF-10A) and liver cells (FL83B) [126]. Havrdova
et al. (2016) also evaluated the in vitro toxicity of
different kinds of CDs (CDs-PEG, CDs-Pri, CDs-PEI)
on mouse fibroblasts (NIH/3T3). The results suggest
that neutral CDs-PEG is the most promising for bio-
logical applications as they do not induce any
abnormalities in cell morphology, intracellular traf-
ficking, and cell cycle up to concentrations of 300 lg/
mL. Negatively charged CDs-Pri arrested the cell
cycle at the G2/M transition, stimulated proliferation
however they did not enter the cell nucleus. In con-
trast, positively charged CDs-PEI is found to be the
most cytotoxic ones since they have the capacity of
entering into the cell nucleus, and inducing the most
significant changes in the G0/G1 phase of the cell
cycle, even at concentrations of around 100 lg/mL
J Mater Sci
b cells incubated with CDs. Reprinted with permission from [165].
B Illustration of injury in the mice lung and liver after single
inhalation exposure of CDs (5 mg/kg) with TEM images.
Reprinted with permission from [167].
[168]. Periasamy et al. (2016) elaborated that CDs
reduce cell viability and cause chromatin condensa-
tion and DNA fragmentation on human mesenchy-
mal stem cells (hMSCs). Cell cycle analysis indicated
that CDs affect cell cycle progression [169]. Furkan
et al. (2019) have synthesized aluminum-doped CDs
(Al-CDs) from licorice root extract and tested their
immunomodulatory and immunostimulatory activi-
ties on mammalian macrophages in vitro. Pristine
CDs have a slight anti-inflammatory effect and have
no immunostimulatory potential. Therefore, while
CDs cannot be used as adjuvants, Al-CDs that have
strong pro-inflammatory activity based on TNFa and
IL1b production by unstimulated macrophages have
the potential to be used as both strong adjuvants and
adjuvant carriers [170]. In another study by Furkan
J Mater Sci
et al. (2019) have synthesized surface-functionalized
carbon nanodots (CDs) with various passivation
agents (polyethylene glycol (PEG), polyvinyl alcohol
(PVA), and alginate) from carob molasses and
investigated the effect of on in vitro inflammatory
function of mammalian macrophages of surface
functional groups on CD. CDs exhibited versatile
in vitro immunomodulatory activities on macro-
phages by changing pro-inflammatory production
levels depending on the surface functional group. As
a result, PVA functionalized CDs showed anti-in-
flammatory activity, while alginate functionalized
CDs showed a pro-inflammatory effect [171].
Gaddam et al. (2017) found that the fluorescence
behavior exhibited by CDs was utilized for heavy
metal ion sensing of Pb2?, Hg2?, and Cd2? ions in
aqueous media. Interestingly, both carbon nanodots
(CDs) and carbon nanobeads (CNBs) are biocom-
patible to normal cell lines but cytotoxic to cancer cell
lines, observed during several in vitro experiments
(cell viability assay, cell cycle assay, apoptosis assay,
ROS determination assay, caspase-9 activity assay).
Additionally, CDs exhibit bright green fluorescence
in B16F10 cells [172].
A study conducted by Lategan et al. (2018) found
that the effects (cell viability, biomarkers of inflam-
mation, cytokine biomarkers of the acquired immune
system, and a proteome profile analysis) of CDs on
the immune system were assessed using RAW264.7
cells and whole blood cell cultures. CDs were cyto-
toxic to RAW and whole blood cell cultures at 62.5,
250, and 500 lg/mL, respectively. Biomarkers asso-
ciated with inflammation were induced by CD con-
centrations 250 and 500 lg/mL under basal
conditions for both RAW and whole blood cell cul-
tures, respectively [173]. Chatzimitakos et al. (2018)
evaluated CDs on the four epithelial cell lines and
also found that properties of the as-synthesized CDs
on three cell lines have negligible toxicity whereas an
increase in HEK-293 cell viability is demonstrated,
granting cell proliferation properties [174].
Oxidative stress-associated toxicity of carbon dots
Oxidative stress is referred to as an imbalance
between the production of reactive oxygen species
(ROS) and the cells’ ability to reduce ROS, which
might be due to an increased ROS production, a
decrease in the cell’s defense mechanisms, or a
combination of both [175]. Overproduction of ROS
may also induce oxidative stress, resulting in cells
failing to maintain normal physiological redox-regu-
lated functions further resulting in oxidative modifi-
cation of proteins to generate protein radicals [176],
initiation of lipid peroxidation [177], DNA strand
breaks and modification to nucleic acids [178], mod-
ulation of gene expression [179], thereby leading to
cytotoxicity, cell death, and genotoxic effects [180]. In
order to minimize the effects of ROS-oxidative dam-
age to cellular components, biological systems have
developed a complex antioxidant system, comprised
of both enzymatic and non-enzymatic defense
mechanisms. The antioxidant defense system has
evolved to provide a balance between the production
and removal of ROS. These are catalyzed by several
different enzymes, including Phase I and Phase II
enzymes. Phase I enzymes, such as cytochrome P450,
initiate the detoxification process by introducing a
polar moiety that renders a lipophilic contaminant
more hydrophilic. The activity of Phase I enzymes
typically leads to an increase in ROS production.
Phase II enzymes are involved in conjugating
metabolized xenobiotics to endogenous molecules.
Phase III involves further modification and excretion.
The toxicity of CD is significantly less than Si-based
nanodots or metal nanoparticles. However, they are
not entirely non-toxic [26]. They are known to reduce
lactate dehydrogenase (LDH) activity and trypan
blue test viability in HeLa cells [182]. Recent research
suggests that the cytotoxicity induced by CDs con-
jugated amino-clay is selectively targeted toward
cancerous cells, with much less cytotoxic effects on
non-transformed cells [183]. The cytotoxicity of the
CDs passivated with functional groups, such as PEG
(amine-terminated polyethylene glycol), PEI-EI
(poly(propionyl ethyleneimine-co-ethyleneimine)),
PEI (polyethyleneimine), BPEI (branched poly-
(ethylenimine)), and PAA (poly(acrylic acid)), were
also evaluated in cytotoxicity assays. The PEGylated
CDs in all available configurations were non-cyto-
toxic up to concentrations much higher than that is
necessary for cell imaging and related applications
[184]. Gao et al. evaluated the organosilane molecules
(3-aminopropyl) trimethoxysilane (APTMS)-based
CDs for mitochondrial tracking of normal/cancerous
cell differentiation (Fig. 9) and they found APTMS
CDs elicited negligible toxicity toward HeLa, MCF-7,
and ATII cells even at a concentration of 100 lg/mL
[181]. Further support for low CD toxicity is provided
by research on zebrafish embryos, which

Figure 9 Illustration of
a One-step solvothermal
synthesis of APTMS CDs with
APTMS and glycerol,
b applications of APTMS CDs
in mitochondrial tracking, and
normal/cancerous cell
differentiation. Reprinted with
permission from [181].
demonstrated that zebrafish embryos were well
capable of tolerating CDs produced from crystalline
starch [185]. On the other hand, research conducted
on C60 fullerenes demonstrated that these could
exert cytotoxic effects through the generation of lipid
peroxidation products on the cellular membranes,
without causing changes in total nuclear DNA or
mitochondrial number [186].
Das et al. (2014) have shown that CDs can be
helpful for long-term cell tracking in vitro without
important photo-bleaching and photo-oxidation-in-
duced cytotoxicity and this material can work as a
new alternative fluorometric assay to standard
in vitro ROS estimation assays such as DCFH-DA
and NBT (Fig. 10) [33]. Hsu et al. (2013) found that
the inhibitory activity of CDs on MCF-7 and MDA-
MB-231 cancer cells is associated with the generation
of more significant amounts of reactive oxygen spe-
cies [163]. Havrdova et al. (2016), similarly evaluated
the in vitro toxicity of different kind of CDs (CDs-
PEG, CDs-Pri, CDs-PEI) on mouse fibroblasts (NIH/
3T3). Negatively charged CDs-Pri arrested the G2/M
phase of the cell cycle, stimulated proliferation, and
led to higher oxidative stress; however, they did not
enter the cell nucleus [168]. Recently, Lu et al. (2019)
J Mater Sci
found that the as-prepared CDs-OH exhibits strong
fluorescence, excellent photostability, and low cyto-
toxicity and also shows that the CDs-OH could
scavenge free radical groups [187].
Genotoxicity assessment of carbon dots
An important issue relating to the toxicity of NPs in
biological media is the ability to cause damage to the
genetic material, particularly since NPs can cross the
cell membranes. Genotoxic assessments of various
NPs have been mainly reported on in vitro studies.
Reported abilities of NPs include chromosomal
fragmentation, DNA strand breakages, point muta-
tions, oxidative DNA adducts, and alterations in gene
expression profiles and consequently may initiate
and promote mutagenesis and carcinogenesis.
One notable absence is that of genotoxicity testing
conducted on CD. For this purpose, well-established
genotoxicity tests, such as Alkaline Comet Assay
[188, 189] or Cytokinesis-blocked Micronucleus
Assay [190] (and have also been demonstrated to be
useful in testing for nanoparticle toxicity) [191], as
well as other genotoxicity tests, can be used to
ascertain the toxic profile of these materials. For
J Mater Sci
Figure 10 a Cytotoxicity assay results of CD, b AFM image of
cells without CD exposure, c AFM image of cells after incubation
with CDs, d hemolysis assay results of CD, e RBC aggregation
study post-CD exposure, f WBC aggregation study post-CD
exposure, g platelet aggregation study post-CD exposure, h DIC
example, in 16 HBE cells, a high concentration of CD
exposure resulted in oxidative damage and
decreased proliferation rate. Besides, CDs could form
a complex with BSA leading to the structural alter-
ation of some functional proteins [192]. In animal
models, when CDs were administrated through the
tail vein injection in rats, the oxidative damage and
the disrupted immunologic function were observed
in the target organs, which eventually induced the
compensable pathological lesions [193]. Periasamy
et al. (2016) found that the gene expression mea-
surements indicated that CDs significantly upregu-
lated the p53, TNF3, CDKNIA, and NFKBIA genes
and downregulated the EGR1 gene in hMSCs [169].
Ecotoxicological assessment of carbon dots
The ecotoxicological effect is a major determinant of
the viability of any new agent. Uptake of
Image of the cells, i cytoskeletal labeling with CD, j nuclear
labeling with Hoecht-33372, and k merged micrograph of all the
three frames. (All scale bars at 100 mm for h–k). Reprinted with
permission from [33].
nanoparticles into the aquatic biota is a major con-
cern. Nanomaterials have the capacity to cross-bio-
logical barriers, gaining entering due to their small
size. Metallic nanoparticles have, in particular, raised
a concern about their environmental fate, and new
methods have been proposed to ascertain their
environmental persistence [194, 195]. The toxicity of
various nanomaterials Ag NP [196–201], CuO NP
[202, 203], TiO2 NP [204], and Ni NP [205] has been
studied in various aquatic species, such as Daphnia
magna [201, 203], fish [197, 206], algae [207], and
marine [208] and freshwater [209] crabs. Therefore,
further testing on these structures is necessary to
determine their precise toxicity profiles.
In addition to their cytotoxicity and genotoxicity,
environmental toxicity profiles of CDs are also
understudied. The toxicity of CDs on rare minnow
(Gobiocypris rarus) embryos at different developmen-
tal stages were investigated by Xiao et al. (2016) [210].

This study presented that the CDs exposure has sig-
nificant development toxicity on rare minnow
embryos/larvae. In a recent study, Yao et al. (2018)
reported the toxic effect of CDs on the aquatic envi-
ronment by exposing zebrafish (Danio rerio), zoo-
plankton (Daphnia magna), and phytoplankton
(Scenedesmus obliquus) with CDs [211]. The results
indicated that CDs (up to 200 mg/L) could be
depurated by Danio Rerio with negligible toxicity.
Researchers highlighted that the toxicity might result
from the pressure of induced oxidative stress coor-
dinate with the dysregulated development-related
gene expression mediated by the CD exposure
(Fig. 11-I). According to the study carried out by Kim
et al. (2017), authors made a series of toxicity
assessment and presented that the synthesized CDs
are highly biocompatible to various biological entities
including 18 bacteria species, Petunia axillaris seed-
lings, and Artemia franciscana nauplii [212]. Further-
more, the particles were shown to have low- to non-
toxic effects on human embryonic kidney (HEK-293)
Figure 11 I DNA damage. Effects of different concentration CDs
(control (a), 1 mg/L (b), 5 mg/L (c), 10 mg/L (d), 20 mg/L (e),
40 mg/L (f), and 80 mg/L (g) on DNA damage of rare minnow
embryos/larvae cells by comet assay. Reprinted with permission
from [210]. II (a) Mortality of the CDs tested against brine
shrimps, (b) Fluorescence microscopy images of brine shrimps
((1) negative control, (2) 1 k gCDs, and (3) 3.5 k gCDs, top:
J Mater Sci
cell lines, breast (MCF-7), oral squamous (CAL-27)
carcinoma cell lines in the same study (Fig. 11-II). In
another study, Li et al. (2016) showed that CDs bind
to calcified bone structures of live zebrafish larvae
with high affinity, selectivity, and low toxicity
(Fig. 11-III) [213]. Authors claimed that CDs are
expected to be more environmentally safe than many
other nanoparticles due to the in-built biodegrad-
ability of many carbon compounds. Therefore, con-
cerns such as bioaccumulation or biomagnification
are less of a concern with CDs than other
nanoparticles.
Multiple studies have succeeded in the develop-
ment of degradable nanoparticles made of organic
materials [214–216]. Biodegradable CDs could
potentially confer many advantages; however, a ser-
ies of studies have shown the potential risky impact
of CDs on the natural water ecosystem. Thus, the
biological and environmental toxicity of CDs gradu-
ally attracted significant research interest, which is
required for the safety evaluation for further
kex = 405 and bottom: kex = 488 nm), c 1 k gCDs infiltrated into
Petunia axillaris seedling leaves ((1) after 10 m and (2) after 2 h,
top: room light and bottom: 365 nm UV light) and d Cell viability
assessed at 450 lg mL-1 CD concentration after 24 h incubation.
Reprinted with permission from [212]. III A CDs bind to calcified
bone structures of live zebrafish larvae with high affinity and
selectivity. Reprinted with permission from [213].
J Mater Sci
application [210]. The use of nanomaterials in con-
sumer products and their potential environmental
and human health risks are of increasing concern.
Thus, the availability of appropriate methodologies is
needed to address the key issues in nanotoxicology
and to gain a better understanding of NP toxicity and
the mechanisms behind (cytotoxicity, genotoxicity,
oxidative stress, and inflammatory responses).
Conclusions and future aspects
The benefits of carbon dots over most types of
nanomaterials synthesized from non-carbonaceous
sources are now well established in the literature.
Some of these superior characteristics are crucial for
the enlargement of safety margins in clinical and/or
patient-oriented applications, such as imaging and
treatment. While the future industrial applications of
carbon dots as fluorescence and optic probe, light-
emitting diodes, nucleus targeted delivery, catalytic
agents, energy storage media, and/or medical agents
are all but undeniable, the toxicity profile of these
agents will also need to be independently determined
for each application. Our study suggests that the
formulation, independent of the carbon dot itself,
maybe equally important, if not more important, than
the carbon dot itself. The collection of recent litera-
ture discussed herein indicates and implies that more
sophisticated follow-up studies are warranted and
even necessary, to definitively and conclusively
demonstrate the safety of carbon dots and other
nanomaterials not only to human and animal health
but also to the ecosystem.
An integral component to establishing a safety
profile, independent of the synthesis method applied,
would be the elucidation of the physicochemical
characteristics of the nanoparticle precursors and
nanoparticles themselves in each step of the synthesis
method. If such safety parameters cannot be reliably
established, precise characterization of the toxico-
logical profiles of these materials helps define an
operational envelope in which these materials may be
used safely. Thus, nanosafety standards, guidelines,
and reference points are still in the process of being
established, and due to the quantum mechanical
nature of these particles, they cannot be reliably
established by extrapolation from the physicochemi-
cal data derived from macro-sized materials. Nano-
materials have been touted as the technology of the
future, and it is reasonable to expect that essential
procedures and frameworks applying to other
materials shall need to be applied to nanomaterials as
well, such as the well-established approach of risk
assessment. Determination of physicochemical char-
acteristics of nanomaterial precursors and nanoma-
terials themselves will double as a preliminary risk
characterization step, allowing for the detailed
assessment of potential risks posed by nanomaterials,
if any.
Acknowledgements
MOA thanks to the doctoral scholarship of Scientific
and Technological Research Council of Turkey
(TUBITAK, Grant No. 117M215) and Council of
Higher Education of Turkey (YOK) for the doctoral
scholarship.
Compliance with ethical standards
Conflict of interest The authors declare that there
are no conflicts of interest regarding the publication
of this paper.
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