1 s2.0 S2352507X22000506 Main

Nano-Structures & Nano-Objects 32 (2022) 100921
Contents lists available at ScienceDirect
Nano-Structures & Nano-Objects

journal homepage: www.elsevier.com/locate/nanoso
Bioinspired quantum dots: Promising nanosystems for biomedical

application
∗ ∗
Kshitij RB Singh a , Vanya Nayak a , Piyali Sabui b , Sadhucharan Mallick c , , Jay Singh a , ,
∗
Ravindra Pratap Singh d ,
a
Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh (221005), India
b
Department of Zoology, The University of Burdwan Golapbag, Bardhaman, West Bengal, India
c
Department of Chemistry, Faculty of Science, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh (484887), India
d
Department of Biotechnology, Faculty of Science, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh (484887), India
article info a b s t r a c t
Article history: Quantum dots (QDs) are semiconducting nanocrystals exhibiting a unique morphology and
Received 8 April 2022 morphology-dependent optical, electrical and biological properties. The synthesis, characterization
Received in revised form 10 July 2022 and applications of QDs are highly active fields of investigation. However, recently biological routes
Accepted 29 September 2022
to synthesize quantum dots have gained a lot of attention as they produce highly biocompatible
Keywords: and non-toxic QDs that possess excellent morphologies and tunable properties. Moreover, the green
Bioinspired quantum dots synthesis of QDs eliminates the use of hazardous chemicals and solvents, and therefore, becomes
CQDs a cost-effective and environment-friendly approach. Owing to these properties, the bioinspired QDs
GQDs show broad applications in biomedical domains like diagnosis and treating different diseases. Further,
Graphene this review aims to impart a detailed discussion on the biomedical utilities of bioinspired quantum
Biomedical applications dots by highlighting surface modification techniques and biosafety aspects of quantum dots, making
Sensing this review one of its kind.
© 2022 Elsevier B.V. All rights reserved.
1. Introduction properties are size-dependent [1]. QDs are three-dimensionally

confined semiconductor nanocrystals (NCs) that exhibit quantum
The ever-increasing demands of humans have resulted in the confinement phenomena, which cause the bandgap to widen
development of new approaches that can ease their lifestyle and and produce a size-dependent spectrum of colours, therefore,
simultaneously protect the environment from degrading. Nan- the emission colour of QDs can be changed by tuning their size
otechnology remains one of the leading technologies that has and composition. Different types of QDs can also be categorized
aided in achieving new scientific standards as it utilizes materials based on their composition and structure, and different atoms
whose dimensions are in the nano range (1–100 nm). These present from groups II–VI (e.g., CdS, CdSe, CdTe, ZnS, ZnSe, ZnTe,
uniquely small nanomaterials show a high surface-to-volume ZnO), III–V (e.g., InP, InN, GaN, GaAs, InAs), group IV (e.g., Si,
ratio, helping them to exhibit distinct properties that bulk matter Ge), groups I–VII (e.g., AgBr) in binary and their alloyed material.
cannot achieve. There are many different types of nanomateri- They are potent emitters with tunable size-dependent emissions.
als, but recently, after metal-based nanoparticles, quantum dots The quantum confinement effect occurs when electronic charge
(QDs) have gained a lot of attention, also termed as semicon- carriers are constricted in all three spatial dimensions within the
ductor nanomaterials possessing distinct size-dependent optical nanocrystals. The most observable impact of such confinement
and electrical characteristics. Additionally, apart from many other is excellent luminescence, in which the NCs can produce vari-
domains, like robotics, aeronautics, environmental, agricultural, ous colours based on their size. Elevated photostability, broad
etc., these QDs have gained remarkable utilities in the biomed- absorption spectra, high extinction coefficients and customizable
ical domain and are majorly used in the diagnosis of various emissions wavelengths are just a few of the advantages QDs offer
diseases, like neurodegenerative diseases, cancer, etc. QDs are as lumiphores for bio-applications.
crystalline dielectric semiconducting nanoparticles or illuminat- Additionally, semiconductor QDs are quickly gaining traction
ing nanocrystals whose size ranges from 1–10 nm and their as a practical diagnostic basis that can easily access various cellu-
lar function at the molecular scale. Fluorescent probes are consid-
∗ Corresponding authors. ered essential for real-time imaging of live cells and are valuable
E-mail addresses: sadhucharan@igntu.ac.in (S. Mallick), for researchers [2]. With fast photobleaching and broad over-
jaysingh.chem@bhu.ac.in (J. Singh), ravindra.singh@igntu.ac.in (R.P. Singh). lapping emission lines, fluorophores like Alexa-Fluor, rhodamine
https://doi.org/10.1016/j.nanoso.2022.100921
2352-507X/© 2022 Elsevier B.V. All rights reserved.
K.R. Singh, V. Nayak, P. Sabui et al. Nano-Structures & Nano-Objects 32 (2022) 100921
and fluorescein are commonly utilized as fluorophores, but are an electron and a hole. Quantized energy levels in QDs are closer
restricted in long-term imaging and multi-coloured detection to atoms than to their bulk counterparts, making them exhibit
[3–6]. When compared to organic fluorophores, QDs have many unique optical properties. Further, quantum confinement of a
distinct character qualities, one being their interesting optical QD depends on the exciton Bohr radius (EBR) because the ex-
spectra. The advantages of QDs as lumiphores for biological appli- citation energy increases as the size decreases, which can only
cations include excellent photostability, extraordinary brightness, be achieved by the QDs; therefore, QDs can show unique opti-
high stability and extinction coefficients, wide absorption spectra, cal characteristics such as high quantum yield (QY) and molar
adjustable emission wavelengths across the ultraviolet to infrared extinction coefficients, broad absorption, narrow and symmetric
regions, and narrower luminescence. Because of their inorganic photoluminescence spectra, large Stokes shifts and exceptional
composition, QDs are also utilized as a unique type of fluorescent resistance to photo- and chemical degradation [3,5,7–10,14,15].
tag when combined with biological sciences [3,5,7–10]. How- Their emissions can be modulated over the UV, visible, near-
ever, the synthesis, characterization and potential applications infrared and mid-infrared spectral regions. Generally, it has been
of QDs are still active research areas [11,12]. QDs involve nu- observed that the energy gap of a particle highly depends on the
merous application zones, including photovoltaics, light-emitting size of the crystal, as a high energy gap is found when the size of
diodes (LEDs), liquid-crystal displays (LCDs), photoconductors the particles is very small, and in that case, more energy will be
and photodetectors, biomedicine, environmental and photocatal- required to excite the QD system, and subsequently, more energy
ysis. The biological applications of chemically synthesized QDs are will be released when the system returns to the ground state. This
restricted due to the high cost as it demands a high reaction tem- results in the emission colour shifting from red to blue. Further,
perature, inert atmosphere protection and a relatively complex in a QD, an exciton is developed when a photon with a higher
synthesis process [13–19]. Bio-mediated QD preparation has been energy than the bandgap is absorbed, resulting in the stimulation
used to eliminate laborious and costly physicochemical methods. to a high conduction band state. This stimulation leads to the
It is a cost-effective and non-hazardous technique. Under an generation of an electron and hole, creating a bound state known
aqueous and ambient environment, biological templates direct as an exciton due to the high degree of confinement. Moreover,
the nucleation of QDs and determine the crystal structure and the increased Coulomb interaction in QDs, unlike in bulk material
size. The production of QDs takes place in a cellular environment semiconductors, results in alterations in the energy spectrum
that is both mild and well-organized. The expression of specific formed by the close binding of excitons, pushing them to interact
genes control several stages of the intracellular synthesis of QDs, with each other. Additionally, the inorganic nature of QDs makes
such as creating precursors, forming NCs and encapsulating the them photochemically resistant, which allows for more dynamic
final products [20–23]. Biocompatibility is essential for using QDs imaging. Furthermore, QDs are extremely bright due to their high
in biomedical applications; therefore, synthesizing QDs through absorption extinction coefficients and fluorescent QY. The emis-
biological routes results in developing pure QDs with high bio- sion from a single QD can be distinguished through a fluorescent
compatibility. Non-compatibility with the biological system is a microscope by the naked eye. These properties have enabled the
severe barrier caused by chemical and physical synthesis, but development of next-generation fluorescence imaging studies,
among all other techniques, organic-phase synthesized QDs ex- useful in biology and permitting scientists to understand different
hibit high toxicity to biological systems that restricts their direct biological activities at the molecular level [3,5,7–10,14,15].
applicability in the biomedical domain. Significant attempts are Since QDs are so small, they have size-dependent character-
being made to water-solubilize and bio-functionalize chemically istics; therefore, their remarkable optical features, such as broad
produced QDs to resolve this issue. excitation spectra, narrow, tunable and Gaussian emission spec-
There are many previous literature data that have discussed tra, which can be stimulated at a single wavelength, and high
the biomedical importance of quantum dots in different do- photostability have received a lot of attention. Moreover, QDs are
mains [6,17,24–31], but this review aims to entail a detailed also very efficient multiphoton absorbers that could be benefi-
discussion on the biogenic synthesis of QDs by highlighting mi- cial in three-dimensional multiphoton microscopy and imaging,
croorganisms, plants and biomass-based QDs. Further, a compre- which is a fast-growing field in biological and medical applica-
hensive discussion is presented on the quantum dots’ properties tions. When excited by a suitable light source, QDs can form
and different surface modification techniques. Moreover, utili- electron–hole pairs, termed excitons, and their recombination
ties of different QDs (metal, carbon quantum dots (CQDs) and can result in bright emission, known as luminescence, whereas
graphene quantum dots (GQDs)) in the biomedical domain are photoexcitation of QDs produces electron/hole pairs which re-
discussed in detail and a brief overview of their toxicological combine to produce fluorescent light emission. Moreover, lu-
aspects makes this review a one of its kind, as depicted in Fig. 1. minescence QDs are zero-dimensional constructs in which the
electronic charge carrier is confined in all three spatial dimen-
2. Properties sions within the nanocrystal, known as the quantum confinement
effect. Ekimov and Onushchenko first discovered the growth tech-
Mark Reed coined the term ‘‘quantum dot’’ by describing the nique of microscopic semiconducting CuCl microcrystals in a
arrangement of these extremely small semiconductor nanocrys- glassy dielectric matrix in 1980 [9]. They demonstrated that their
tals as an intermediary between an atom and a bulk material method permits changing the size of the grown CuCl microcrys-
with the capability to transport electrons [7]. They are referred to tals in a tunable manner from tens to thousands of angstroms
as tiny manufactured semiconductor partials with a size ranging [8,9]. These semiconductor nanocrystals exhibit quantum con-
from 2–10 nm, demonstrating that their optical and electrical finement, which results in a single atom-like electronic structure,
properties diverge more than those of their bulk counterparts. which are, therefore, sometimes recognized as artificial atoms
QDs are zero-dimensional that can emit light of a particular [8,9]. Fluorescence is perhaps the most visible impact of this, in
wavelength if excited by light source. Further, QDs with shorter which the nanocrystals can create distinct colours based on their
wavelengths exhibits violet, blue or green colours. QDs (5–6 nm) size. The electrons of these particles are trapped in a tiny region
of longer wavelengths emit yellow, orange or red colours. Gen- due to their small size. Overall, these semiconductor QDs display
erally, QDs follow the Pauli’s exclusion principle for quantizing commendable optical properties, including bright luminescence, a
the energy when their radius becomes smaller than the Bohr wide excitation profile, small emission peaks and good photosta-
radius, which is defined as the average distance present between bility. By altering the size of the QDs, the absorption and emission
2
Fig. 1. A systematic description of different topics related to biogenic QDs covered in this review.
spectra might well be accurately controlled [7,10,32–34]. Optical the growth, size and shape, or fluorescence emissions. Thus, the
probes for targeted labelling, temperature monitoring, imaging biosynthesis technique can avoid harsh environments, which are
and solar cell sensitizers have been examined using these QDs common in chemical synthesis reactions, providing a greener
nanostructures. approach to biocompatible QD synthesis. To date, many QDs have
been effectively synthesized from a varied range of microorgan-
3. Eco-friendly and sustainable synthesis isms, extending from prokaryotes to eukaryotes and even living
mammals, and the QDs’ primary features have been established
Synthesis is considered a crucial step in nanotechnology as [20–23].
it helps to determine the properties of the materials, which Nanoscale syntheses of QDs have attracted technical and re-
ultimately results in defining their suitable applications. The QDs
search attention since their beginning. However, because of the
can be synthesized using physical, chemical and biological ap-
toxicity and expense difficulties with the current chemical syn-
proaches. The physical processes include vapour deposition and
thesis techniques, commercialized preparation and subsequent
laser irradiation of macroscopic particles, which are simple, con-
integration for practical applications have been restricted. As
venient and eco-friendly. However, these synthesized QDs gen-
erally show a lot of surface defects, low stability and a low QY. a result, alternate environmentally acceptable synthesizing pro-
Therefore, chemical approaches, like organic and water-phase cesses are urgently needed. Microbial factories have a lot of
synthesis, were adopted which can be used to make narrow size potential for achieving this goal. These QDs crystallites with a
distribution QDs with good optical properties. Despite substantial near-infrared photoresponse have revolutionized the concept of
advances in simplifying the synthesis pathways, enhancing QY, semiconducting nanocrystalline research, allowing scientists to
regulating the morphology of QDs and explaining the mechan- achieve better characteristics in labelling and tracking of cells,
ics of the synthesis of QDs, chemical synthesis procedures that detection of DNA, in vivo imaging, development of biosensors,
yield luminous QDs often rely on harsh experimental parameters communications systems, LED display, lasers, photodetectors and
and hazardous organic solvents [3,5,7–10,14,15]. Furthermore, photovoltaic gadgets. Due to their particular optical perspec-
surface modification is necessary to accomplish the desired func- tives, QDs have been identified as suitable nanoparticles for ul-
tionality [35]. On the other hand, biosynthesis approaches are trasensitive optical sensing of insecticides, chemical substances,
found to be a better alternate to chemical approaches, being biomolecules and a variety of metals. QDs could be made by vapor
under moderate conditions and that provide QDs with intrin- and liquid phase deposition, as well as colloidal synthesis. The
sic bio-stability and biocompatibility without the need to use chemical manufacture of CdS, CdSe and CdTe generates a large
extra capping agents and encapsulation treatment. Size-tunable amount of organic and inorganic pollution in the environment.
emissions, excitation of various-sized QDs from a single light It has been noted that sulfur, sodium, selenium, chloride and
source at the same time and component-adjustable broad spec- tellurium ions are the most common water-contaminants in the
tral windows are some features of biosynthesized QDs, which
chemical production of CdSe, whereas carbon, sulfur and nitrogen
are just like chemically synthesized QDs but in an enhanced
oxides are the most common by-products discharged into the
form. Overall, the biologically synthesized QDs are cost-effective,
atmosphere. Furthermore, chemical synthesis employs a number
environmentally benign, easily scaled up, free of toxic chemi-
of organophosphorus solvents, the cost of which can reach up
cals, biocompatible, proceeds at room temperature and prevents
the formation of harmful by-products. The use of biological sys- to 90% of the total manufacturing expense. Therefore, the choice
tems as reaction platforms show certain characteristics, includ- of solvents is thus critical in determining the overall impact
ing the natural occurrence of metal-reducing and metal-binding of conventional chemical pathways; hence, the development of
agents (such as amino acid residues, proteins, enzymes, pep- environment-friendly and economical techniques for synthesiz-
tides, etc.) that are capable of reducing metallic ions, collecting ing QDs is necessary. Many distinct biological templates act as
metals and protecting QDs, and simple platform manipulation stabilizing agents to govern the synthesis of CdS, CdSe and CdTe
can be achieved via genetic engineering to control the QDs by QDs, including peptides, nucleotides and fusion proteins [20–23].
expressing certain biomolecules. High temperature, severe de- Some of the biological methods employed for synthesizing QDs
oxygenation or hazardous chemical solvents have little effect on are discussed in Table 1.
3
Table 1
Various biological methods for QDs synthesis.
S.No. Source QDs Size Morphology Application Ref.
1. Ficus johannis ZnTe QDs 8 nm Ultra-small photoluminiscent The synthesized QDs showed [36]
QDs were obtained. antimicrobial and antifungal
activities.
2. Ficus johannis CdTe 3.7 nm Spherical, cubic structure and The synthesized QDs exhibited [37]
QDs very small QDs were obtained. excellent antimicrobial,
antifungal and anti-oxidant
properties.
3. Yeast CdTe 3.6 nm The obtained QDs were The synthesized QDs exhibited [38]
QDs spherical, crystalline in nature biocompatibility and can be
and show good solubility. used for in bio-imaging.
4. Rhizopus CdSe and – The QDs showed good These QDs were used for [39]
stolonifer CdTe crystallinity and bio-imaging in human breast
QDs polycrystalline. It was also adenocarcinoma MCF-7 cell
observed that extracellular lines.
polymeric substances of the
yeast capped the QDs.
5. Hairy root CdS QDs 1.5-8.5 nm The synthesized CdS QDs These QDs can be used as [40]
culture of showed good optical fluorophores in cell biology.
Linaria characteristic like specific
maroccana L. absorption and luminescent
spectra, and an ellipsoid shape
was observed.
6. Dimethyl CQDs 3 nm The CQDs obtained showed These CQDs showed good [41]
diallyl good optical properties. antibacterial activity against
ammonium gram-negative and -positive
chloride (DDA) bacteria.
and glucose
7. Watermelon TiO2 QDs 7 nm These QDs exhibited good The synthesized TiO2 QDs were [42]
peel optical properties and spherical very biocompatible and
structure. exhibited good antimicrobial
activity against Bacillus subtilis,
Escherichia coli, Cryptococcus
neoformans, Candida albicans,
Aspergillus niger and A.
fumigatus. Additionally, they
also exhibited excellent
anti-oxidant and anticancer
properties.
3.1. Synthesis of QDs using microorganisms yeast Candida glabrata, grown in the presence of cadmium ions.
These CdS nanocrystallites are coated with peptide, but varia-
The use of microbes to synthesize semiconductor QDs is a tion in the coating peptide depends on the growing medium’s
relatively new and unexplored field. Microorganisms are used as nutritional circumstances. The yeast generates intracellular CdS
platforms for manufacturing QD materials since bio-systems are nanoparticles coated with a combination of glutathione- and the
both natural and efficient. Current issues in chemical synthesis, -glutamyl cysteine dipeptide when cultured in rich nutritional
like environmental consequences, energy loss and safety, must broth [43,44,46]. The scientists further reported that the yeast be-
be addressed as soon as possible. Within their properly regu- gins the biosynthesis of QDs in the mid-log phase of their growth,
lated intracellular environment, microorganisms show a lot of though they do not present any mechanistic hypotheses on the
potential to biosynthesize QDs [20–23]. Initially, the biosynthe- biosynthesis process. On the other hand, sulfate-reducing bacteria
sis of QDs was first performed in 1989 using the yeasts Can- are very well analysed for the synthesis of ZnS and CdS biofilms.
dida glabrata and Schizosaccharomyces pombe (S. pombe) in the
The glutathione-related peptides help in achieving intracellular
presence of cadmium ions in solution [43,44]. The growth and
synthesis of CdS in Saccharomyces cerevisiae by the sequestra-
nucleation of CdS QDs to peptide-capped intracellular nanocrys-
tion of Cd2+ ionic species and subsequently transforming CdS
tallites of size 2 nm were revealed to be controlled by short
within the cells [20–23]. Recently, Cui et al. [47] demonstrated
chelating peptides within the general framework. The findings
an innovative biological strategy for the controlled synthesis of
were corroborated by molecular insights into the production of
monodispersed CdS QDs [43,44]. This fundamental understanding multicolour CdSe QDs using living yeast cells as a synthesizer.
of CdS biosynthesis supports the observation that when yeast Controlling the co-incubation durations of the selenocompounds
is exposed to cadmium salt chelating peptides, it synthesizes of selenocysteine and selenomethionine yeast cells with CdCl2
metal (phytochelatin analogues). The metal causes a Cd-glutamyl resulted in CdSe QDs of various sizes and fluorescence wave-
complex to form, followed by a rise in intracellular sulfide con- lengths. The distinctive fluorescence features of CdSe QDs are
centrations. CdS nanocrystallites are formed by these CdS com- used directly to assess the biosynthetic step visually. Further, they
plexes and accumulate in the vacuoles. Later, Kowshik et al. also demonstrated that high-quality CdSe QDs emitting at various
demonstrated that CdS and PbS QDs’ intracellular biogenesis was single fluorescence wavelengths could be produced intracellularly
initiated in S. pombe and Torulopsis yeast species strains, exhibit- and controlled at 30 ◦ C in an oxygen and water-free environment
ing semiconductor properties individually, and it was recorded rather than at 300 ◦ C. This excellent colour controllability of the
that the PbS nanocrystallites were of the size 2–5 nm [23,45]. CdSe photoluminescence offers innovative visions for sustainable
Further, cadmium sulfide nanocrystallites were formed in the chemistry [47].
4
Exploring new metal-related biomineralization, biodetoxifi- Microbe-reinforced mineralization of metals into biocompat-
cation and enzyme-based activity helps in understanding QD ible nanoparticles could help in the bio-synthesis of QDs ma-
formation mechanisms in living organisms. To begin, the natural terials. Further, to synthesize monodisperse and well-controlled
response of microorganisms to heavy metal ions (e.g., cadmium (6 ± 2 nm) CdS QDs in a biological environment, Mahle et al.
ions) is bio detoxifying, which allows heavy metals to be trans- employed the self-assembly property of chemical species. More-
formed to low-valent metal compounds or complexes of meta over, biological growth parameters, like the age of the cell and
and protein (e.g., phytochelatin and metallothionein). Further, precursors such as the sulfide source cysteine, HCl and cad-
numerous microorganisms undergo a number of physiological mium, affect the synthesis of CdS QDs; therefore, CdSe QDs were
processes throughout the biomineralization process, making it synthesized by quenching Cd ions through organic molecules
an effective way to immobilize metal ions on the solid-phase exported from Pseudomonas aeruginosa cells. Different character-
inorganic materials. Saa et al. [48] had reported that in the growth ization techniques confirmed that the precipitation of CdS QDs
of QDs, the enzymatic reaction is essential. Acetylcholine esterase, occurred in the cell wall due to the interaction between the
for example, converts acetylthiocholine to thiocholine, increas- precursors and cell wall components. Additionally, these CdS
ing the breakdown of sodium thiosulfate (Na2 S2 O3 ) to generate QDs exhibited tunable photoluminescence with configurable sur-
hydrogen sulfides (H2 S), which afterwards react with Cd2+ ions face functionalities [54,55]. Moreover, prokaryotic cells, like bac-
to form CdS QDs [48]. Several enzymatic reactions can produce teria, are also found to be suitable for synthesizing QDs with
hydrogen sulfides that are useful for synthesizing CdS QDs, for an exactly tuned morphology because they contain a single-
instance, alkaline phosphatase is used to hydrolyse thiophosphate compartment feature. For instance, the bacterium Escherichia coli
and glucose oxidase for the catalytic oxidation of 1-thio-β -D- (E. coli) is of specific importance since its genetic tools and cellular
glucose and methionine γ -lyase, and S-adenosyl-L-monocysteine metabolisms are well characterized. As a result, it is possible
hydrolase is employed to fragment S-adenosyl-L-homocysteine. to guide the assembly of the genetic characteristics required for
Further, they also proposed two new sensitive fluorogenic tech- QD synthesis. Microbial cells have demonstrated a strong ability
niques for the enzymatic activity of S-adenosyl-L-homocysteine to biosynthesize QDs in their well-controlled intracellular envi-
hydrolase (AHCY), which is employed to hydrolyse its substrate ronment; however, the mechanism of QD biosynthesis is poorly
S-adenosyl-L-homocysteine (AdoHcy) to L-homocysteine (Hcy). understood [20–23]. Eukaryotes are also being investigated for
In the existence of Cd(NO3 )2 , methionine-lyase (MGL) catalyses their ability to biosynthesize QDs, and it has been discovered that
fungal cells can produce QDs in the extracellular environment.
the breakdown of Hcy to hydrogen sulfide, which generates CdS
Fusarium oxysporum was the first fungal culture to generate QDs
QDs [48–50]. Furthermore, the enzymatic activities can produce
by converting sulfate ions to sulfide ions using an extracellular
tiny biomolecules (such as glutathione and phosphate) that can
environment that produced sulfate reductase enzymes, which
act as surface ligands to help stabilize the QDs. These findings
then combine with aqueous Cd2+ ions to form very durable CdS
provide crucial information for manufacturing and collecting QDs
QDs [56].
in live organisms. Direct biosynthesis methodologies capable of
synthesizing biocompatible QDs are strongly desirable due to the
3.2. Synthesis of QDs using plant extracts
practical uses of QDs in biology and medicine. These resulting
QDs should show high solubility, durability in a physiological
To construct value-added QDs various environmentally sus-
milieu, fluorescence in a cellular environment that can be easily
tainable and eco-friendly techniques are frequently used, that
absorbed by cells, harmless to the living tissues and capable of
are enhanced by high-temperature treatments [36,40,57]. Green
labelling molecules selectively. These strict criteria can be met
synthesis methods are gaining popularity as viable alternatives
by living beings as the synthesis machinery. Controlling biological
for the long-term production of QDs with low toxicity to living
processes to govern intracellular production is challenging, how- organisms and the environment. Green synthesis QDs provide
ever Li and group developed a mechanism-oriented technique for added benefits over classical syntheses, such as lower energy
producing fluorescent CdSe QDs in genetically engineered yeast inputs and costs of production, which reflect well enough for
cells using metabolic engineering in 2013. They demonstrated mass production. Plant-mediated green synthesis of QDs has re-
that the glutathione metabolic pathway is responsible for con- cently been the focus of a number of scientists as a simple, rapid,
trolling the intracellular synthesis of CdSe QDs through genetic effective and environmentally acceptable technique. Natural com-
techniques. Moreover, the yeast cells can be homogeneously con- ponents and secondary metabolites found in plant extracts, in-
verted into more efficient cell factories at a single-cell level by cluding tannins, alkaloids and lipids, can help protect, stabilize
giving a selected way in the cellular metabolism to direct them and encapsulate QDs. Plant extract-based surfactants have var-
towards CdSe QD formation [51]. Scientists have been paying ious advantages over chemical-based QDs stabilizers, including
close attention to attaching the biological manufacturers to syn- biodegradability, biocompatibility and low cytotoxicity. By em-
thesize QDs, looking for lessons from nature’s tools in building ploying the aqueous extract of the Ficus johannis plant, Alvand
miniature effective QDs in living organisms in very well and et al. [36] showed an easy, fast and effective plant-mediated
innovative methods. However, the biosynthesis of QDs is reason- strategy to synthesize stable and ultra-small ZnTe QDs with a
ably novel and not fully explored [20–23]. Further, in 2014 Luo size of 8 nm. Plant extracts were prepared using ultrasonic and
et al. [52] described an in situ process of biosynthesizing CdSe QDs microwave methods, followed by the precursors’ stabilization to
using Saccharomyces cerevisiae co-incubated with the precursor produce ZnTe QDs. Further, based on the optical characterization,
CdCl2 and 5 mM Na2 SeO3 for 24 h [52]. Additionally, Yang et al. a wide absorption band around 390 nm and an intense emis-
established a new technique for the repeatable generation of sion peak at 463 nm were obtained that showed the synthesis
extracellular, water-soluble CdS QDs by utilizing an engineered of the ZnTe QDs. Various tests confirmed that the ZnTe QDs
strain of Stenotrophomonas maltophilia (SMCD1), which is pre- possessed biological activities, like antioxidant, antibacterial and
cisely developed to control the size of the particle in the 2–4 nm antifungal activities, when tested against bacteria and fungi [36].
range [35,53]. These sustainable synthesized QDs, combined with Similarly, Shivaji et al. [57] demonstrated a biogenic method
low-cost Cd and S resources, room temperature and aqueous for the synthesis of bright yellow colour CdS QDs from tea leaf
synthesis environments, will finally lead to the economical, green extract (Camellia sinensis) using cadmium sulfate (CdSO4 ) and
synthesis of CdS QDs [35,53]. sodium sulfide (Na2 S) as precursors. The organic moieties present
5
in the Camellia sinensis extract stabilized the highly homoge- from leftover frying oil, in which concentrated phosphoric acid
neous spherical CdS nanoparticles, whose size ranged from 3 and sulfuric acid were used as the carbonization agent. These
to 5 nm [57]. Their experimental outcomes indicate that these synthesized CQDs were found to exhibit pH-sensitive fluorescent
synthesized CdS QDs exhibit promising antibacterial, bioimaging behaviour that can be applied for developing fluorescent probes
and therapeutic activities. Additionally, Borovaya et al. reported for imaging and sensing pH changes in live cells [68]. Further,
a biocompatible CdS QDs synthesis using the biologically sourced Pan and his colleagues were the first group to report the facile
hairy root culture of Linaria maroccana L. UV–visible spectroscopy synthesis of GQDs showing blue luminescence through the hy-
and electron microscopy revealed a bright yellow colour colloidal drothermal method from crude biomass. These synthesized GQDs
dispersion of CdS with an ellipsoid or spherical shape and a par- showed large sp2 domains that can react with different oxidizing
ticle size ranging from 1.5 to 8.5 nm. Moreover, it was observed reagents [69].
that root biomass, which is rich in secondary metabolites, was Coffee grounds were also used to synthesize GQDs that also
employed in the biosynthesis of CdS QDs [40]. exhibited blue fluorescence, and when these GQDs were function-
Recently, the synthesis of CQDs has captured tremendous at- alized by PEI, they exhibited high band-edge luminescence that
tention as they are easy to synthesize and only require a carbon- can be used for bio-imaging- and sensing-based applications [70].
containing source that can be found naturally almost everywhere. Moreover, recently, another novel method has been developed
There are several green synthetic approaches that have been em- that combines both top-down and bottom-up approaches to syn-
ployed for the synthesis of CQDs, for example, using collagen [58], thesize GQDs on a large scale using different biomass wastes as
lemon peel [59], orange juice, shells of peanuts [60], soy milk [61], precursors. In this method, firstly, a bottom-up approach was
cashew gums [62], garlic [63] and humic substances [64], but used to convert the biomass waste into large area sp2 carbon
most of the natural carbon sources do not provide homogene- flakes, and then top-down approaches were used to cut these
ity and the desired purity in the synthesized CQDs. One of the carbon flakes into small pieces of sp2 carbon domains. The ob-
major limitations in using these natural sources is the seasonal tained GQDs exhibited varying characteristics that can be applied
fluctuations based on their geographical locations, also their way in different domains, and the whole technique was found to
of cultivation plays a vital role in defining their properties. Fur- be facile, easy and economical for the large-scale production of
ther, Foeniculum vulgare (fennel seeds) were used to synthesize GQDs. For instance, rice husk was used to synthesize GQDs that
mono-dispersed CQDs through a thermal decomposition method, emitted blue light at 365 nm under a ultraviolet lamp and were
as shown in Fig. 2. These synthesized CQDs did not required therefore found suitable for bio-imaging and photonic applica-
any additional surface passivation to improve fluorescence and tions [71]. Heavy oil is also considered as unwanted stock as it
exhibited an excellent photoluminescence activity along with an
gives the lowest yields in fuel products and is made up of various
excitation-independent emission. These synthesized CQDs can be
aromatic and heteroatom compounds which makes it a potential
used in bio-sensing and cellular imaging applications [65]. Sim-
precursor for high scale production of materials consisting of
ilarly, another study reported the facile green synthesis of CQDs
carbon. Therefore, heavy oil was used as a precursor in producing
that exhibited well defined and reproducible photoluminescence
various QDs consisting of carbon-like graphene and carbon QDs.
properties. These CQDs were synthesized hydrothermally using
For instance, Ma et al. [72] hydrothermally synthesized highly
starch and tris-acetate-EDTA (TAE) as the carbon source. It was
fluorescent carbon QDs using four components obtained by sep-
reported that the synthesized CQDs were ready to use and did
arating petroleum. The reported QDs were found to emit strong
not require any further purification, and at the same time it was
fluorescence, low toxicity, high yield and a good quantum yield of
observed that they were stable for a long period of time (>1 year)
64%. Further, it was noted that red QDs can be used in the imaging
either in solution or freeze dried. However, it was observed that
of macrophages. Therefore, this method was proved to produce
when these CQDs were freeze dried, they converted to a white or
highly fluorescent petroleum based carbon QDs with high yield
a slightly brown colour from their original brown colour, but they
and simultaneously it can also be adopted to solve the problem
retained their photoluminescence in aqueous solution, therefore
of high value-added utilization of asphalt [72]. However, studies
making them a potential agent to be employed in bio-imaging
applications, as shown in Fig. 3 [66]. on biomass-synthesized QDs are still at a very juvenile stage and
need thorough research for biomedical applications. This review
3.3. Synthesis of QDs using biomass wastes aims at compiling various different data to provide a detailed
overview of these QDs in the biomedical domain, along with their
Biomass is a biodegradable, organic and complex substance cytotoxic assays.
that is present in abundance and is obtained from different
sources, like grass, organic domestic garbage (organic), waste 4. Surface modification techniques
residues of agriculture, poultry, fishery, forestry, etc. Basically,
biomass waste is composed of carbon sources like cellulose, Recent research shows that replacing the core–shell structure
lignin, hemicellulose, etc. Moreover, the synthesis of QDs from of QDs with biocompatible ligands or polymers is one way to suc-
biomass waste is highly considered because it is renewable, eco- cessfully decrease the toxicity generated by conventionally syn-
friendly, present in abundance and cost-effective. For instance, thesized QDs. Moreover, designs of heavy metal-free and metal-
by using pyrolysis methods nitrogen-doped carbon quantum dots free QDs compositions are considered more realistic techniques
(N-doped CQDs) were synthesized with a quantum yield of 9.91%, because of the starting materials’ nontoxic and environmentally
good stability and photobleaching resistance, and were highly re- benign nature. Nontoxic or even less toxic QDs are investigated
sistant to large changes in pH. Moreover, it was observed that the and divided into heavy metal-free and metal-free QDs to address
surface of these synthesized N-doped CQDs consisted of various heavy metal toxicity and environmental impacts related to the
functional groups, like amino, hydroxyl, carboxyl, etc., and they use and disposal of cadmium-based QDs. Heavy metal-free QDs
can be utilized for live-cell multicolour imaging [60]. In a similar are often ternary I–III–VI-based QDs, whilst ‘‘metal-free QDs’’
way, walnut shells were used to synthesize fluorescent CQDs that are QDs formed of carbon, silicon or biomolecules, but because
exhibited high photostability, stable up-conversion fluorescence, of the adverse effects of binary nanocrystals in the II–IV family
high tolerance to ionic strength and good biocompatibility, which (PbS, CdS, CdSe, and CdTe), nontoxic ternary group I–III–VI QDs,
can be further applied for live-cell and tissue imaging [67]. Sim- silicon- and carbon-based QDs, have received much attention as
ilarly, a one-step synthesis of sulfur-doped CQDs was achieved alternatives [73–75]. These materials are made up of elements
6
Fig. 2. The systematic process of synthesizing CQDs from fennel seed through a pyrolysis method.
Source: reproduced with permission from A. Dager et al. (2019) [65].
from Group I (Cu, Ag), Group III (Al, Ga, In, Tl) and Group VI (S, with the help of a single excitation light source, they can be fur-
Se, Te). AgInS2 , CuInS2 and ZnS–AgInS2 are examples of group ther used in biomedical labelling, cellular reporters and effectors,
I–III–VI QDs. Non-toxic QDs are employed in biological imaging, LEDs and sensors. Fig. 4 represents different surface modification
medicine delivery, genetic disorder diagnosis and immunoassay techniques and their advantages.
recognition of biomolecules [76].
Surface modification is necessary to achieve desired func- 4.1. Salinization
tionality [77,78]. Biocompatibility is a necessity for employing
QDs in biology and medicine research. Non-biocompatibility is With the increasing demand of biocompatibility of quantum
a key issue with most chemically manufactured QDs, particu- dots, focus has now greatly moved towards environment friendly
larly organic-phase QDs, limiting their use in the biomedical synthesis approaches. Since, toxic metal ions are used in the
domain. The hydrophobic organic ligands present on the QDs preparation of QDs, to decrease their toxicity, salinization is used.
surface that are produced in the organic phase possess the most For instance, Bruna et al. showed in 2019 that Halobacillus sp.
significant challenge, limiting their practical applications in the (DS2) could make CdS QDs in the presence of a high concentration
biological environment [77,78]. Both ligand exchange, including of NaCl in a mechanism that was associated with their ability to
produce S 2- under these circumstances. Purified biosynthesized
substituting the initial surfactant coating with a water-soluble
CdS was evaluated by UV–Vis, TEM, EDX, XPS and FTIR, and their
stabilizer, and encapsulation, like changing hydrophobic QDs with
stability was assessed at different concentrations of NaCl [64].
amphiphiles strategies, can be used to make hydrophobic QDs
The existence of NaCl in biologically synthesized QDs is a novel
suitable for biomedical use. The fabrication of QDs in biolog-
feature and it is most likely the result of the interaction of NaCl
ical and biomimetic systems can provide good biocompatibil-
with biomolecules that make up the organic capping of QDs, such
ity to the QDs. On the other hand, biosynthesis methods can
as peptides and proteins [79,80]
be carried out under moderate conditions and provide the QDs
with intrinsic biocompatibility and bio-stability without the re- 4.2. Encapsulation and ligand exchange method
quirement for extra cap exchange and encapsulation treatment.
Biomolecules can be used as functional ligands to alter QDs and The hydrophobic organic ligands present on the QDs’ surface
templates for making biocompatible QDs. To encapsulate QDs, generated in the organic phase are the key hurdle that limits their
some biomolecules can self-assemble into well-defined nanos- usage in the biological field. The ligand exchange approach (the
tructures, like nanocages. For instance, viral capsid proteins can initial surfactant layer is replaced with a water-soluble stabilizer)
easily self-assemble into non-enveloped virus-like nanocages for and the encapsulation method (amphiphilic molecules replace
encapsulating QDs, resulting in high bioactivity and biocompat- hydrophobic QDs) can make hydrophobic QDs suitable for bi-
ibility. Furthermore, the number of self-assembled proteins is ological applications. The encapsulation technique includes the
unique for each type of virus; the size of virus-like nanocages coating of QDs with amphiphilic molecules composed of func-
can be controlled and genetic engineering approaches that edit tional groups like –NH2 , -SH, –COOH or polyethylene glycol (PEG),
capsid proteins can provide virus-like nanocages with desired silica, etc. Here, hydrophobic capped QDs are encapsulated by the
functional results. Since their PL can be tuned by modifying size hydrophilic terminal of an amphiphilic ligand that aids in dis-
of the particle and the varying PL can be excited concurrently persing QDs in an aqueous solution. Moreover, the encapsulation
7
Fig. 3. The preparation of starch-derived fluorescent carbon nanodots and nitrogen-based-carbon nanodots.
Source: reproduced with permission from T.T. Meiling et al. (2016) [66].
Fig. 4. Various surface modification techniques and their advantages.
8
method also helps in overcoming the limitation of poor lumi- 4.3. Coating of QDs
nescence quantum yields that are aggregated and precipitated
at the time of surface modifications. Currently, monodispersed 4.3.1. Amphiphilic polymer coatings
QDs encapsulated in stable polymers show variable surface chem- Compounds that show a lipotropic and hydrophilic nature are
istry. Yong et al. [81] enclosed hydrophobic, highly luminous known as amphiphilic molecules. These amphiphilic molecules
CuInS2 /ZnS QDs in functionalized phospholipid micelles, allowing are composed of a hydrophilic ‘‘head’’, mainly consisting of polar
for conjugation of folic acid for targeted distribution [81]. One groups like amine salt and choline, and a long aliphatic chain,
of the processes of encapsulation is termed as silanization. It termed as the lipophilic ‘‘tail’’. By modifying QDs using the am-
is a surface coating method in which the surface of the QDs is phiphilic polymer coating method, the QDs are stabilized and
coated with silica to prevent exposure of the QDs’ surface on at the same time it simplifies the synthesis method [88]. The
any biological medium. Silanization is the most common method tail of the amphiphilic molecules is aimed to directly link for
used to enhance the biocompatibility of QDs for in vivo utili- the trioctylphosphine oxide (TOPO) molecule, using the ultra-
ties [82,83]. Here, silica is used as it is chemically inert, non-toxic, sonication method. Whereas, the hydrophilic head of TOPO binds
transparent and safe to use. Additionally, they can be easily with H2 O to enhance the water solubility of the QDs. This bind-
functionalized making them compatible to form bonding with dif- ing of TOPO molecules on QDs act as a lap that protects the
ferent biomolecules, like antigen, aptamer, antibodies, proteins, QDs and enhances their stability [89]. Moreover, polyethylene
etc. Additionally, it has been observed that when QDs are coated glycol (PEG) and poly(acrylic acid)-1,2-distearoyl-sn-glycero-3-
with monodispersed silica, they exhibit high fluorescence and phospho-ethanolamine (PAA-DSPE) are some of the most com-
simultaneously becomes less prone to aggregation. For instance, monly used amphiphilic molecules [90]. Using chloroform in
the water-in-oil microemulsion method was used to encapsulate rotary evaporation is considered as an efficient method for mod-
green CdZnSeS/ZnS QDs in silica (CdQD@SiO2 ). These obtained ifying the surface of QDs with amphiphilic molecules, but the
QDs were very small in size, showed resistance against aggre- purity of the QDs can be greatly affected. Initially, these organic
gation and possessed an excellent luminescent quantum yield, solvents can create problems to the environment and increase
together with optical and chemical stability [84]. biotoxicity, however, with the introduction of plant based varsols,
One of the most common methods adopted for surface modi- like lemon oil and turpentine, researchers have started to use
fication of QDs is the multidentate ligand (MDT) method, whose them in place of chloroform. These plant-based varsols have
principle involves the formation of a coordinated complex by improved the quality of the QDs and decreased their toxicity,
bonding an amino or carboxyl group of the ligands with a centre
but simultaneously they have also hampered the purity of the
ion, like CdSe, CdS, etc., of the QDs. A multidentate ligand is
QDs, therefore creating a hindrance for large scale industrial
defined as bonding of two or more atoms to one central atom at
production [87].
the same time. Cucurbituril is highly used in the MDT method as
With the help of designed amphiphilic polymeric coatings that
it is a compound that has two cavities. The cucurbituril-modified
carry acetylene functional groups, Janczewski et al. [91] estab-
QDs are highly stable in a complex environment. Additionally,
lished a method for water solubilization of hydrophobic CdSe/ZnS
it has been noted that the MDL surface modified QDs shows
QDs. They first made CdSe/ZnS QDs by pyrolysing organometal-
increased synthesis efficiency [85,86]. However, the MDL tech-
lic compounds in coordinating solvents (TOPO and HDA). Poly
nique also presents some disadvantages, like in some cases it has
(isobutylene-alt-maleic anhydride) reacts with n-octylamine to
been reported that the MDL-modified QDs showed a decreased
produce the copolymer. The hydrophobic alkyl chains connected
intensity of luminescence and activation energy. However, these
to the polymer backbone, combined with the hydrophilic car-
disadvantages can be overcome by controlling the reaction con-
boxylic groups, give the copolymer its amphiphilic properties.
ditions [87]. The stabilizing ligand shell plays an important role
Then, a water solution consisting of the amphiphilic polymer was
in the QDs bi-functionality. It allows QDs to be hydrophilic and
stable in a variety of biological environments, such as fluids, mixed with a tetrahydrofuran (THF) suspension of pure nanocrys-
tissues and cells. tals to transport water to the QDs. Evaporation of THF caused
Various QDs have been synthesized through the solubiliza- the QDs to wrap around the polymeric micelles, as subsequently
tion process, which caps the QDs with functional groups such observed [91].
as –NH2 , –SH or –COOH. This capping of QDs help to con-
trol the attachment of bio-recognition components. Similarly, 4.3.2. Micellar phospholipid coatings
to synthesize water-soluble QDs, water-soluble precursors along Despite many efforts of surface modification, problems like
with water-soluble precursors are used in aqueous phase syn- aggregation, impure QDs and non-specific adsorption still per-
thetic preparation methods. Another method involves removing sisted in the biological environment, which made researchers
the initial hydrophobic coating and replacing it with aqueous curious for developing advanced techniques that will help them
molecules, like monodentate and bidentate thiols, oligomeric to overcome these problems without hampering the physico-
phosphine ligands, various polymers or silica. Initially, the hy- chemical properties of the QDs [24,92]. Therefore, a new method
drophobic QDs are encapsulated in various carrier vehicles, such of coating was developed in which ZnS-overcoated CdSe Qds were
as surfactants, liposomes and silica covering. The ligand exchange incapsulated inside a hydrophobic core of micelles made up of
strategy normally requires two steps: firstly, the removal of phosphatidylcholine (PC) and also n-poly(ethylene glycol) phos-
native surfactants (e.g., TOPO, HAD and octadecyl amine (ODA)), phatidylethanolamine (PEG-PE) [93,94]. PEG-PE micelles form hy-
and then making water-soluble QDs by restoring the surfactants drophilic polymer-grafted lipids that are also utilized in different
with capping ligands. The QDs may have improved stability, biomedical applications, like diagnostics, imaging and delivery of
size and optical properties as a result of the substituted ligands. drugs [95,96]. These micelles have a definite morphology that
For conversion of hydrophobic QDs to hydrophilic QDs, various makes them a suitable candidate for surface modifications. Ad-
ligands are used, such as bi-functional molecules composed of ditionally, their outer surface is made up of a dense layer of PEG
hydrophilic groups (e.g., carboxylic acid, amino and polyethy- polymers, making them less immunogenic and antigenic, which
lene glycols (PEG) group) and metal element-binding groups. helps them repel different biomolecules. Furthermore, the length
Moreover, due to their abundance, exceptional affinity and great and amount of PEG can be modified accordingly [97]. For instance,
efficiency, thiol-containing compounds are the most generally in an experiment performed by Dubertret and his colleagues,
utilized ligands. each QDs was encapsulated with phospholipid block–copolymer
9
micelles. They further conjugated these prepared QDs with DNA such as macromolecules, long-chain organic matter, proteins,
that helped them to act as in vitro fluorescent probes, which enzymes and nucleic acids, in a nonspecific manner. Although
hybridized the specific complementary sequences. It was noted the concept of bioconjugation of QDs through electrostatic inter-
that these conjugated QDs were non-toxic and exhibited good actions is quick and straightforward because it does not require
fluorescence, reduced photobleaching, low non-specific adsorp- the addition of chemicals or crosslinkers, it has several draw-
tion and were highly stable in bio-environments when observed backs. For most circumstances, the electrostatic contact is weak,
in embryos of Xenopus [98]. In addition, phospholipids can be em- mainly while competing molecules are present. QDs are particu-
ployed to encapsulate QDs [81,91]. Phospholipid micelles made larly useful for imaging biomolecules, cells, tissues and animals
up of amphiphilic phosphatidylcholine (PC), PEG-PE and n-poly in multidimensional, multifunctional and multiplexing modes.
(ethylene glycol) can encapsulate ZnS/CdSe core–shell QDs. The Extended imaging of cells, architecture and functions of sub-
generated phospholipid-QD micelle exhibits bright fluorescence, cellular organelles has become possible due to the introduction
photobleaching resistance and high colloidal stability in biological of bioconjugated QDs. As a result, fabrication, optical property
environments, and can be employed to track embryogenesis in optimization and bioconjugation of QDs have emerged as im-
real time [99]. portant research fields. In particular, biosensing, administration
of drug, and in vitro and in vivo imaging are highly useful fields
4.3.3. Microsphere/microbead coatings of bioconjugated QDs [102–107]. The reaction of one functional
Han et al. made multi-coloured zinc sulfide–capped cadmium group with another, leading to the construction of a covalent link,
selenide QDs tagged polymeric microbeads, coupled those beads is called covalent conjugation between QDs and biomolecules.
to streptavidin and performed early biological experiments with The use of functional crosslinkers can realize covalent bind-
these beads. Monodispersed ZnS-capped CdSe QDs emitting fluo- ing. Commercially accessible crosslinkers include homo-, hetero-
rescence in the three primary colours (red, green and blue) were and tri-functional crosslinkers with various lengths and cross-
generated and subsequently incorporated into polymer beads at bridging types. Zero-length crosslinkers, such as 1-ethyl-3-(3-
exact ratios. Finally, they reported a multiplexing coding system dimethyl aminopropyl) carbodiimide hydrochloride (EDC) and N,
based on the QDs’ unique optical features. Under ideal condi- N′ -dicyclohexyl carbodiimide (DCC), facilitate the joining of two
tions, imaging and spectroscopic studies show that the single- molecules by adding no more elements. The kind of functional
colour encoded beads are highly consistent and reproducible. At groups available on the QDs’ surface is determined by the surface
the single-bead level, DNA hybridization experiments reveal that functionalization approach chosen. As a result, it establishes the
target and coding signals can be read at the same time. This covalent binding approach and crosslinker selection. The most
spectrum coding strategy will improve gene expression research, common functional groups for bioconjugation are carboxylic acid
high-throughput screening and clinical applications [100]. groups, which can be coupled to free amino groups present in
immunoglobulins, enzymes, proteins, etc., by developing simple
4.4. Bioconjugation amide bonds through zero-length crosslinkers [102–107]. More-
over, the non-covalent interaction is indicated by the presence of
QDs must be conjugated with biorecognition elements in a se- the surface or surface ligands on the QDs. Electrostatic interac-
quential manner so that they can identify and join with biomolec- tions between opposing charged molecules are the simplest and
ular targets and penetrate into the cell membrane via several most often utilized noncovalent bioconjugation approach [109].
paths [101–108]. To form QD conjugates, binding of biological
recognition components on the surface of QDs or with the surface 5. Biodistribution and toxicity of biogenic QDs
ligands of the QDs is required. QDs combined with peptides,
polymers, antibodies, ligands, antibodies and proteins show bril- Biodistribution and toxicology studies are mandatory studies
liant and persistent fluorescent marker properties to perform that are made compulsory by the regulatory authorities. These
targeted and nonspecific imaging of cells, subcellular organelles studies are performed to make sure that any cell therapy based
and single molecules. Xuewen He et al. [104] described a one-pot product is safe for use and they help in getting a better grasp
process in an aqueous solution that produced highly luminous on the fate of the cell developed in vivo. One of the significant
red to NIR protein-functionalized Znx Hg1−x Se QDs in one sec- features of a general toxicological study is the absence of tumour
ond at ambient temperature. These Znx Hg1−x Se QDs have strong formation, which is generally required in the phase I of clinical
red-to-near-infrared photoluminescence that is ideal for bioimag- studies. However, long-term effects on patients can eliminate the
ing [104]. Most as-synthesized QDs have hydrophobic caps on necessity of additional preclinical analysis to explore the tumour
their surfaces, making them incompatible in the aqueous phase. causing efficiency of the product. Biodistribution analysis is a
Therefore, modifying the surface of the QDs has thus become a part of the initial phase II study, which is utilized to analyse
major research area, with two subcategories: synthesis of shells the fate of the cells after their administration in the body [110].
on core-only QDs, and modifying the surface of the core and The possible toxicity of QDs in vivo and clinical imaging is still a
core/shell QDs by utilizing biocompatible substances [77,79]. QDs significant concern. However, because cadmium-based QDs tox-
are modified with various biomolecules, like enzymes, peptides, icity is no longer an issue for in vitro diagnostics, multicolour
antibodies, polysaccharides and small-molecule receptor ligands, QDs for diagnostic techniques and pathologies are likely to be-
to prepare fluorescent probes that can be further used for recep- come the most essential and medically significant application
tor imaging. Among these QDs, antibody-coated QDs were found of these semiconductor QDs in the coming years [22,111–113].
to be the most potential fluorescent probes [108]. Although QD cytotoxicity is irrelevant to in vitro cell biosensing,
Covalent and non-covalent binding are the two basic tech- it is considered crucial for in vitro and in vivo bioimaging. QDs
niques for conjugating QDs with biorecognition components. uptake by cells can result in various morphological and biochem-
When antibodies, proteins, aptamers, peptides, nucleic acids, ical changes, such as cell functioning loss, chromosomal damage
monosaccharides, etc. are covalently or non-covalently attached and ultimately cell death. The influence of QDs on organisms
with QDs, they form bio-conjugated QDs [102–107]. They are and cells has been thoroughly investigated over the last twenty
commonly employed for biosensing and extracellular and intra- years, resulting in a large amount of literature with hundreds of
cellular selective and nonspecific targeting. Because QDs have a articles. There is cytotoxicity information, with a wide range of
vast surface area, they can be used to adsorb giant molecules, experimental designs in the biocompatibility studies and many
10
QDs examined. Despite this, a truly comprehensive model for (ROS) levels that initiates apoptosis in cells, resulting in the
describing the potentially harmful effects of QDs does not exist. formation of carcinogenic cells [125].
The following are some of the general conclusions reached. After Apart from biological hazards, QDs can cause damage in the
the ligand shell of QDs has been removed from the intracellular environment as they ultimately enter the atmosphere due to
environment, hazardous ions such as heavy metals are released their rapid advancement in commercial and biomedical appli-
into the cytoplasm, causing cytotoxicity [22,111–113]. Therefore, cations [22,111–113]. A series of approaches has been estab-
this review aims at delivering a detailed literature overview of lished to study the biodistribution and toxicity of biogenic QDs
the biodistribution and studies used to analyse the toxicity of [112,113]. During the weathering process, residual QDs may re-
different QDs. lease hazardous metallic ions into the environment, which could
affect Chlamydomonas reinhardtii, microbes, macro-invertebrates
5.1. Biodistribution and even human beings. In addition, thorough cytotoxicity screen-
ing of QDs is required for their biological and biomedical appli-
Biodistribution studies are regarded as one of the most im- cations. Since most QDs, e.g. CdS, CdSe and CdSe/ZnS, are formed
portant studies in the biomedical domain as it is an in vivo of heavy metal ions (e.g., Cd2+ ), they pose a risk to humans, and
test-article distribution that is performed in certain non-clinical limiting their practical uses. The cytotoxicity evaluation of QDs
living organisms to support early therapeutic effects of drug has recently attracted much attention. Moreover, conventional
development. QDs may bring risks to human health and the envi- semiconductor QDs formed of heavy metal ions show toxic effects
ronment under certain situations, despite their potential societal that create severe safety issues, like ill-health and environmental
benefits, such as medication targeting and in vivo bio imag- implications. Before considering the toxicity of QDs, it is essential
ing [114]. The critical limits in biodistribution are the ability to keep in mind that no two QDs are alike, and each form of QD
to regulate QDs. Biodistribution only targets organs, prevents has its own set of characteristics. Overall, it can be stated that the
long-term accumulation in the body and minimizes long-term cy- toxicity of QDs is determined by their size, charge, concentration,
totoxicity. However, various factors resulting from both intrinsic exterior functional groups, oxidative, photolytic and mechanical
physical and chemical characteristics and environmental condi- stability, as well as their physicochemical characteristics and
tions influence the absorption, allocation, metabolism, excretion ambient circumstances [22,111–113].
and toxicity of QDs. Moreover, size, concentration, charge, exte-
rior coating bioactivity (capping material and functional groups), 5.2.1. Demonstration of toxicity and biodistribution through in vitro
as well oxidative, photolytic and mechanical stability have all and in vivo studies
been employed as determining factors in the toxicity of QDs. Generally, rat models are been highly used over mice models
Many reports have reported that QDs cause hepatic toxicity as to study the toxicity and biodistribution studies of QDs as rat
they are slow to degrade and accumulate in the liver. Addition- models have large blood volume and size of organs making them
ally, Cd-based QDs are known to cause various morphological and a suitable animal for various biochemical and histological analy-
functional impairments in the liver, as observed in various in vivo sis. However, a large amount of QDs are required if large animals
studies [115]. Recently, Liu and colleagues reported toxic effects are used in the experiment. In one of the experiments performed
of CdSe/ZnS QDs on liver, like inflammation and dysfunction, by Yaghini et al. (2018) [126], to study the biodistribution and
when administered intravenously [116]. The toxicity of QDs is toxicity of indium-based water soluble QDs in rats through intra-
still a controversial topic as some studies have reported low or no venous administration, they reported an accumulation of QDs in
toxic effects of QDs, whereas others have reported toxic effects. the spleen and liver after 90 days, and their elimination kinetics
For instance, in a study performed by Hauck and colleagues was found to be same as subcutaneous administration. Addi-
observed no toxicity caused by CdSe/ZnS QDs in Sprague-Dawley tionally, trace quantities of indium were detected in the colon
rats [117]. On the other hand, it was observed that CdSe/ZnS and intestine; it was assumed that either a few QDs or certain
QDs showed a toxic effect on the liver [118], lung [119,120] and products made up of indium got accumulated via hepatobiliary
kidneys [121]. However, very limited data is available for in vivo pathways. However, no organ damage or any histopathological
biodistribution of QDs in the biomedical domain and this creates lesions were reported for up to 4 weeks of intravenous admin-
an open room for the exploration of the biodistribution aspect of istration. Further, no signs of toxicity in other organs, like lungs,
QDs as it has became one of the important factors in determining pancreas, etc., were reported in complete blood count and serum
the applications of QDs. biochemistry tests [126].
The toxicity of QDs has been observed in vitro and in vivo;
5.2. Toxicity Brunetti et al. [111] determined that water-soluble InP/ZnS
core/shell QDs are a safer and better alternative to CdSe/ZnS
The toxicity of QDs are directly related to the cellular uptake, QDs for biomedical application. They tested the toxic effects of
which depends on the properties of QDs. Therefore, it becomes CdSe/ZnS and InP/ZnS QDs in fruit flies fed with QD-supplemented
important to reduce the toxicity of the synthesized QDs so as food that had similar physical and chemical characteristics except
to use them in biomedical applications. However, it has been for the nature of the particle core, clearly demonstrating that
observed that the toxicity of QDs is high when entering the cell as InP/ZnS QDs are a significantly healthier alternative to CdSe/ZnS
compared to those that are present on the surface or circulating QDs. CdSe/ZnS QDs showed harmful effects on epithelial A549
in the blood [122]. Most of the research on determining the cells and SH SY5Y nerve cells (human neuroblastoma) in vitro.
toxicity of QDs is based on two factors, the physicochemical InP/ZnS QDs, on the other hand, were quite well-tolerated in
properties and composition of QDs. The toxicity of QDs is often all of the tests. They primarily used real-time qPCR to study
directly proportional to their concentration, implying that highly the processes relating to QD toxicity, examining gene expression
concentrated QDs are far more harmful. The toxicity of Cd- and differences in response to stress and damage to genetic material.
Pd-based QDs has received much attention. Further, just after six Fruit flies have long been employed to investigate drug toxicity in
years from the discovery of QDs for bio-imaging applications, that an in vivo system. They are fed either with food of two different
is in 2004, the toxicity of Cd-based QDs was identified [123,124]. concentrations, that is 100 pM and 500 pM of QDs, or food having
While studying the toxicity of Cd-based QDs on a cellular level, it the same volume of QD supernatant solution. Finally, the Dredd
has been noted that Cd2+ increases the reactive oxygen species overexpression experiment results revealed that the CdSe/ZnS
11
6.1. Metallic QDs
Biologically synthesized metallic QDs have recently gained

much potential in biomedical applications. Biologically synthe-
sized metallic QDs coupled with biological entities or specific lig-
ands have outperformed traditional probes in detecting
malignant cells. Moreover, owing to their unique physical, chem-
ical and optical properties, and their capability to bind vari-
ous biomolecules to their surface, metallic QDs have become
an intriguing choice for biosensing. Further, metallic gold QDs
(Au QDs) containing multi-layered Au atoms have been used
in plasmonic applications, chemistry, medicine and metamateri-
als [129]. Since, Au QDs are non-toxic, inert and biocompatible,
they are found to be the perfect nanomaterials for the biomedical
field. It is important to note that Au QDs have many analogous
properties toe Au NPs; though Au NPs do not fluoresce like Au
Fig. 5. Intravenous injection of InP/ZnS QDs in BALB/c mouse and study of their
toxic effects on different organs.
QDs and Au QDs cannot exhibit visible surface plasmon reso-
Source: reproduced with permission from Lin et al. (2015) [127]. nance absorption, unlike the most well-known spherical Au NPs.
However, they show fluorescence in the visible to the NIR range,
making them ideal for optoelectronics, catalysts, biological sci-
QDs induced death in Drosophila by generating apoptosis. The ences, detectors and sensors. Similarly, cadmium telluride (CdTe)
is considered as an important group II–VI semiconductor material
toxicity of CdSe/ZnS QDs appears to be linked to the discharge
as it has a large exciton Bohr radius of 7.3 nm and a narrow
of harmful Cd2+ ions, indicating that Cd2+ ions are excreted from
bulk band gap of 1.5 eV, and has shown broad applications in
the particle core, despite the two-layer ZnS shell [111]. However,
electronics, biomedical, energy, etc. Additionally, their utilities
these toxicities can be decreased by modifying the surface of the
are also widely explored in live cell bio-imaging applications due
QDs through different ways, as discussed in the above section.
to good photostability, high quantum yield and a narrow emission
For instance, Lin et al. [127] injected PEGylated InP/ZnS QDs
range that cannot be obtained by traditional organic dyes [130].
intravenously in mice and reported no observable in vivo toxic
Semiconductors QDs were used in new ways to develop current
effects in the experimental period of 84 days, making them a
proteins and DNA detection methods. Additionally, the QDs can
suitable agent for biomedical industries and optical probes, as also be used as biological luminous markers that can detect
shown in Fig. 5 [127]. Similarly, in another experiment, PEGylated molecular structures. The most common method for multicolour
Ag2 Se QDs of size 29 nm were quickly cleared from the circu- cell labelling with QDs is receptor-mediated diffusion or nonspe-
latory system of mice after intravenous injection [128] and the cific endocytosis, which induces basic cell functions to transfer
same observations were noted in another experiment that used nanoparticles across the cellular membranes [76,131]. However,
PEGylated InP/ZnS QDs of size 58 nm [127]. Overall, it can be QDs need to be functionalized before use in the biomedical
concluded that the addition of any biopolymers has the potential domain to enhance their biocompatibility, water solubility and
to inhibit the mononuclear phagocytic system of the QDs and can target detection ability. For instance, Bao et al. [112] proposed the
also clear the QDs from the circulatory system. protein-assisted extracellular bacteria-based synthesis of CdTe
QDs, in which they revealed that these CdTe QDs were directly
6. Biomedical applications of QDs synthesized through E. coli-secreted proteins. These CdTe QDs
exhibited a tunable fluorescence emission and good crystallinity.
Although heavy metal QDs with surface treatments and heavy Further, a surface protein capping layer was used to enhance
the biocompatibility of the synthesized QDs. Additionally, using
metal-free QDs are promising for biomedical application, devel-
HeLa cell fluorescent imaging, it was also revealed that these
oping safer and greener QD nanomaterials is essential.
QDs could be efficiently employed for in vitro imaging of cell
Biomolecules may be recognized at low levels and used as an-
and bio-labelling applications [112]. In a similar ways, wheat
tibacterial and apoptotic agents using these ultra-small bio-
endosperm cells and genetically engineered yeast cells were used
conjugated QDs particles. In comparison to conventional organic
to synthesize Ag2 S QDs and Ag2 Se, respectively, that were capable
dyes or fluorescent dyes, QDs with optimal signal brightness, ex-
of imaging living cells [132]. On the other hand, metal-based
cellent photostability and the capability to be activated by various
nanomaterials are popular therapeutic agents that are highly used
fluorescence hues are advantageous in labelling and imaging of to treat various neurodegenerative diseases, different types of
live cells. The surface of the QDs must be successfully functional- cancers, diabetes, etc. Using them in the form of quantum dots
ized to provide high biocompatibility, water solubility and precise fascinated researchers and therefore made them determine their
target detecting capabilities to fulfil their medical goals. Carbon potential in the biomedical domain to treat different types of dis-
dots made from algal or plant extracts are more biocompatible, eases. For instance, the sol–gel hydrothermal technique was used
have lower cytotoxicity and are chemically inert, making them to synthesize ZnO QDs where green soy fatty acids were used as
excellent for bio-imaging and bio-labelling. Semiconductor QDs the precursor. The prepared ZnO QDs showed anti-proliferative
are employed in various applications, including optoelectron- activity against HeLa, human nasopharynx carcinoma, human
ics, biomolecular imaging, etc. They can be used in biosensing, colon adenocarcinoma, human breast cancer and human foreskin
bioimaging, DNA identification, communications, lasers, photode- fibroblast cell lines; therefore making them a suitable anticancer
tectors, photovoltaic systems, tumour and microRNA detection, agent [133]. An overall representation of the mechanism of metal
medication delivery, photodynamic therapy and microbiological chalcogenides killing cancer cells is demonstrated in Fig. 6.
labelling. This review has compiled various different literatures Moreover, quantum dots also show excellent antibacterial
and aims at providing a systematic and detailed discussion on activity by destroying microbial cells through disrupting cell
the biomedical applications exhibited by various QDs. walls or membranes, generating ROS and inhibiting cell growth
12
Fig. 6. An illustration of the cytotoxic effect created by metal chalcogenide QDs on cancer cell lines. The cell undergoes certain morphological alterations, like
generation of excessive ROS, increase in intracellular levels of Ca+2 , damage in DNA, mitochondrial dysfunction, auto-phagocytosis, stress on endoplasmic reticulum,
disruption of inside organelles and apoptosis of cells. (Abbreviations: Reactive Oxygen Species (ROS), Death Associated Protein 6 (DAXX), Fas-associated Protein with
Death Domain (FADD), Fas-associated Factor 1 (FAF), ATP-dependent Proteolysis Factor 1 (APF1), Caspases are Group of Protease enzymes having a Crucial Role in
Cell Apoptosis or Autophagy)
Source: reproduced with permission from B.A. Omran et al. (2021) [134].
by binding with their genetic materials, as illustrated in Fig. 7 which attained an equilibrium with 78.94% after 24 h. On the
[135–137]. Further, surface modifications with different materials other hand, methotrexate was slowly released and attained its
can promote their attachment to the cell membranes and enhance equilibrium with 63.84% after 30 h. The cytotoxicity of the sample
the bacterial cells’ ROS production. For instance, copper oxide was found to be dose-dependent as cell viability decreased to 32%
quantum dots that were synthesized from algae exhibited good after a dose of 1 gm/ml for methotrexate; however, the study
antibacterial properties against bacteria gram-positive bacteria revealed that Fe3 O4 -Ag2 O QDs/cellulose fibers nano-composites
(Staphylococcus aureus) and gram-negative bacteria (Enterbacter are safe to use as they produced almost no cytotoxic effects by
areogenes), and recorded inhibition zones of 16 mm and 14 mm, themselves [141]. Using the sulfide-producing facultative anaer-
respectively. However, it was observed that these copper oxide obe bacteria Pseudomonas aeruginosa, Mahle et al. discovered a
QDs exhibited better antibacterial activity against gram-positive method for fabricating surface-functionalized molybdenum disul-
bacteria because of the difference in the cell membranes, where fide (MoS2 ) QDs [54]. These MoS2 QDs have a QY of 42%, demon-
gram-negative bacteria are rich in lipids, lipopolysaccharides strating that QDs can be used as an optical sensor to detect the
and proteins. Additionally, binding of nucleic acid strands with concentration of glucose at the pico-molar level, making them
Cu2+ also destroyed the growth of bacterial cells [138]. Simi- perfect for early detection of diabetes and a variety of biomedical
larly, Syed and Ahmad, in 2013 for the first time, showed the applications. By increasing the reaction affinity between both the
antibacterial activity of CdTe quantum dots synthesized using the QDs and the analytes, the surface organic groups of MoS2 QDs
fungus Fusarium oxysporium when testing against Gram-negative enhanced the detection of glucose and H2 O2 [54].
bacteria (E. coli and Pseudomonas aeruginosa) and Gram-positive
(Staphylococcus aureus and Bacillus subtilis). It was observed that 6.1.1. Heavy metal-free ternary group I-III–VI QDs
the proteins secreted by fungus acted as stabilizing agents and Since binary nanocrystals in the II–IV group showed adverse
therefore eliminated the need of using external chemical-based consequences with regard to biocompatibility, non-toxic ternary
stabilizing agents. Overall, these synthesized QDs could be used as group I–III–VI QDs have a role as a better substitute. AgInS2 ,
an excellent antibacterial agent [139]. Likewise, Aspergillus flavus CuInS2 , AgInSe2 , CuIn2.3 Se4 , CuIn5 Se8 and ZnS–AgInS2 are ex-
was used to synthesize zinc sulfide QDs (ZnS QDs), which were amples of group I–III–VI QDs [76,81]. These QDs provide more
studied for their antibacterial activity against E. coli, where the control over the bandgap energies. Sizes and compositions can be
zinc ion aided in the generation of ROS that ultimately disrupted used to adjust their optical characteristics. CuInS2 , for example,
the bacterial cell [140]. Overall, QDs induce oxidative stress has a low bandgap energy of 1.45 eV and can emit in the NIR
in the bacterial cells that interrupt the normal mitochondrial range. Due to the effect of quantum size, the emission peak
pathways. Further, excess ROS damages the membrane phos- of CuInS2 can be adjustable from 693 to 835 nm by altering
pholipids and hampers the polarization of the mitochondrial the reaction temperature. The NIR and homogeneously emitting
membrane. Cellulose nanofibers (CNFs) decorated with Fe3 O4 - CuInS2 QDs also showed a typical quantum confinement regime
Ag2 O QDs were bound with methotrexate and etoposide that as well as a broad shoulder in the long-wavelength direction.
exhibited in-vitro release of drug and anti-cancer activity. The re- As-synthesized CuInS2 -based QDs with reduced toxicity and ex-
lease of the drug at a constant speed was observed for etoposide, cellent optical properties were found to be a good candidate for
13
Fig. 7. Illustrates QD-assisted killing of bacterial cells via disruption in the cell wall or membrane, generation of excessive reactive oxygen species (ROS), binding
with genetic material to cease cell growth, and damage to protein.
biomedical fluorescent labelling [142]. Further, Bao et al. explored (GQDs), CQDs and polymer dots are all examples of carbon-
microbiologically generated CdTe QDs having adjustable fluores- based QDs [144–148]. Currently, much of the research on QDs
cence emission for cytotoxic activity and HeLa cell imaging. Bao is focused on new developing materials. CQDs and GQDs have
et al. [111] fabricated highly fluorescent biocompatible CdTe QDs gained tremendous attention in this new QDs category for their
with a fluorescence emission from 488 to 551 nm [111]. The as- broad-spectrum utilities in biomedical applications and catalytic,
synthesized QDs’ high crystallinity may have a lot of promise optical and biomedical properties. CQDs are a new type of carbon
in bio-imaging and bio-labelling purposes. Similarly, ZnS QDs nanomaterial with unique and tunable photoluminescence prop-
were synthesized using heavy metal tolerant Aspergillus sp., and erties, low toxicity, high photostability, biocompatibility, small
their anti-bacterial activity in terms of oxidative stress responses size and ease of surface functionalization, making them widely
and related cellular leakage was then examined. The toxicity of used in bioimaging, environmental monitoring, chemical analysis,
different QDs is very much known and highly discussed, but targeted drug delivery, diagnosis of diseases and therapeutic
the evidence showing the antibacterial capacity of biologically- applications. Moreover, CQDs show non-linear optical properties
mediated QDs is rare. However, this study showed excellent due to the strong confinement regime and are quasi-spherical
antibiotic activity against usual pathogenic gram-positive bacteria carbon nanoparticles having sp2 carbon, oxygen, and other dop-
(Staphylococcus aureus and Bacillus subtilis) and -negative bac- ing compounds [149,150]. Chemical inertness, biocompatibility,
teria (Escherichia coli and Klebsiella pneumonia). The diameters cellular membrane permeability, adjustable surface groups, solu-
of the zone of inhibition of Staphylococcus aureus, Bacillus sub- bility in water and low cytotoxicity characterize CQDs and GQDs
tilis, Escherichia coli and Klebsiella pneumonia were observed as with widths less than 10 nm, making them perfect for biomed-
32 ± 0.10 (control 35 ± 0.31), 28 ± 0.38 (control 25 ± 0.27), ical, optoelectronic and energy-related applications. CQDs have
39 ± 0.5 (control 42 ± 0.35), and 27.2 ± 0.61 (control 0.19) enormous potential in fluorescence bio-imaging and multi-mode
(Fig. 8 A). Additionally, it has been previously stated that QDs imaging of cells and tissues due to their high fluorescence qual-
show better toxicity against gram-negative bacteria. However,
ities, minimal cytotoxicity and superior biocompatibility [151].
bacterial membrane organization is generally responsible for the
Biomedical imaging has emerged as one of the most promising
susceptibility of bacteria to the QDs. Further, it has been observed
and most recognized applications of CQDs. CQDs generated in
that the negative charge present in lipopolysaccharide of the
diverse ways feature non-blinking PL and excellent photostability
outer membrane of gram-negative bacteria and teichoic acid in
due to the enormous rigid-conjugated structural system follow-
gram-positive bacteria are directly involved in the interaction of
ing surface passivation. In biological applications, these benefits
cells with ZnS QDs. This study also explained the mechanism of
have permitted single-molecule tracking and long-term real-time
the antibacterial activity of ZnS QDs through cytoplasmic leak-
imaging. CQDs have a broad range of utilities in biomedicine, as
age analysis, where DNA and protein leakage at different points
well as in vivo and in vitro cell imaging, as therapeutic agents, in
were tested. Although it was not possible to depict the time-
gene delivery and cancer treatment. Folate-functionalized CQDs
dependent cytoplasmic leakage indices for both DNA and protein
for different bacteria, with the help of Fig. 8B it can be interpreted with hydrodynamic diameters of 5–15 nm are helpful as imag-
that the supernatant of cytoplasmic materials was observed for ing probes. Bhunia et al. [146] have investigated their perfor-
up to 3–4 h and after that protein content started to decrease, mance as fluorescent cell labels. Nontoxic CQDs are suggested
which directly results in membrane disruption due to the release to be a powerful replacement for toxic cadmium-based semi-
of proteolytic enzymes by the bacteria [143]. Furthermore, PL conductor nanocrystals [146]. Moreover, CQDs are also utilized
spectral analysis of these biogenic ZnS QDs in both the presence in developing sensors that can detect various bio-analytes. For
and absence of bacteria gave primary indications of the possible instance, Solanki and her co-workers synthesized bio-inspired
ROS mediated oxidative stress that was generated by the QDs, carbon quantum dots (bCQDs) (Fig. 9A) through a single-step syn-
which ultimately resulted in the cell [22]. However, not much thesis by hydrothermally treating the leaf extract of Cinnamomum
work has been reported regarding biogenically synthesized heavy tamala. Further, they investigated the bCQDs’ sensing capability
metal-free ternary group I–III–VI QDs and their applications in the to determine different concentrations of ciprofloxacin antibiotics
biomedical domain; though it is suggested that they may carry (Fig. 9B). From the results of the sensing studies utilizing fluores-
revolutionary powers in the near future. cence spectroscopy, it was evident that bCQDs could sense the
concentration of ciprofloxacin antibiotics in the linear range of
6.2. CQDs 1 to 100 µM, with a limit of detection of 6.06 µM. This study
shows that the bCQDs were able to sense ciprofloxacin antibiotics
CQDs are fluorescent carbon nanoparticles fewer than 10 owing to the charge transfer between bCQDs and ciprofloxacin
nanometers in dimension [73–75]. Graphene quantum dots and hydrogen bonding interactions (Fig. 9C) [152].
14
Fig. 8. (A) Zone of inhibition for antibacterial activity of ZnS QDs against gram-positive and -negative bacteria: (a) Staphylococcus aureus, (b) Bacillus subtilis, and
(c) Escherichia coli (d) Klebsiella pneumoniae. (B) Cellular leakage indices for (a) Nucleic Acid and (b) Protein against time for bacteria in the presence of ZnS QDs.
Source: reproduced with permission from J.M. Jacob et al. (2019) [22].
Fig. 9. (A) Biological synthesis of carbon quantum dots using leave extract of Cinnamomum tamala extract, (B) Sensing of various ciprofloxacin concentrations by
bioinspired carbon quantum dots utilizing fluorescence spectroscopy, along with a linear fitting of the obtained sensing data, and an interference study with other
antibiotics, and (C) Mode of mechanism data of ciprofloxacin sensing via bioinspired carbon quantum dots.
Source: reproduced with permission from N. Chaudhary et al. 2022, Mater Lett [152].
It has been reported that the biosynthesis of CQDs is very green hydrothermal method [153]. Further, a study reported
easy as it only requires a carbon source that will act as a carbon that water-soluble carbon dots could efficiently deliver heparin,
precursor during the formation of the carbon QDs. Further, the an anti-coagulative drug, and doxorubicin, an anti-cancer drug,
biomedical potentialities of quantum dots are increased if the which prevented blood clotting and showed targeted drug deliv-
precursors used to synthesize the CQDs naturally possess medic- ery of doxorubicin, with a high drug loading capacity of the car-
inal benefits. For instance, Sawant along with his colleagues, bon quantum dots. Additionally, the research showed that when
prepared curcumin-loaded ginger herb-based carbon dots coated doxorubicin was loaded with heparin-carbon quantum dots, it
TiO2 nanoparticles that exhibited anticancer and anti-psoriatic increased the blood compatibility as well as simultaneously pre-
activities. Here, curcumin was preferred because of its hydropho- venting the spread of cancer cells. Moreover, the presence of
bic nature and the quantum dots were synthesized through a electrostatic interactions helped in the easy delivery of heparin
15
and doxorubicin under acidic conditions, and simultaneously it possibilities for bioimaging and optical sensing. They also act
was also noted that the side effects of doxorubicin were also as excellent transporters for drug delivery, while providing si-
decreased, therefore suggesting that the doxorubicin and heparin multaneous visual monitoring of release kinetics due to their
loaded carbon quantum dots can also find utility in image-guided modest size of 3–20 nm, crystalline structure and biocompat-
drug-delivery for image-guided cancer therapy [154]. Similarly, ibility. Their unique catalytic, physical and chemical features
CQDs are also known to possess great antibacterial properties, for also hold promise for various biological applications [86–88].
instance, it was reported that waste peel of Ananas comosus was Micrometer-sized graphene sheets have been proven to have
used to synthesize CQDs possessing non-linear optical properties better drug and gene loading abilities due to their high spe-
(NLO CQDs) and to study their antibacterial properties, they cific surface area and persistent interaction with a variety of
were tested against clinical pathogens, namely, Bacillus cereus, molecules via stacking, hydrophobic interaction, electrostatic in-
Pseudomonas aeruginosa, Staphylocccus aureus, E. coli and Vibrio teraction or physical adsorption. While GQDs inherit these ad-
cholrea. Generally, the antibacterial activity of CQDs is exhibited vantages, they are smaller thus allowing easier cell uptake and
due to their extremely small size, the effect of charge transfer are more biocompatible to reduce cytotoxicity. GQDs passivated
and zeta potential, but the presence of nitrogen and hydroxyl with polyethylene glycol (GQDs-PEG) were shown to have a good
groups on the CQDs also helps in exhibiting antibacterial activity. drug loading capacity 2.5 mg/mg of anticancer agent doxorubicin
Moreover, the negatively charged cell membrane of bacteria is at pH 7.4 [147]. By hydrogen bonding, the surface-passivated PEG
attracted to the positively charged CQDs, which results in mem- on GQDs can boost the green-photoluminescent brightness and
brane integrity loss, making CQDs a perfect antibacterial agent. loading medication. For the pancreatic cancer-specific delivery
Further, the same study also reported the antioxidant activity of drugs and bioimaging application, Nigam et al. employed
of the prepared CQDs. Therefore it can be concluded that the hyaluronic acid-functionalized GQDs-labelled human serum al-
CQDs synthesized from the waste extract of pineapples possess bumin nanoparticles. They described this nano formulation as
excellent morphology and can act as a good anti-bacterial agent significantly enhancing the drug’s bioavailability and sustained
against clinical bacterial pathogens as well as showing great anti- release property to pancreatic cancer cells in vitro [148]. Rojas-
oxidation activities [155]. CQDs have also been found to be useful Andrade made graphene oxide quantum dots (GOQDs) by chem-
in treating periodontal disease, which is a prevalent chronic ically exfoliating carbon fibers and they displayed antibacterial
inflammatory disease affecting gums around the teeth (periodon- action towards Staphylococcus epidermidis in the dark and under
tium) and mainly humans are affected by this disease [156]. visible light. These findings suggest that GOQD structural de-
In this disease, the pathogen forms a biofilm around the teeth fects are connected to cytotoxicity and phototoxicity, laying the
that gradually eliminates the tooth-supporting tissues, which can groundwork for the rational development of low-cost, efficient
eventually lead to the loss of a tooth [157]. For instance, CQDs antimicrobial treatments [162].
of size 1–5 nm were prepared from chlorophyll and were conju- Further, Sam and his colleagues conducted a comparative
gated with metronidazole (MET), which is a standard antibiotic. study where they showed high anticancer activity of GQDs
These conjugated chlorophyll-derived CQDs with MET (cCQD- containing curcumin by combining three different kinds of
MET) were internalized into the cultured cells of the periodontal curcumin–graphene composites, namely graphene oxides (GOs),
pathogen Porphyromonas gingivalis (P. gingivalis) at different con- double-oxidizes graphene oxide (DGO) and GQDs, that acted as
centrations. Overall, it was observed that the dosage is reduced hydrophobic cancer drugs. It was observed that the interactions
by almost six times when MET is conjugated with the synthesized between the oxygen groups and curcumin decided the loading
cCQDs. Additionally, these cCQDs also exhibited excellent fluores- capacity of curcumin, and since the oxygen-containing func-
cence properties that can be used for the imaging and tracking of tional groups on the surface of the graphene were pH-dependent
the drug. This technique can be used to develop a smart drug that also affected the drug release behaviour and drug loading
delivery system for treating intercellular infections at low dosage capacity. Overall, it was found that the GQD-curcumin com-
and simultaneously reduces the antibiotic resistance and side posites showed a high drug loading capacity of 40,800 mg/g
effects of the antibiotics [158]. Overall, biologically synthesized and were therefore considered as the best anti-cancer agent
CQDs are a potential biomedical agent that possess superior among all other curcumin–graphene composites. Additionally,
biological properties and can effectively act as antibacterial [158], the curcumin–graphene composites did not exhibit any fluores-
anti-oxidant and anti-cancerous agents [159]. cence activity, but after the curcumin was released, the GQDs
exhibited their remaining fluorescence, revealing that they can
6.3. GQDs also be used as a probe for tumour imaging and drug delivery
agent simultaneously, as illustrated in Fig. 10 [163]. Moreover,
The unique properties of graphene, like high water solubil- it has been suggested that the biologically synthesized GQD-
ity, good electrical conductivity, biocompatibility, low cytotoxi- based polymer composites exhibit sp2 type hybridization and
city, stable photoluminescence and high surface to volume ratio π -stacking, which increases their drug loading capacity, and that
have made it attract the attention of the researchers worldwide. cannot be achieved by other nanomaterials [164–168]. Further,
Moreover, its versatility has been explored in the biomedical gene therapy is regarded as a futuristic technique that aims
domain due to its excellent photoluminescence [160]. However, to solve different genetically inherited diseases, like neurode-
the mechanism of photoluminescence is still not clear, which generative disease, cancer cystic tissue corruption, etc. but for
limits its biomedical utilities. Graphene and its derivatives have successful gene therapy, it requires a gene carrier having the
received a lot of attention because of their distinct physical, ability to protect the DNA from nucleoside degradation and
chemical and mechanical characteristics, which can be used in aids in high-yield DNA cell uptake. For this purpose, GQD-based
a variety of ways [161]. GQDs have emerged in recent years polymer composites are preferred as a better alternative for
as superior and universal fluorophores due to their exceptional viral vectors as they can show better in vitro and in vivo gene
combination of key advantages, which include outstanding pho- therapies. Additionally, GQDs are also used in photothermal (PTT)
tostability, tiny size, biocompatibility, tunable PL property, ex- and photodynamic therapy (PDT). PTT is the most widely used
ceptional multiphoton excitation property, electrochemilumines- technique to inhibit the growth of cancer cells without damaging
cence, ease of derivatization with biological molecules, as well normal or healthy cells by using electromagnetic wave radiation
as chemical inertness. These luminescent GQDs open up new and adsorbent nanomaterials in the infrared region. PTT converts
16
Fig. 10. Synthesis of curcumin–graphene composites (GO-Cur, DGO-Cur and GQD-Cur) showing their anti-cancer activity on mice.
Source: reproduced with permission from S. Some et al. 2014, Scientific Reports [163].
light energy into heat energy that directly targets the cancer morphology, degree of crystallinity and nanoscale impact can
cells and destroys cell membranes, resulting in the death of improve the fluorescence and luminescence of QDs [175]. Ad-
the cancer cells. Moreover, gold nanoparticles, carbon nanotubes ditionally, heavy metal toxicity and specific targeting properties
and graphene are highly used in PTT, but graphene is the most of QDs still remain a challenge, but it has been suggested that
preferred because it has a high efficiency of producing heat from specific targeting can be improved by incorporating receptor–
the light and is more biocompatible as compared to the other ligand on the nanoparticles. Additionally, the QY of QDs with long
nanomaterials. Recently, it was discovered that the effectiveness wavelength emissions still need a lot of enhancement. However,
of PTT can be enhanced by merging a drug with the bioactive high values, more than 90% in blue region, have been reported,
GQD-based polymer composites [169,170]. PDT uses visible light but due to uncertain QY standard choices, it becomes difficult to
to activate the light-sensing compound, which generates free obtain high wavelengths. Further, bio-imaging using biogenic QDs
radicals that are used to kill rapidly growing cells [268]. Apart having an emission above 650 nm in the red or infrared region
from cancer treatment, PDT is also used in the treatment of acne holds a great future if auto-fluorescence of neighbouring tissues
and psoriasis. Since GQDs are found to be stable in different pH and other areas are avoided [176].
ranges and light, they are resistant to biological corrosion and are
biocompatible, therefore, they are more considered in PDT. 8. Conclusion and prospects
7. Current challenges Technology-driven society has led to a generation of various

materials and techniques that are helpful to living beings and ease
The biological synthesis of QDs still needs deep investigations their lives. One of the technologies that has remarkably impacted
and the most important drawback of plant-mediated green syn- the science domain is nanotechnology, that uses materials whose
thesis is that the synthesized QDs are not completely separated dimensions lie in the nano range, helping them to exhibit unique
from the plant biomass and the additional separation steps can properties, which ultimately results in finding their utilities in
result in the generation of negative interference [171]. Moreover, various domains. Overall, nanotechnology is a multi-disciplinary
standardization of QDs is difficult because both the fluorescence domain that can be applied in every field. However, amongst
and QY of the QDs are related to the surface morphologies, various kinds of nanomaterials, quantum dots have gained enor-
therefore to synthesize effective QDs, all parameters before the mous attention in the last few decades. They are extremely small
synthesis need to be specified [172]. Additionally, the presence in size, ranging from 1–10 nm, and therefore exhibit excellent
of different phytochemicals creates a challenge in the synthesis properties like optical, electrical, biological, chemical, physical,
of QDs. Thus, more studies are still needed in the synthesis structural, etc. Quantum dots have successfully managed to oc-
of biological capping and stabilizing molecules with a precise cupy significant utilities in the biomedical domain in diagnosing
chemical configuration. Furthermore, the synthesis of QDs at an and treatment of diseases. However, with their increasing us-
industrial level is still not attainable [173]. A continuing challenge age, concerns regarding their toxicity and biocompatibility have
is to increase the quantum yield of QDs while fully employing also increased, which has led to the synthesis of quantum dots
their inherent properties and tuning their fluorescence emis- through biological methods. Since biological methods use biolog-
sion spectra for biomedical utilities [174]. It has been suggested ical materials like plant extracts, microorganisms (bacteria, fungi
that precisely controlling the green synthesis protocols, surface and algae), enzymes, nutrient media, etc. for the synthesis of
17
quantum dots, the biologically-derived quantum dots exhibit low Data availability
cytotoxicity and high biocompatibility. Moreover, the properties
of these synthesized quantum dots can be enhanced by fabricat- This is review article, so no need of data sharing is required.
ing their surface with different materials that helps in improving
their stability, specificity and solubilization, therefore different Acknowledgements
methods like salinization, encapsulation, bioconjugation, etc. are
being widely used to enhance the properties of quantum dots K.R.B.S. and V.N. are thankful to BHU (IoE grant project) for
and help them achieve more potential in a broad spectrum of financial support throughout this work. P.S. expresses gratitude
applications. Further, these unique properties of quantum dots of thanks to her respective affiliated institution. J.S. expresses
have helped them find profound application in the biomedical do- gratitude for the DST-INSPIRE faculty Fellowship, BHU, India (IoE
main, where they are highly used as fluorescent probe materials grant), and UGC New Delhi, India for providing financial support.
in imaging purposes, act as drug, nutrient and gene carriers, used Finally, R.P.S. and S.M. are thankful to the Honourable Vice-
to develop clinically important sensors that can rapidly detect chancellor, Indira Gandhi National Tribal University, Amarkantak,
diseases and are also used in the treatment of various cancer and Madhya Pradesh, India, for providing financial assistance to work
neurodegenerative diseases. smoothly and diligently.
Further, researchers are now focused on developing new bi-
ological synthesis methods for achieving high quality products
Funding
with small scale production of QDs and large scale distribution.
The enzymatic route for cadmium sulfide precipitation is used in
This work did not receive any specific grant from funding
the green manufacture of CdS QDs. However, a study investigat-
agencies in the public, commercial or not-for-profit sectors.
ing the impact of biological variables is needed to understand
the exact biological mechanism of the synthesis of cadmium
precipitation. Cadmium was supplied to bacterial cells at different References
phases of growth and the amount of cadmium sulfide precipitated
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Nano-Structures & Nano-Objects 32 (2022) 100921

Contents lists available at ScienceDirect

Nano-Structures & Nano-Objects

Bioinspired quantum dots: Promising nanosystems for biomedical

1. Introduction properties are size-dependent [1]. QDs are three-dimensionally

Fig. 4. Various surface modification techniques and their advantages.

6.1. Metallic QDs

Biologically synthesized metallic QDs have recently gained

7. Current challenges Technology-driven society has led to a generation of various

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