Phototherapy with layered materials derived quantum dots

Abstract

Quantum dots (QDs) originating from two-dimensional (2D) sheets of graphitic carbon nitride (g-C₃N₄), graphene, hexagonal boron nitride (h-BN), monoatomic buckled crystals (phosphorene), germanene, silicene and transition metal dichalcogenides (TMDCs) are emerging zero-dimensional materials. These QDs possess diverse optical properties, are chemically stable, have surprisingly excellent biocompatibility and are relatively amenable to surface modifications. It is therefore not difficult to see that these QDs have potential in a variety of bioapplications, including biosensing, bioimaging and anticancer and antimicrobial therapy. In this review, we briefly summarize the recent progress of these exciting QD based nanoagents and strategies for phototherapy. In addition, we will discuss about the current limitations, challenges and future prospects of QDs in biomedical applications.

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Houjuan Zhu

Houjuan Zhu received her PhD degree in Chemistry from the University of Science and Technology of China in 2015, and then she worked as a Research Fellow in the Department of School of Chemical and Biomedical Engineering at Nanyang Technological University (NTU) from 2015 to 2017. She is currently a Research Fellow in the Department of Chemical and Biomolecular Engineering at the National University of Singapore (NUS). Her research focuses on the design and synthesis of nanomaterials including two-dimensional quantum dots and semiconducting polymer nanoparticles in cancer therapy, mainly phototherapy.

Nengyi Ni

Nengyi Ni received her Bachelor of Engineering degree from the Department of Chemical and Biomolecular Engineering at the National University of Singapore, and is currently studying there as a PhD student. Her research interests include the investigation and control of biological effects by nanomaterials to therefore enhance therapeutic outcomes in cancer treatment.

Suresh Govindarajan

Govindarajan Suresh is a Research Fellow at the Department of Chemical and Biomolecular Engineering, National University of Singapore (NUS). He received his Bachelor's and Master's degrees (Physics) from Bharathidasan University, Tiruchirappalli, Tamil Nadu, India and PhD from VIT University, Vellore, Tamil Nadu, India. He was a Research Scientist in the Department of Urology, Singapore General Hospital, Singapore before moving to NUS. His research interests are developing novel nanomaterials for hyperthermia treatment and photothermal therapy and translational cancer research.

Xianguang Ding

Xianguang Ding received his PhD degree in Biophysics from the University of Science and Technology of China. After working as a senior research scientist in Suzhou Mesolight co., Ltd for developing QLED, he moved to the National University of Singapore (NUS) and worked as a Research Fellow in the Department of Chemical and Biomolecular Engineering and Centre for Advanced 2D Materials. His interest is semiconductors for surface plasmon enhancement and point-of-care diagnostics.

David Tai Leong

David Tai Leong is an Associate Professor at the Department of Chemical and Biomolecular Engineering, National University of Singapore (NUS). He obtained his PhD in Biology and Bachelor's degree in Chemical Engineering from the NUS and received his post-doctoral training at the Howard Hughes Medical Institute at the University of Pennsylvania. His research interests span across a fundamental understanding of the biological effects of nanomaterials to their applications in nanomedicine, biosensing and nanotoxicology.

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1. Introduction

Two-dimensional (2D) nanomaterials have gained tremendous research interest due to the great success achieved by graphene materials in the past few decades.^1–3 The commonly reported 2D nanomaterials are graphene,^4,5 hexagonal boron nitride (h-BN),^3,6,7 graphitic carbon nitride (g-C₃N₄),^8,9 transition metal dichalcogenides (TMDCs),^10–16 monoatomic buckled crystals (phosphorene), germanene^17,18 and silicene,^19–21 all of which exhibit a wide range of applications due to their catalytic, electronic, thermal, optical, chemical, and magnetic properties.^22–26

In recent years, a growing number of inorganic QDs derived from their larger 2D counterpart have attracted more attention, such as graphene QDs,^4,5,27,28 h-BN,^29,30 TMD QDs,^31–37 g-C₃N₄ QDs.^38–40 This unique class of QDs is endowed with better dispersity in both aqueous and non-aqueous solutions, larger surface-to-volume ratios, easier functionalization, doping, higher tunability in physiochemical properties and fluorescence.^41–43 Due to these unique and diverse properties, QDs have been explored to widely apply in various research fields including bioimaging,^44–48 cancer therapy,^49–52 sensing,^44,53–56 optoelectronics,^57,58 catalysis and energy storage.^59–61

Phototherapy is an attractive non-invasive remotely activated medical modality for the treatment of various diseases.^62,63 It can be widely divided into photodynamic therapy (PDT) and photothermal therapy (PTT). During the process of phototherapy, the phototherapeutic agent has to be delivered to the diseased site and subsequently irradiated with light at a particular wavelength; PDT utilizes photosensitizers (PS) that are activated to generate reactive oxygen species (ROS) by light, consequently inducing irreversible damage of cells.^64–68 In PTT, the photothermal agent absorbs near infrared (NIR) light to produce heat, directly leading to the ablation of cells.^69–71 Nanomaterials driving light-triggered PDT and PTT are promising next generation agents with their excellent specificities that bring about a more defined therapeutic at a much lower applied dose with lowered systemic side effects compared to the traditional radio- and chemotherapies.^72–74

To improve the therapeutic efficiency of phototherapies in tumors, a wide variety of PS and PT agents, such as semiconducting polymer quantum dots,^72,74,75 gold nanostructures,^76,77 metal nanoparticles,^78,79 metal sulfide nanoparticles,^80–82 two-dimensional materials,^16,83 oxide nanoparticles^84–86 and carbon derivatives,⁸⁷ are explored as potential phototherapeutic agents. In comparison with these nanomaterials, QDs possess several key merits as PT agents including widely tunable fluorescence properties, good photostability and chemical stability, excellent solubility and biocompatibility.⁸⁸

The studies on QDs in many fields are still at the preliminary stage due to the poor understanding and unexploited applications. Although some excellent reviews have comprehensively and comparatively summarized the synthesis, properties and applications of QDs,^89,90 a review that specifically focuses on QD based phototherapy is currently missing. This review summarized the recent progress of QDs originating from two-dimensional nanomaterials for phototherapy. The phototherapeutic QD agents in recent literature are summarized (Table 1). The various strategies by which different QDs are applied in PDT and PTT together with insights into their present limitations and challenges will inspire further translation of these QD technologies into biology and medicine.

Table 1 Summary and comparison of QD based phototherapy

System	Light source	Application	PCE for PTT/^1O2 QY for PDT^a	Analyte	Ref.
a PCE: photothermal conversion efficiency of PTT agents; ^1O2 QY: singlet oxygen quantum yield of PDT agents; N.A: not reported.
MoS2 QDs	White light, 0.1 W cm^−2	PDT	N.A.	Human endothelial cells (HMVEC), 3D tumor spheroids	32
MoS2 QDs	630 nm laser	Up-conversion and down-conversion bioimaging guided PDT	N.A.	HeLa cells	49
MoS2-GSH nanodots	808 nm laser, 0.5 W cm^−2	PTT	N.A.	4T1 cells, 4T1 tumor-bearing mice	102
MoSe2 nanodots	785 nm laser, 2 W cm^−2	PTT	PCE of 46.5%	HeLa cells	103
MoS2 QD doped disulfide-based SiO2 nanoparticles with hyaluronic acid and Ce6	808 nm laser, 1.5 W cm^−2;	PDT/PTT	PCE of 22.34%	4T1 cells, 4T1 tumor-bearing mice	104
	660 nm laser, 1 W cm^−2
MoS2 QDs@polyaniline	808 nm laser, 1.5 W cm^−2	PA/CT image-guided PTT/RT	PCE of 31.6%	4T1 cells, 4T1 tumor-bearing mice	106
MoS2 QDs	Solar light	PDT		S. aureus, E. coli and S. aureus infected wounds	107
WS2 QDs	808 nm laser, 1 W cm^−2	PA/CT image-guided PTT/RT	PCE of 44.3%	HepG2 cells and HeLa cells, BEL-7402 tumor-bearing mice	50
WS2 nanodot based nanoplatform integrating hyaluronic acid (HA), polyaniline (PANI), and Ce6	808 nm laser, 1.5 W cm^−2;	FL/PA/CT imaging guided triple-collaborative PTT/RT/PDT	N.A.	4T1 cells, 4T1 tumor-bearing mice	105
	670 nm-laser, 1.0 W cm^−2
GQDs	White light (400–800 nm), 6.5 mW cm^−2	PDT	^1O2 QY of 1.34	HeLa cells female, BALB/nu mice with subcutaneous breast cancer (MDA MB-231 green-fluorescent protein) xenografts	51
Nitrogen doped GQDs functionalized with an amino group	800 nm excited two-photon excitation (TPE) light, 2.3936 mW, 239.36 nJ per pixel	TPE imaging guided PDT	0.53	KB-50 cancer cells	52
Aptamer-conjugated GQDs/porphyrin derivative	980 nm laser, 0.72 W cm^−2;	Fluorescence-guided PDT/PTT	PCE of 28.58% ^1O2 QY of 1.08	A549 cells	110
	635 nm laser, 0.16 W cm^−2
Folic acid (FA)-functionalized GQDs with loading IR780 iodide	808 nm laser, 1 W cm^−2	NIR fluorescence imaging guided PTT	PCE of 87.9%	HeLa cells, BALB/c nude mice bearing HeLa tumors.	119
GQDs	808 nm laser, 0.5 W cm^−2	PTT/PDT	N.A.	MDA-MB-231 cells	120
GQDs	470 nm laser, 1 W	Autophagy-inducing PDT	N.A.	U251 human glioma cells	121
Upconversion nanoparticle (UCNP) coated GQDs and loading hypocrellin A	980 nm laser, 0.3 mW	Chemo-PDT	N.A.	HeLa cells	122
GQDs	470 nm laser, 1 W	PDT	N.A.	Methicillin-resistant Staphylococcus aureus and Escherichia coli	123
GQDs	UV light	Gamma irradiated PDT	N.A.	N.A.	124
GQD immobilized on Mn3O4 coated with polydopamine (PDA)	670 nm laser, 3 mW cm^−2	MRI and NIR imaging guided PDT	N.A.	A549 cells, A549 tumor-bearing mice	125
Sulphur doped GQDs and methylene blue	660 nm LED light, 12 W	PDT	N.A.	MCF-7 cells	126
GQD-PEG loading Ce6	650 nm laser, 20 mW cm^−2	PDT	N.A.	HeLa cells, nude mice bearing HeLa tumor	131
GQD integrated in MnO2	810 nm femtosecond pulses	Two-photon confocal fluorescence guided PTT	N.A.	HeLa	132
GQDs decorated by silver nanoparticles	425 ± 10 nm LED light, 3 mW cm^−2	Chemo-PDT	N.A.	HeLa and DU145 cancer cells	135
GQDs	800 nm excited TPE light, 2.64 mW, 264 nJ per pixel	TPE guided PDT	N.A.	MDR bacteria	136
Sulphur doped GQDs combined with methylene blue	660 nm-LED, 12 W	PDT	N.A.	E. coli and M. Luteus colonies, IMR-90 and A549 cell lines	137
Nitrogen-doped GQDs	670 nm laser, 1 W cm^−2	PDT	^1O2 QY of 0.60, 0.49 and 0.41	E. coli bacteria	138
N-GQDs integrated in mesoporous silica nanoparticles and loading DOX	622 nm LED light,	Chemo-PDT	N.A.	MDA-MB-231 cells	139
	6.8 mW cm^−2
Nitrogen-doped GQDs conjugated Rose Bengal	480 nm-xenon lamp	PDT	N.A.	MCF-7 cells, ear blood vessels of mice	140
Upconversion nanoparticle (UCNP) coated GQDs and targeted TRITC	980 nm laser, 1.5 W cm^−2	PDT	N.A.	4T1 cells and 4T1 tumor bearing mice	141
Upconversion nanoparticle (UCNP) coated GQDs and targeted folic acid, carboxybutyl triphenylphosphonium	980 nm laser, 1 W cm^−2	PDT	N.A.	HeLa cells and HeLa tumor bearing nude mice	142
N-Doped GQDs	808 nm laser, 2 W cm^−2	PTT	PCE of 62.53%	A549 and HeLa cells	144
GQDs integrated in magnetic mesoporous silica nanoparticles and loading DOX	808 nm laser, 2.5 W cm^−2	Magnetic hyperthermia and chemo-PTT	N.A.	4T1 cells	145
GQDs integrated in mesoporous silica nanoparticles and loading DOX	808 nm, 2.5 W cm^−2	Chemo-PTT	N.A.	4T1 cells	146
GQDs integrated in silica coated hollow magnetic nanospheres and loading DOX	671 nm laser, 0.2 W cm^−2; 808 nm laser, 0.25 W cm^−2	Magneto-mechanical, chemo-PDT/PTT	PCE of 21.9%	Eca-109 cells	147
GQDs conjugated by aptamer AS1411	808 nm laser, 2 W cm^−2	PTT	N.A.	A549, COS-7, HEK293, HeLa, HepG2, MCF-7	148
Hyaluronic acid (HA)-modified and GQD-gated hollow mesoporous carbon nanoparticles (HMCN) and loading DOX	808 nm laser, 1 W cm^−2	Chemo-PTT	N.A.	HeLa cells and HeLa tumor bearing nude mice	149
BPQDs; PEGylated BPQDs	808 nm laser, 1 W cm^−2	PTT	PCE of 28.4%	C6 cells and MCF7 cells	152
Poly(lactic-co-glycolic acid) (PLGA) nanospheres loaded with BPQDs	808 nm laser, 1 W cm^−2	PTT	N.A.	MCF7 cells, B16 cells, MCF7 tumor-bearing mice	153
PEGylated BPQDs; rhodamine-A/PEG-BPQDs	808 nm laser, 2 W cm^−2	Fluorescence imaging guided PDT/PTT	N.A.	HepG2 cells, 4T1 cells, 4T1 tumor-bearing mice	155
BPQDs; PEGylated BPQDs	670 nm light, 0.16 mW cm^−2	PDT	N.A.	HeLa cells, L02 cells, S180 tumor-bearing mice	156
BPQD-hybridized mesoporous silica framework (BMSF) with in situ synthesized Pt nanoparticles (PtNPs), and decorated with TLS11a aptamer/Mal-PEG-NHS	670 nm laser, 0.1 W cm^−2	Fluorescence imaging guided PDT	^1O2 QY of 0.142 for BPQD and 0.166 for BMSF	HepG2 cells and HepG2-tumor bearing mice	157
g-C3N4 QDs	Microwave (MW) light, 5 W	Microwave induced PDT (MIPDT)	N.A.	UMR-106 cells	158
g-C3N4 QDs: pristine QDs or modified with defects	800 nm laser, 1.0 W cm^−2	Two-photon imaging (TPI) and TPE guided PDT	N.A.	MCF7 cells	159
Antimonene quantum dots (AMQDs); PEGylated AM QDs	808 nm, 1 W cm^−2	PTT	PCE of 45.5%	MCF7 cells, HeLa cells, MCF-7 tumor-bearing mice	164
Titanium carbide MXene QDs	808 nm laser, 0.5 W cm^−2	PA imaging guided PTT	PCE of 52.2%	HeLa cells, MCF-7 cells, U251 cells, HEK 293 cells, HeLa tumor-bearing mice	167
MoO3−x QDs	880 nm laser, 2 W cm^−2	Photoacoustic (PA) imaging-guided PDT/PTT	PCE of 25.5%	HeLa cells, L02 cells, HeLa tumor-bearing mice	171

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2. Transition metal dichalcogenide quantum dot (TMD QD) based phototherapy

Two-dimensional transition metal dichalcogenides (TMDs), due to their comparable structure to graphene, have gained attention recently.^91–93 Their generalized formula and structure consist of monoatomic layer thick, stacked layers of repetitive covalently bonded chemical compounds X–M–X, in which M represents transition metals such as Mo, Ru, and W, while X represents chalcogen atoms including S, Se and Te.^89,94 To obtain TMD QDs with top-down approaches, the intra-planar X–M–X bonds need to be broken to form smaller dots with abundant edge atoms. Such top-down approaches are not limited to laser pulse ablation,⁹⁵ free radical etching,⁹⁶ hydrothermal/solvothermal reaction,⁹⁷ intercalation assisted exfoliation,⁹⁸ chemical vapor deposition (CVD) and mechanical exfoliation and milling.^99,100 Due to quantum confining effects,⁵⁵ TMD QDs are found to show a wider bandgap in comparison with their 2D forms.¹⁰¹ Additionally, high surface to volume ratios, small sizes, chemically reactive sites at the edges and direct band gaps contribute to the extensive interest in these uniquely placed TMD QDs for applications in various fields, such as in energy and catalysis.⁵⁹ In recent years, a few TMD QDs including MoS₂ QDs and WS₂ QDs are emerging as PTT and PDT agents.

Owing to their near infrared (NIR) absorbance, some TMD QDs have been developed as PPT nanoagents to treat cancer. For example, bio-clearable and ultra-small MoS₂ nanodots modified by glutathione (GSH) were developed to be a theranostic agent.¹⁰² These MoS₂ nanodots not only could remarkably photothermally kill cancer cells, but also served as novel photoacoustic (PA) imaging agents for observing efficient tumor accumulation after intravenous (i.v.) injection. Because of their smaller sizes when compared to MoS₂ nanosheets, these MoS₂ nanodots showed more efficient clearance via urine. The photothermal treatment of tumors using MoS₂ nanodots achieved excellent therapeutic efficacy. Similarly, Wang et al. obtained MoSe₂ nanodots (NDs) with an ultrasmall size of 2–3 nm through ultrasonication-assisted liquid exfoliation from bulk MoSe₂.¹⁰³ These nanodots absorbed strongly at NIR wavelengths with a PCE of about 46.5% with efficient HeLa cell ablation under NIR laser (785 nm) irradiation and yet induced negligible cytotoxicity without irradiation.

Since MoS₂ QDs on their own have limited blood circulation time and are rapidly cleared from the body, Li et al. designed an amino-modified biodegradable agent composed of MoS₂ QD doped disulfide-based silica (SiO₂) nanoparticles (denoted as MoS₂@ssSiO₂).¹⁰⁴ This MoS₂@ssSiO₂ obtained by inserting the MoS₂ QDs into SiO₂ nanoparticles not only could be degraded and excreted through the redox reaction of glutathione (GSH), but also increased the blood circulation time, in turn inducing a high tumor uptake compared with separate MoS₂ QDs. Through adsorption of both chlorin e6 (Ce6) and hyaluronic acid (HA) on the outer shell, MoS₂@ssSiO₂ has a corresponding photodynamic and tumor-targeting effect, and is guided by fluorescence/CT/multispectral optoacoustic tomography (MSOT) combined PTT/PDT of the tumor. Besides, this group further integrated HA, polyaniline (PANI), Ce6, and tungsten sulfide (WS₂) nanodots into a single platform (HA-WS₂@PANI/Ce6) for fluorescence/PA/X-ray computed tomography (CT) imaging-guided combinational radiation therapy/PTT/PDT of tumors.¹⁰⁵ In another study, the same group fabricated versatile MoS₂ QDs@polyaniline (MoS₂@PANI) based inorganic−organic nanohybrids for PA/CT image guided combinational PTT/radiotherapy (RT) of tumors, achieving better anticancer efficiency.¹⁰⁶ Another similar dual-modal PA/CT imaging guided synergetic PTT/RT theranostic nanoagent, which was only composed of WS₂ QDs, was reported to achieve better therapeutic efficacy by Zhao and Gu's group.⁵⁰

Besides exerting the photothermal effect, some TMD QDs such as MoS₂ QDs were demonstrated to be better photosensitizers, which could realize the efficient PDT of tumors through producing ROS under light irradiation. Recently, Leong's group developed a general bottom-up synthesis reaction to synthesize TMD QDs with variable defect states (Ding–Leong reaction). They showed the versatility of this synthesis method by preparing a wider library of TMD QDs (Fig. 1a).³² The reactions were very fast (10–20 s) with very mild conditions such as room temperature, aqueous and atmospheric conditions. As the protocol was bottom-up, the reaction stoichiometric ratio of the precursors can be easily controlled to engineer defects at room temperature. With these defect-variable TMD QDs, it was shown experimentally that on increasing crystallinity defects there was a significant increase in ¹O₂ QY (Fig. 1b). The positive correlation between the defect degree and photodynamic properties was also verified at the cellular level (Fig. 1c). With these discoveries, MoS₂ QDs with more defects showed higher photodynamic killing in cancer cells and in 3D tumor spheroids (Fig. 1d and e). This research provides a simple synthetic strategy to expand the existing TMD QD library and a tool for researchers to investigate the defect effects on their properties for applications in many different fields.

Fig. 1 (a) Schematic illustration of the synthesis and mechanism of MoS₂ QDs with different defects, the inset showing the corresponding photographs and TEM images of different defective MoS₂ QDs. Scale bar: 50 nm. (b) Representative decomposition profiles of ABDA for different defect status MoS₂ QDs with light irradiation at different time points. (c) Fluorescence images of SW480 cells stained with intracellular ROS indicator H₂DCFH-DA. Scale bar: 50 μm. (d) In vitro cytotoxicity and photocytotoxicity of MoS₂ QDs with different defects. (e) The photographs of 3D tumor spheroids penetrated with different defective MoS₂ QDs.

Additionally, Dong and Zhang's group prepared small sized MoS₂ QDs of approximately 15 nm with a layered thickness of 2 nm, which presented remarkable down- and up-conversion photoluminescence behaviors. These MoS₂ QDs were prepared by ultrasonication of bulk MoS₂ powder in tetrabutylammonia through breaking of Mo–S bonds.⁴⁹ These optical properties make these quantum dots good candidates for imaging probes. Besides, MoS₂ QDs demonstrated superior ¹O₂ generation over protoporphyin (PpIX). In addition to cancer therapy, MoS₂ QDs may also have promising antimicrobial application under environmental conditions. Yin's group reported that MoS₂ QDs could produce multiple ROS species types under simulated solar light irradiation, leading to remarkably enhanced antibacterial activity. In vivo experiments showed that MoS₂ QDs significantly enhanced wound healing.¹⁰⁷

3. Graphene quantum dot (GQD) based phototherapy

Graphene quantum dots (GQDs) may consist of one or more graphene layers. Each single atomic thickness layer is made up of carbon atoms packed into a planar honeycomb crystal structure with excellent thermal and chemical stability. GQDs are found to have low cytotoxicity,¹⁰⁸ good biocompatibility,¹⁰⁹ and the ability to generate reactive oxygen species (ROS) upon photoexcitation and can be used for PDT against bacteria or cancer. Also, GQDs can transfer electrons to conjugated drugs or photothermal agents which can increase anticancer activity.¹¹⁰

The outstanding properties of GQDs have inspired surging interest in some fields for example in electronics,^111,112 optics,^113,114 sensors,^115,116 drug delivery,¹¹⁷ bioimaging,¹¹⁸ and photothermal^119,120 and photodynamic therapy.^121–126 Even though cadmium based semiconductor quantum dots have exploitable optical properties for bioimaging applications, they still suffers from low biocompatibility and high intrinsic toxicity.^127,128 The GQDs might be a viable alternative to cadmium based semiconductor quantum dots with their excellent biocompatibility, chemical inertness, wavelength dependent luminescence and easy scalability traits.¹²⁹

The clinical use of photosensitizer porphyrin derivatives such as Ce6 and verteporfin is hampered by their hydrophobic nature.¹³⁰ To overcome these solubility issues, GQDs hidden within redox-triggered cleavable PEG shells have been used as a conjugated platform to anchor down the photosensitizer molecules, without affecting their photodynamic efficiency whilst improving their hydrophilicity and therefore avoiding rapid clearance from the system. The planar π conjugated structure of GQDs quenches photoactive Ce6's fluorescence and ¹O₂ generation in a non-tumor environment. However, when exposed to tumor relevant GSH, the PEG shell undergoes reductive cleavage for a responsive burst release of Ce6. This system showed excellent in vivo/ex vivo imaging coupled with high PDT efficacy and superior biocompatibility.¹³¹ Besides this combination, another GQD-based multifunctional two-photon nanoprobe composed of GQD and MnO₂ nanosheets was designed for intracellular tumor-related GSH detection (triggered release) and amplified PDT in cancer cells.¹³² A porphyrin derivative (P) was conjugated with GQDs coated with polyethylene glycol (PEG) to form GQDs-PEG-P which showed good stability, low cytotoxicity and excellent biocompatibility when tested on A549 and MCF-7 cancer cells. Importantly, the nanomaterial displayed a PCE of 28.58% and high QY of ¹O₂ generation.¹¹⁰

Another nanoassembly of polydopamine stabilized GQDs-Ce6 was developed which effectively induced tumor cell ablation through enhancing photodynamic effects by delivering the nanoassembly to the targeted Toll-like receptor 9 on the cell surface, continuously stimulating to enhance T lymphocyte infiltration.¹³³

Ge et al.⁵¹ reported a GQD based PDT nanoagent which can generate ¹O₂ through a multistate sensitization process with a high ¹O₂ QY of ∼1.3, highest among the PDT agents. A new ¹O₂-generating mechanism increases the QY of GQDs through multistage sensitization. Such a phenomenon is not observed in conventional photosensitizers such as PpIX or phthalocyanines (Fig. 2a). The ¹O₂ generated by GQDs in the presence of 2,2,6,6-tetramethylpiperidine (TEMP) and 5-tert-butoxycarbonyl 5-methyl-1-pyrroline N-oxide (BMPO) under 532 nm laser irradiation is shown by the Electron Spin Resonance (ESR) spectrum (Fig. 2b). Also, the ability of GQDs to generate ¹O₂ has been verified through a chemical trapping method using Rose Bengal (RB) as a photosensitizer and disodium 9,10-anthracendipropionic acid (Na₂-ADPA) as a trapping agent. This comparison showed that the degradation of Na₂-ADPA was larger than that of RB resulting from GQDs under light irradiation (Fig. 2c). The results in HeLa cells showed that the GQDs have low cytotoxicity and biocompatibility in the dark even at 1.8 μM (Fig. 2d). The in vivo experiments in mouse models showed the fluorescence imaging capability of GQDs (Fig. 2e). The mouse group treated with GQDs under light irradiation destroyed tumors and no tumor was observed to regrow after 17 days in the group with GQDs under light irradiation (Fig. 2e).

Fig. 2 GQDs with high ¹O₂ generation with high QY. (a) The high QY of GQDs stems from a new ¹O₂ generating mechanism termed multistate sensitization (MSS). (b) ESR spectrum showing the generation of ¹O₂ under irradiation. (c) The ability of GQDs to generate ¹O₂ compared with RB. (d) Cytotoxicity of GQDs is almost zero up to 1.8 μM. (e) GQD based PDT in vivo on a mouse model destroyed tumor without regrowth.

Thakur et al.¹²⁰ prepared GQDs from eco-friendly withered leaves of fig trees. The GQDs were tested for in situ labelling probes on cancer cells. When GQDs were taken up by cancer cells and irradiated with an IR laser (808 nm), concentration dependent ROS was generated. These GQDs maintained high photoluminescence stability despite continuous irradiation up to 30 minutes. Passivating nanomaterials with PEG improved their circulation time in vivo and reduced the interaction with macrophages and monocytes in vivo.¹³⁴

Through PEGylation, a new form of Ag-GQD was prepared and loaded with a chemotherapeutic drug doxorubicin (DOX).¹³⁵ This nanomaterial system was tested in vitro on HeLa and DU145 cancer cells. When combining the photodynamic effect through the addition of QDs, the combined drug–photosensitizer treatment synergistically increased cell death when irradiated with a 425 nm radiation source. Doping of GQDs could tune their PDT capability. Kuo et al.⁵² reported amino group functionalized GQDs doped with nitrogen (amino-N-GQDs) with an absorption wavelength of ∼800 nm which had a quantum yield of 33% with strong photoluminescence. The nitrogen doping improved ROS generation and eliminated methicillin-resistant bacteria, Staphylococcus aureus. Their studies revealed that nitrogen doped GQDs exhibited stronger PDT compared with undoped GQDs, which is similar to the photodynamically anti-microbial properties of other GQDs that had been successfully used to kill bacteria.^136,137

In another study, it has been reported that increasing nitrogen doping further to 5.1% from 2.9% could increase ROS generation considerably when photo-excited with 670 nm light. This trend can be seen in the quantum yield decreases of N-GQD (5.1% N), N-GQD (2.9% N) and GQD with decreasing defects (0.259, 0.165, and 0.137 respectively).¹³⁸ Additionally, an efficiency controllable PDT was designed through varying the doping amount of nitrogen atoms.¹³⁹ Furthermore, dual chemo-photodynamic therapy was achieved by loading a nucleus-targeting drug. Sun et al.¹⁴⁰ prepared nitrogen doped GQDs coupled with photosensitizers RB for two photon induced PDT. The material had good photo-stability and biocompatibility. The N-GQDS-RB exhibited high cytotoxicity through irradiation with a one- or two-photon laser. Up-conversion nanoparticles (UCNP) have also been reported to combine with GQDs to enhance the highly efficacious PDT through emitting UV-vis light under NIR excitation to active GQDs for producing ¹O₂ efficiently.^141,142

GQDs have an interesting ability to convert NIR light waves strongly into heat which can kill cancer cells.¹⁴³ GQDs doped with N increased the PCE to 62.53%.¹⁴⁴ GQD capped magnetic mesoporous silica nanoparticles (MMSN) generated heat under a magnetic field or NIR irradiation and concurrently released doxorubicin.¹⁴⁵ A multimodal therapeutic system of magneto-mechanical, photothermal, photodynamic and chemo therapies (DOX) was designed for cancer therapy through integrating GQDs into silica coated hollow magnetic nanospheres; similarly DOX loaded mesoporous silica nanoparticle (MSN) capped GQDs (GQDs-MSNs) exhibited pH and temperature responsive drug release behavior, and when irradiated with near-infrared light, the heat generated killed cancer cells.^146,147 A multifunctional zeolite imidazolate framework-8 (ZIF-8) was used as a drug carrier with embedded GQDs as photothermal seeds, and the DOX was released under acidic conditions.¹⁴³

The nature of the photodynamic effect is that it is non-specific and cells within the immediate vicinity at the point of excitement are subjected to the same oxidative damage regardless of whether the cells are the targeted cells or merely spectators. Therefore, targeting becomes an important consideration especially when developing a highly potent photodynamic agent. Wang et al.¹⁴⁸ developed active targeting theranostic GQDs based on aptamer AS1411. This specific aptamer acts as a bio-targeting moiety against tumor cells with high specificity and induces cell death even at low dosage. The small size, biocompatibility, stable fluorescence, and NIR responsiveness of GQDs complement the targeting aptamer. Similarly, HA-modified and GQD-integrated hollow mesoporous carbon nanoparticles (HMCN) were used to encapsulate drugs for targeting of CD44 cell surface receptors, overexpressed on cancer cells.¹⁴⁹

4. Atomically thin black phosphorus quantum dot (BPQD) based phototherapy

An emerging 2D material, black phosphorus (BP), has notable potential prominence in electronics due to its structural properties.¹⁵⁰ BP possesses a layered structure and a layer-dependent bandgap that increases from 0.3 eV for the bulk material to 2.0 eV for the monolayer form.¹⁵¹ Ultrasmall derivatives of BP nanosheets, known as BP quantum dots (BPQDs), possess notably useful properties too. These BPQDs have been reported to be ∼2.6 nm in size and show promising NIR photothermal performance, displaying a large extinction coefficient at 808 nm and a high PCE of 28.4%.¹⁵²

Yu's group further examined the potential of BPQDs as photothermal agents through the synthesis of biodegradable nanospheres from poly(lactic-co-glycolic acid) (PLGA) loaded with black BPQDs for PTT applications.¹⁵³ The nanospheres (NS), which were ∼100 nm in size, were rationally designed to allow for high PTT efficiency and more precise control of the biodegradation rate (Fig. 3a). Under physiological conditions, the external PLGA shell of the BPQDs/PLGA NS would gradually degrade through hydrolysis into lower molecular weight fragments without (Fig. 3b) or with light excitation (Fig. 3c). The in vivo photothermal killing effect with the NS was studied with MCF7 and B16 cells, where a steady decline in cell viability was dose-dependent on BPQD loading (Fig. 3d). The in vivo biodistribution of the NS was studied through Cyanine 5.5 (Cy5.5) fluorescence imaging of tumors in mice, with observations that the fluorescence intensity increased up to the 24 h timepoint, revealing continuous accumulation of the NS within tumors. The intensity could also be maintained till 48 h (Fig. 3e). Quantitative biodistribution in mice revealed a high concentration of BPQDs/PLGA NS in the tumor, in addition to the liver, spleen and kidneys (Fig. 3f). In vivo photothermal cancer therapy was conducted in mice injected with different treatment agents and their tumor volumes were tracked across time. Mice with the BPQD/PLGA NS treatment revealed gradual shrinking of the tumors, which were eliminated after ∼16 days (Fig. 3g).

Fig. 3 Biodegradable nanospheres (NSs) prepared from BPQDs and PLGA used in PTT application. (a) Schematic illustration of BPQDs/PLGA NSs degrading under the physiological environment. (b) Absorbance spectra of the BPQDs/PLGA NSs after dispersal in PBS, with their corresponding photographs depicted in the inset. The concentration of BPQDs within NSs was 10 ppm. (c) Photothermal heating curves of BPQDs/PLGA NSs after dispersal in PBS, followed by irradiation with an 808 nm laser (1 W cm⁻²) for 10 min. (d) Relative viability of MCF7 and B16 cancer cells after 4 h incubation with BPQDs/PLGA NSs, followed by irradiation with the 808 nm laser (1 W cm⁻²) for 10 min. (e) Cy5.5-labelled BPQDs/PLGA NSs were intravenously injected into Balb/c nude mice bearing MCF7 breast tumors and visualized in vivo with fluorescence at different time points post-injection. (f) The biodistribution of the Cy5.5-labeled NSs in tumors and major organs was analyzed through the fluorescence intensity at different time points post-injection. (g) Growth curves of MCF7 tumors across different groups of nude mice treated with PBS, PLGA NSs, BPQDs (1 mg mL⁻¹) and BPQDs/PLGA NSs (1 mg mL⁻¹), respectively, after NIR laser irradiation.

In addition to PTT applications, BPQDs are also gaining prominence for their potential role in PDT. BP nanosheets have been reported to allow for efficient generation of ¹O₂.¹⁵⁴ For instance, Liu and colleagues designed a multifunctional BPQD-based system for both bioimaging and combinatory PTT/PDT application.¹⁵⁵ The PEGylated BPQDs exhibited strong NIR photothermal performance and yielded cytotoxic ¹O₂ for PDT. In vitro and in vivo investigations revealed that the combined phototherapy was more effective for cancer cell ablation than either therapy employed on their own. BPQDs also demonstrated high loading of organic fluorescent dyes for tumor imaging purposes. Additionally, Huang's group synthesized BPQDs with a hydrodynamic diameter of 5.4 nm that could be renally cleared as intact particles.¹⁵⁶ Recently, Liu's group designed a hepatocellular carcinoma (HCC)-specific targeting aptamer “TLS11a”-modified BPQD-hybridized nanocatalyst to enhance its PDT performance.¹⁵⁷ The nanocatalyst was constructed with a BPQD-hybridized mesoporous silica framework (BMSF) with in situ synthesized Pt nanoparticles (Pt NPs), which respectively acted as a photosensitizer to produce ROS and hence served as a catalyst to react with H₂O₂ to produce O₂ that could amplify the PDT effect through positive feedback mechanisms in the hypoxic tumor microenvironment (TME). Thereafter, modification by TLS11a aptamer/Mal-PEG-NHS targets HCC cells. In vivo and in vitro experiments further demonstrated the nanoagent's active targeting property and excellent photodynamic effects in hypoxic TME with minimal side effects.

In general, BP nanosheet- and BPQD-based phototherapy platforms and systems are attractive as phosphorus is a common element within the human body, essential to life at the cellular level¹⁵⁸ and hence regarded as likely benign at worst.¹⁵³ Moreover, ultrasmall BP is expected to yield nontoxic degradation products that exist in the body.¹⁵⁸ Like most nanomaterials in consideration for phototherapy, real clinical applications would depend on successful optimization of biocompatibility, bodily clearance and other necessary safety requirements.

5. Graphitic carbon nitride (g-C₃N₄) antimonene, transition metal oxide (TMO), and MXene quantum dot (QD) based phototherapy

Graphitic carbon nitride (g-C₃N₄), a metal-free conjugated polymer with semiconductor properties has been well known as a photocatalyst due to its ability to catalyze redox reactions under light irradiation. Additional advantages such as biocompatibility, adjustable band gap and position, and low expected production cost further boost g-C₃N₄ as an interesting phototherapy materials candidate.¹⁵⁹ Recently, g-C₃N₄ has also been examined as a photosensitizer for PDT applications, where its water-splitting activity was explored as a novel strategy to counter hypoxic tumor microenvironments that resist PDT.¹⁶⁰

In 2017, Chu et al. used 5 nm g-C₃N₄ for microwave induced PDT.¹⁶¹ Nanomaterial mediated microwave-induced PDT (MIPDT) was previously developed by the research group as a potential method of addressing deep-seated cancers.¹⁶² In the paper by Chu et al., in vitro studies showed the entry of g-C₃N₄ into UMR-106 osteosarcoma cells with an increase in singlet oxygen generation under microwave induction. Analysis of cell viability revealed the performance of g-C₃N₄ as a potential agent for MIPDT. In another example, Wu et al. used g-C₃N₄ QDs with defects as a dual-functional platform that could perform two-photon excited photodynamic therapy (TPE-PDT) and two-photon imaging (TPI).¹⁶³ Three forms of g-C₃N₄ QDs were designed. The CN-DPT QDs, synthesized by copolymerizing melamine with a phenyl monomer, showed high performing TPI coupled with efficient generation of ROS for TPE-PDT. Overall, the work demonstrated the emerging potential of g-C₃N₄ as part of a dual-functional TPI and TPE-PDT therapeutic system.

Antimonene (AM) is an emerging 2D material derived through exfoliating bulk antimony, with certain advantageous physical properties over other notable 2D materials, such as BP and graphene.¹⁶⁴ Although AM is yet to be explored in detail for therapeutic applications, its similarity to other 2D materials made exploring its potential use in phototherapy a possibility to examine. Recently, Tao et al. synthesized ultrasmall AM quantum dots (AMQDs) and examined their potential as a photothermal agent, obtaining a PCE of 45.5% for the PEG-coated AMQDs, which was higher than that of BP.¹⁶⁵ AMQDs were synthesized through liquid exfoliation with a combined sonication method involving an ultrasound probe in an ice-bath, followed by coating with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly ethylene glycol)] (DSPE-PEG) to yield PEG-coated AMQDs that were stable in aqueous medium without aggregation (Fig. 4a). After 808 nm laser irradiation, PEG-coated AMQDs generated photothermal heating curves that are concentration-dependent (Fig. 4b). NIR irradiation was further used to investigate the killing effect on MCF7 cancer cells, where the decline in cell viability was also concentration-dependent on PEG-coated AMQDs (Fig. 4c). MCF7 tumor-bearing mice were treated and temperature changes were monitored using IR thermal imaging (Fig. 4d). Growth curves of tumors revealed that only when PEG-coated AMQDs were irradiated with an NIR laser could there be an observable decline in tumors (Fig. 4e). Overall, AM remains a very recent material to be applied in phototherapy and clinical applications will depend on further in vivo characterization. However, the outstanding photothermal conversion efficiency will make AM an important material to consider for phototherapeutics.

Fig. 4 Antimonene QDs (AMQDs) employed in PTT applications. (a) Schematic illustration of the synthesis of PEG-coated AMQDs. (b) Temperature change in aqueous PEG-coated AMQD solutions of different concentrations when irradiated with the 808 nm NIR laser (2 W cm⁻²). (c) Cell viability of MCF7 human breast cancer cells treated with PEG-coated AMQDs of various concentrations and subjected to 5 min irradiation with the 808 nm NIR laser (2 W cm⁻²). (d) IR thermal images of MCF7 tumor-bearing nude mice with different treatments (G1: saline; G2: only NIR; G3: only PEG-coated AMQDs; and G4: PEG-coated AMQDs + NIR (808 nm, 1 W cm⁻²)). (e) Growth curves of MCF tumors across different groups of mice after treatments G1 : G4.

Transition metal oxide (TMO) nanomaterials refer to the group of inorganic particles that commonly include iron oxides and molybdenum oxides. The suboxide (oxygen deficient) phase of molybdenum oxide (MoO_3−x) is one example of such materials with growing research into their phototherapy applications. MoO_3−x QDs were discovered to display high optical absorbance in the NIR region due to a strong localized surface plasmon resonance (LSPR) effect.¹⁶⁶ For instance, Ding et al. developed MoO_3−x QDs with good bioimaging and combined PDT-PTT capabilities.¹⁶⁷ These QDs exhibited a PCE of 25.5% and could simultaneously generate ROS, suggesting their potential as an agent for combined PDT-PTT. The QDs demonstrated killing of cancer cells both in vitro and in vivo, without localized irradiation with an 808 nm laser, and there is no apparent damage to major organs. Liu and Hu's groups synthesized MoO_3−x QDs at room temperature under ultraviolet irradiation, deriving QDs with a PCE as high as 40.01%.¹⁶⁸ The cytotoxicity and photothermal performance of the QDs were tested in vitro with encouraging results but have yet to progress to in vivo testing.

MXenes are a class of 2D transition metal materials consisting of their carbides, carbonitrides and nitrides, with a hydrophilic nature and high volumetric capacitance that can exceed those of carbon electrodes, resulting in notable interest in their energy storage device applications.¹⁶⁹ However, in 2017, MXenes were first reported for their potential in the PTT technology space, where Ti₃C₂ nanosheets possessed a PCE of 30.3% with ablation of tumors in in vivo studies.¹⁷⁰ However, like within the former paper, hydrofluoric acid (HF) was almost always used as the etching agent to yield MXenes from the bulk phase. In an effort to avoid using the strongly corrosive and potentially difficult to fully remove HF, Liu and Yu's group designed a HF-free synthesis method, yielding MXene QDs with aluminum oxoanions on the surface, which possessed a large extinction coefficient of 52.8 L g⁻¹ cm⁻¹ at 808 nm and a high PCE of up to 52.2%.¹⁷¹ The MXene QDs were capable of tumor ablation under irradiation and had no observable toxicities when examined both in vitro and in vivo.

6. Limitations and challenges

In recent years, some exciting achievements on QDs have emerged tending more to the application end of the scientific pipeline. However, the much fundamental research is still in the early stage and some challenges still exist, which are waiting to be tackled for future live translation. Firstly, considering the structure of QDs being dependent on the synthesis strategy it is also important to explore their properties and applications. Thus, the development of synthetic methods to more precisely control the TMD QDs such as their sizes, thicknesses, defect degrees, edge configurations and chemical modifications should be given more attention in the future. For example, due to the relative chemical inertness or fewer physical interaction sites on the surface of QDs, strategies on surface modification are lacking, leading to challenges in their bioapplications. However, this point is limited by some shortcomings in the synthesis of QDs, including the complex procedure, low yield, time-consuming process, and low-scale and high-cost production, in most cases. Therefore, finding ways to optimize the synthetic method of QDs is still a burning problem. In addition, as for the properties of QDs, more relevant studies centered on the electrochemical, catalytic, optical and electrical properties of some QDs, such as TMD QDs, h-BN QDs, phosphorene, MXenes, germanene and silicone, can provide even more clarity on linking their physicochemical makeup to their properties. Until now, the mechanism of photoluminescence (PL) has been incompletely understood. When referring to the PL behaviors of QDs, their relatively low quantum yield and wide emission spectra remain to be a question, limiting their extensive applications in biosensing, bioimaging and nanomedicine. In addition, the in-depth exploration of QDs with NIR fluorescence, which is beneficial for deep-tissue applications, is still lacking in studies. Lastly, QD based PTT/PDT theranostics is still unfortunately constrained by the inherent tissue penetration depth of visible or NIR light.

7. Summary and perspectives

As an advanced category of quantum dots which are emerging zero-dimensional materials, QDs are gaining increasing attention because of their outstanding physicochemical properties, such as optical, catalytic, chemical, electrochemical, and electronic characteristics.^46,59 The new types of QDs are extended to GQDs, TMD QDs, g-C₃N₄ QDs, h-BN, phosphorene, MXenes, germanene and silicone, which show their booming applications in a diverse range of fields. These QDs inherited some unique characteristics from their 2D counterparts on catalysis and energy applications. In particular, with the help of additional advantages based on their lower dimensionality, such as highly tunable PL properties, low toxicity, good biocompatibility and molecular size, the QDs have demonstrated their potential capability for biosensors, antibacterial materials, bioimaging probes, and especially PDT/PTT of deep tumors.

Despite this excellent characterization, QDs also have some limitations and challenges that we have reported in this review. To address these issues, novel synthetic methods for QDs should be developed: (I) with an easy procedure, high production yield, and large-scale and low-cost production and (II) to find a way to control the sizes, thicknesses, defects and edges, in turn regulating the optical and chemicophysical features. For example, surface modifications on the QDs could be applied to adjust the PL properties, such as enhancing the quantum yield and forming green, even red fluorescent TMD QDs, h-BN, phosphorene, MXenes, germanene and silicone. Additionally, a better understanding of the mechanism of PL from QDs is one main goal to be pursued in the future, which is beneficial for deepening application potential. In particular, novel QDs with strong absorbance in the second NIR region (>950 nm) or high photoluminescence in the NIR region (>700 nm) and high photostability and biocompatibility should be synthesized and developed into QD based nanotheranostics (PDT/PTT based theranostics) to achieve enhanced tissue penetration. To enhance their deep tumor penetrance, total reliance on the EPR may not be wise as the EPR effect is determined by the tumor.^172–174 Instead, inducing endothelial leakiness with nanomaterials (NanoEL) at the tumor vasculature could be a more controllable strategy to increase access to the interior of the tumor.¹⁷² The various QDs reviewed here are highly suited for inducing Type II (indirect) NanoEL through photoactivatable oxidative stress at the tumor vasculature.¹⁷² Moreover with greater control of basic nanomaterials physicochemical parameters such as size, surface charge and density, further fine tuning of both Type I (direct) and Type II (indirect) NanoEL effects can bring about tunability of the degree of accessibility for both nanomedicine and conventional drugs or quick restoration of the endothelial barrier.^175–178

Although the development of QDs is essential and still in the early stage, they have proven to be promising for understanding fundamental biology, early diagnosis and theranostics. As the field of 2D QDs expands, more efforts are expected to be dedicated to the design and development of new QDs for future biomedical applications beyond photodynamic and photothermal agents. Successful development for further biological applications can be aided by a better understanding and mitigation of potential toxic effects that could occur.¹⁷⁹

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge the funding provided by the National Research Foundation, Prime Minister's Office, Singapore, under the Competitive Research Program (Award No. NRFCRP13-2014-03).

Notes and references

1. Y. Liu, X. Dong and P. Chen, Chem. Soc. Rev., 2012, 41, 2283–2307.
2. X. Wang, G. Sun, P. Routh, D. H. Kim, W. Huang and P. Chen, Chem. Soc. Rev., 2014, 43, 7067–7098.
3. F. Bonaccorso, L. Colombo, G. Yu, M. Stoller, V. Tozzini, A. C. Ferrari, R. S. Ruoff and V. Pellegrini, Science, 2015, 347, 1246501.
4. H. J. Zhu, Y. J. Zhang, L. L. Zhang, T. Yu, K. Zhang, H. Jiang, L. J. Wu and S. H. Wang, J. Mater. Chem. C, 2014, 2, 7126–7132.
5. H. J. Zhu, H. D. Xu, Y. H. Yan, K. Zhang, T. Yu, H. Jiang and S. H. Wang, Sens. Actuators, B, 2014, 202, 667–673.
6. H. Li, R. Y. Tay, S. H. Tsang, X. Zhen and E. H. Teo, Small, 2015, 11, 6491–6499.
7. Z. Lei, S. Xu, J. Wan and P. Wu, Nanoscale, 2015, 7, 18902–18907.
8. Y. Noda, C. Merschjann, J. Tarabek, P. Amsalem, N. Koch and M. J. Bojdys, Angew. Chem., Int. Ed., 2019, 58, 9394–9398.
9. J. Liu, Y. Zhang, L. Zhang, F. Xie, A. Vasileff and S. Z. Qiao, Adv. Mater., 2019, 31, e1901261.
10. B. L. Li, H. L. Zou, J. K. Tian, G. Chen, X. H. Wang, H. Duan, X. L. Li, Y. Shi, J. R. Chen, L. J. Li, J. L. Lei, H. Q. Luo and N. B. Li, Nano Energy, 2019, 60, 689–700.
11. B. L. Li, L. Y. Peng, H. L. Zou, L. J. Li, H. Q. Luo and N. B. Li, Small, 2018, 14, 1703560.
12. B. L. Li, H. L. Zou, L. Lu, Y. Yang, J. L. Lei, H. Q. Luo and N. B. Li, Adv. Funct. Mater., 2015, 25, 3541–3550.
13. H. Zhang, H. He, X. Jiang, Z. Xia and W. Wei, ACS Appl. Mater. Interfaces, 2018, 10, 30680–30688.
14. X. Zhang, Z. Lai, Q. Ma and H. Zhang, Chem. Soc. Rev., 2018, 47, 3301–3338.
15. M. Chhowalla, H. S. Shin, G. Eda, L. J. Li, K. P. Loh and H. Zhang, Nat. Chem., 2013, 5, 263–275.
16. H. Zhu, Z. Lai, Y. Fang, X. Zhen, C. Tan, X. Qi, D. Ding, P. Chen, H. Zhang and K. Pu, Small, 2017, 13, 1604139.
17. T. Hartman and Z. Sofer, ACS Nano, 2019, 13, 8566–8576.
18. N. Liu, G. Bo, Y. Liu, X. Xu, Y. Du and S. X. Dou, Small, 2019, 15, e1805147.
19. H. Lin, W. Qiu, J. Liu, L. Yu, S. Gao, H. Yao, Y. Chen and J. Shi, Adv. Mater., 2019, e1903013.
20. A. M. Tokmachev, D. V. Averyanov, O. E. Parfenov, A. N. Taldenkov, I. A. Karateev, I. S. Sokolov, O. A. Kondratev and V. G. Storchak, Nat. Commun., 2018, 9, 1672.
21. W. Zhang, L. Sun, J. M. V. Nsanzimana and X. Wang, Adv. Mater., 2018, 30, e1705523.
22. C. N. Rao, H. S. Matte and U. Maitra, Angew. Chem., Int. Ed., 2013, 52, 13162–13185.
23. X. Huang, C. Tan, Z. Yin and H. Zhang, Adv. Mater., 2014, 26, 2185–2204.
24. P. Miro, M. Audiffred and T. Heine, Chem. Soc. Rev., 2014, 43, 6537–6554.
25. Y. S. Rim, S. H. Bae, H. Chen, N. De Marco and Y. Yang, Adv. Mater., 2016, 28, 4415–4440.
26. D. Deng, K. S. Novoselov, Q. Fu, N. Zheng, Z. Tian and X. Bao, Nat. Nanotechnol., 2016, 11, 218–230.
27. S. H. Lee, D. Y. Kim, J. Lee, S. B. Lee, H. Han, Y. Y. Kim, S. C. Mun, S. H. Im, T. H. Kim and O. O. Park, Nano Lett., 2019, 19, 5437–5442.
28. Y. Yan, J. Gong, J. Chen, Z. Zeng, W. Huang, K. Pu, J. Liu and P. Chen, Adv. Mater., 2019, 31, e1808283.
29. A. L. Exarhos, D. A. Hopper, R. N. Patel, M. W. Doherty and L. C. Bassett, Nat. Commun., 2019, 10, 222.
30. Q. Wang, Q. Zhang, X. Zhao, X. Luo, C. P. Y. Wong, J. Wang, D. Wan, T. Venkatesan, S. J. Pennycook, K. P. Loh, G. Eda and A. T. S. Wee, Nano Lett., 2018, 18, 6898–6905.
31. B. L. Li, L. X. Chen, H. L. Zou, J. L. Lei, H. Q. Luo and N. B. Li, Nanoscale, 2014, 6, 9831–9838.
32. X. Ding, F. Peng, J. Zhou, W. Gong, G. Slaven, K. P. Loh, C. T. Lim and D. T. Leong, Nat. Commun., 2019, 10, 41.
33. C. C. Price, N. C. Frey, D. Jariwala and V. B. Shenoy, ACS Nano, 2019, 13, 8303–8311.
34. X. Lu, X. Chen, S. Dubey, Q. Yao, W. Li, X. Wang, Q. Xiong and A. Srivastava, Nat. Nanotechnol., 2019, 14, 426–431.
35. W. Chen, J. Gu, Q. Liu, R. Luo, L. Yao, B. Sun, W. Zhang, H. Su, B. Chen, P. Liu and D. Zhang, ACS Nano, 2018, 12, 308–316.
36. X. Zhang, Z. Lai, Z. Liu, C. Tan, Y. Huang, B. Li, M. Zhao, L. Xie, W. Huang and H. Zhang, Angew. Chem., Int. Ed., 2015, 54, 5425–5428.
37. B. L. Li, J. P. Wang, Z. F. Gao, H. Shi, H. L. Zou, K. Arigaef and D. T. Leong, Mater. Horiz., 2014, 2019, 563–570.
38. Y. Yu, Y. Yang, J. Ding, S. Meng, C. Li and X. Yin, Anal. Chem., 2018, 90, 13290–13298.
39. Q. Cui, J. Xu, X. Wang, L. Li, M. Antonietti and M. Shalom, Angew. Chem., Int. Ed., 2016, 55, 3672–3676.
40. Z. Song, T. Lin, L. Lin, S. Lin, F. Fu, X. Wang and L. Guo, Angew. Chem., Int. Ed., 2016, 55, 2773–2777.
41. F. Liu, M. H. Jang, H. D. Ha, J. H. Kim, Y. H. Cho and T. S. Seo, Adv. Mater., 2013, 25, 3657–3662.
42. J. M. Yoo, J. H. Kang and B. H. Hong, Chem. Soc. Rev., 2015, 44, 4835–4852.
43. B. L. Li, M. I. Setyawati, L. Chen, J. Xie, K. Ariga, C. T. Lim, S. Garaj and D. T. Leong, ACS Appl. Mater. Interfaces, 2017, 9, 15286–15296.
44. Q. Guan, J. Ma, W. Yang, R. Zhang, X. Zhang, X. Dong, Y. Fan, L. Cai, Y. Cao, Y. Zhang, N. Li and Q. Xu, Nanoscale, 2019, 11, 14123–14133.
45. L. Long, X. Niu, K. Yan, G. Zhou, J. Wang, X. Wu and P. K. Chu, Small, 2018, 14, e1803132.
46. Y. Xu, X. Wang, W. L. Zhang, F. Lv and S. Guo, Chem. Soc. Rev., 2018, 47, 586–625.
47. S. Angizi, A. Hatamie, H. Ghanbari and A. Simchi, ACS Appl. Mater. Interfaces, 2018, 10, 28819–28827.
48. H. Zhu, W. Zhang, K. Zhang and S. Wang, Nanotechnology, 2012, 23, 315502.
49. H. Dong, S. Tang, Y. Hao, H. Yu, W. Dai, G. Zhao, Y. Cao, H. Lu, X. Zhang and H. Ju, ACS Appl. Mater. Interfaces, 2016, 8, 3107–3114.
50. Y. Yong, X. Cheng, T. Bao, M. Zu, L. Yan, W. Yin, C. Ge, D. Wang, Z. Gu and Y. Zhao, ACS Nano, 2015, 9, 12451–12463.
51. J. Ge, M. Lan, B. Zhou, W. Liu, L. Guo, H. Wang, Q. Jia, G. Niu, X. Huang, H. Zhou, X. Meng, P. Wang, C. S. Lee, W. Zhang and X. Han, Nat. Commun., 2014, 5, 4596.
52. W. S. Kuo, Y. T. Shao, K. S. Huang, T. M. Chou and C. H. Yang, ACS Appl. Mater. Interfaces, 2018, 10, 14438–14446.
53. R. Gui, H. Jin, Z. Wang and J. Li, Chem. Soc. Rev., 2018, 47, 6795–6823.
54. P. Zhang, Y. Zhuo, Y. Chang, R. Yuan and Y. Chai, Anal. Chem., 2015, 87, 10385–10391.
55. B. L. Li, M. I. Setyawati, H. L. Zou, J. X. Dong, H. Q. Luo, N. B. Li and D. T. Leong, Small, 2017, 13, 1700527.
56. B. L. Li, J. P. Wang, H. L. Zou, S. Garaj, C. H. Lim, J. P. Xie, N. B. Li and D. T. Leong, Adv. Funct. Mater., 2016, 18, 7034–7056.
57. K. Wang, Y. Chen, J. Zheng, Y. Ge, J. Ji, Y. Song and H. Zhang, Nanotechnology, 2019, 30, 415202.
58. S. Han, X. Yang, Y. Zhu, C. Tan, X. Zhang, J. Chen, Y. Huang, B. Chen, Z. Luo, Q. Ma, M. Sindoro, H. Zhang, X. Qi, H. Li, X. Huang, W. Huang, X. W. Sun and Y. Han, Angew. Chem., Int. Ed., 2017, 56, 10486–10490.
59. X. Wang, G. Sun, N. Li and P. Chen, Chem. Soc. Rev., 2016, 45, 2239–2262.
60. T. F. Jaramillo, K. P. Jorgensen, J. Bonde, J. H. Nielsen, S. Horch and I. Chorkendorff, Science, 2007, 317, 100–102.
61. A. Moshaverinia, C. Chen, X. Xu, S. Ansari, H. H. Zadeh, S. R. Schricker, M. L. Paine, J. Moradian-Oldak, A. Khademhosseini, M. L. Snead and S. Shi, Adv. Funct. Mater., 2015, 25, 2296–2307.
62. J. P. Celli, B. Q. Spring, I. Rizvi, C. L. Evans, K. S. Samkoe, S. Verma, B. W. Pogue and T. Hasan, Chem. Rev., 2010, 110, 2795–2838.
63. L. Cheng, C. Wang, L. Feng, K. Yang and Z. Liu, Chem. Rev., 2014, 114, 10869–10939.
64. K. Liu, X. Liu, Q. Zeng, Y. Zhang, L. Tu, T. Liu, X. Kong, Y. Wang, F. Cao, S. A. Lambrechts, M. C. Aalders and H. Zhang, ACS Nano, 2012, 6, 4054–4062.
65. D. E. J. G. J. Dolmans, D. Fukumura and R. K. Jain, Nat. Rev. Cancer, 2003, 3, 380–387.
66. S. B. Brown, E. A. Brown and I. Walker, Lancet Oncol., 2004, 5, 497–508.
67. D. K. Chatterjee, L. S. Fong and Y. Zhang, Adv. Drug Delivery Rev., 2008, 60, 1627–1637.
68. P. Zhang, W. Steelant, M. Kumar and M. Scholfield, J. Am. Chem. Soc., 2007, 129, 4526–4527.
69. H. Y. Liu, D. Chen, L. L. Li, T. L. Liu, L. F. Tan, X. L. Wu and F. Q. Tang, Angew. Chem., Int. Ed., 2011, 50, 891–895.
70. L. Cheng, K. Yang, Y. G. Li, J. H. Chen, C. Wang, M. W. Shao, S. T. Lee and Z. Liu, Angew. Chem., Int. Ed., 2011, 50, 7385–7390.
71. J. T. Robinson, S. M. Tabakman, Y. Y. Liang, H. L. Wang, H. S. Casalongue, D. Vinh and H. J. Dai, J. Am. Chem. Soc., 2011, 133, 6825–6831.
72. H. Zhu, J. Li, X. Qi, P. Chen and K. Pu, Nano Lett., 2018, 18, 586–594.
73. P. Huang, J. Lin, X. Wang, Z. Wang, C. Zhang, M. He, K. Wang, F. Chen, Z. Li, G. Shen, D. Cui and X. Chen, Adv. Mater., 2012, 24, 5104–5110.
74. H. Zhu, Y. Fang, Q. Miao, X. Qi, D. Ding, P. Chen and K. Pu, ACS Nano, 2017, 11, 8998–9009.
75. H. Zhu, P. Cheng, P. Chen and K. Pu, Biomater. Sci., 2018, 6, 746–765.
76. Y. Cheng, A. C. Samia, J. D. Meyers, I. Panagopoulos, B. W. Fei and C. Burda, J. Am. Chem. Soc., 2008, 130, 10643–10647.
77. S. J. Wang, P. Huang, L. M. Nie, R. J. Xing, D. B. Liu, Z. Wang, J. Lin, S. H. Chen, G. Niu, G. M. Lu and X. Y. Chen, Adv. Mater., 2013, 25, 3055–3061.
78. C. P. Wang, X. P. Cai, J. S. Zhang, X. Y. Wang, Y. Wang, H. F. Ge, W. J. Yan, Q. Huang, J. R. Xiao, Q. Zhang and Y. Y. Cheng, Small, 2015, 11, 2080–2086.
79. M. Manikandan, N. Hasan and H. F. Wu, Biomaterials, 2013, 34, 5833–5842.
80. X. Yi, K. Yang, C. Liang, X. Y. Zhong, P. Ning, G. S. Song, D. L. Wang, C. C. Ge, C. Y. Chen, Z. F. Chai and Z. Liu, Adv. Funct. Mater., 2015, 25, 4689–4699.
81. S. G. Wang, X. Li, Y. Chen, X. J. Cai, H. L. Yao, W. Gao, Y. Y. Zheng, X. An, J. L. Shi and H. R. Chen, Adv. Mater., 2015, 27, 2775–2782.
82. J. Liu, X. Zheng, L. Yan, L. Zhou, G. Tian, W. Yin, L. Wang, Y. Liu, Z. Hu, Z. Gu, C. Chen and Y. Zhao, ACS Nano, 2015, 9, 696–707.
83. T. Liu, C. Wang, X. Gu, H. Gong, L. Cheng, X. Z. Shi, L. Z. Feng, B. Q. Sun and Z. Liu, Adv. Mater., 2014, 26, 3433–3440.
84. G. Tian, X. Zhang, X. P. Zheng, W. Y. Yin, L. F. Ruan, X. D. Liu, L. J. Zhou, L. Yan, S. J. Li, Z. J. Gu and Y. L. Zhao, Small, 2014, 10, 4160–4170.
85. G. S. Song, J. L. Hao, C. Liang, T. Liu, M. Gao, L. Cheng, J. Q. Hu and Z. Liu, Angew. Chem., Int. Ed., 2016, 55, 2122–2126.
86. Q. Chen, L. Z. Feng, J. J. Liu, W. W. Zhu, Z. L. Dong, Y. F. Wu and Z. Liu, Adv. Mater., 2016, 28, 7129–7136.
87. P. Huang, C. Xu, J. Lin, C. Wang, X. S. Wang, C. L. Zhang, X. J. Zhou, S. W. Guo and D. X. Cui, Theranostics, 2011, 1, 240–250.
88. X. T. Zheng, A. Ananthanarayanan, K. Q. Luo and P. Chen, Small, 2015, 11, 1620–1636.
89. X. Cao, C. Ding, C. Zhang, W. Gu, Y. Yan, X. Shi and Y. Xian, J. Mater. Chem. B, 2018, 6, 8011–8036.
90. K. Huang, Z. Li, J. Lin, G. Han and P. Huang, Chem. Soc. Rev., 2018, 47, 5109–5124.
91. X. Duan, C. Wang, A. Pan and R. Yu, Chem. Soc. Rev., 2015, 44, 8859–8876.
92. F. Yu, Q. Liu, X. Gan, M. Hu, T. Zhang, C. Li, F. Kang, M. Terrones and R. Lv, Adv. Mater., 2017, 29, 1603266.
93. K. K. Liu, W. Zhang, Y. H. Lee, Y. C. Lin, M. T. Chang, C. Y. Su, C. S. Chang, H. Li, Y. Shi, H. Zhang, C. S. Lai and L. J. Li, Nano Lett., 2012, 12, 1538–1544.
94. H. D. Ha, D. J. Han, J. S. Choi, M. Park and T. S. Seo, Small, 2014, 10, 3858–3862.
95. B. Li, L. Jiang, X. Li, P. Ran, P. Zuo, A. Wang, L. Qu, Y. Zhao, Z. Cheng and Y. Lu, Sci. Rep., 2017, 7, 11182.
96. S. J. Xu, D. Li and P. Y. Wu, Adv. Funct. Mater., 2015, 25, 1127–1136.
97. W. Gu, Y. Yan, C. Zhang, C. Ding and Y. Xian, ACS Appl. Mater. Interfaces, 2016, 8, 11272–11279.
98. H. Jin, M. Ahn, S. Jeong, J. H. Han, D. Yoo, D. H. Son and J. Cheon, J. Am. Chem. Soc., 2016, 138, 13253–13259.
99. X. Zhao, X. Ma, J. Sun, D. Li and X. Yang, ACS Nano, 2016, 10, 2159–2166.
100. C. Zhu, Y. Huang, F. Xu, P. Gao, B. Ge, J. Chen, H. Zeng, E. Sutter, P. Sutter and L. Sun, Small, 2017, 13, 1700565.
101. L. Lin, Y. Xu, S. Zhang, I. M. Ross, A. C. Ong and D. A. Allwood, ACS Nano, 2013, 7, 8214–8223.
102. T. Liu, Y. Chao, M. Gao, C. Liang, Q. Chen, G. S. Song, L. Cheng and Z. Liu, Nano Res., 2016, 9, 3003–3017.
103. L. Yuwen, J. Zhou, Y. Zhang, Q. Zhang, J. Shan, Z. Luo, L. Weng, Z. Teng and L. Wang, Nanoscale, 2016, 8, 2720–2726.
104. P. Li, L. Liu, Q. Lu, S. Yang, L. Yang, Y. Cheng, Y. Wang, S. Wang, Y. Song, F. Tan and N. Li, ACS Appl. Mater. Interfaces, 2019, 11, 5771–5781.
105. J. Wang, X. Pang, X. Tan, Y. Song, L. Liu, Q. You, Q. Sun, F. Tan and N. Li, Nanoscale, 2017, 9, 5551–5564.
106. J. Wang, X. Tan, X. Pang, L. Liu, F. Tan and N. Li, ACS Appl. Mater. Interfaces, 2016, 8, 24331–24338.
107. X. Tian, Y. Sun, S. Fan, M. D. Boudreau, C. Chen, C. Ge and J. J. Yin, ACS Appl. Mater. Interfaces, 2019, 11, 4858–4866.
108. S. J. Wang, I. S. Coleb and Q. Li, RSC Adv., 2016, 6, 89867–89878.
109. S. N. Baker and G. A. Baker, Angew. Chem., Int. Ed., 2010, 49, 6726–6744.
110. Y. Cao, H. Dong, Z. Yang, X. Zhong, Y. Chen, W. Dai and X. Zhang, ACS Appl. Mater. Interfaces, 2017, 9, 159–166.
111. W. W. Liu, Y. Q. Feng, X. B. Yan, J. T. Chen and Q. J. Xue, Adv. Funct. Mater., 2013, 23, 4111–4122.
112. F. Yuan, T. Yuan, L. Sui, Z. Wang, Z. Xi, Y. Li, X. Li, L. Fan, Z. Tan, A. Chen, M. Jin and S. Yang, Nat. Commun., 2018, 9, 2249.
113. S. Kim, S. W. Hwang, M. K. Kim, D. Y. Shin, D. H. Shin, C. O. Kim, S. B. Yang, J. H. Park, E. Hwang, S. H. Choi, G. Ko, S. Sim, C. Sone, H. J. Choi, S. Bae and B. H. Hong, ACS Nano, 2012, 6, 8203–8208.
114. D. I. Son, B. W. Kwon, D. H. Park, W. S. Seo, Y. Yi, B. Angadi, C. L. Lee and W. K. Choi, Nat. Nanotechnol., 2012, 7, 465–471.
115. N. Li, A. Than, C. Sun, J. Tian, J. Chen, K. Pu, X. Dong and P. Chen, ACS Nano, 2016, 10, 11475–11482.
116. N. Li, A. Than, X. Wang, S. Xu, L. Sun, H. Duan, C. Xu and P. Chen, ACS Nano, 2016, 10, 3622–3629.
117. S. Some, A. R. Gwon, E. Hwang, G. H. Bahn, Y. Yoon, Y. Kim, S. H. Kim, S. Bak, J. Yang, D. G. Jo and H. Lee, Sci. Rep., 2014, 4, 6314.
118. D. Pan, J. Zhang, Z. Li and M. Wu, Adv. Mater., 2010, 22, 734–738.
119. S. Li, S. Zhou, Y. Li, X. Li, J. Zhu, L. Fan and S. Yang, ACS Appl. Mater. Interfaces, 2017, 9, 22332–22341.
120. M. Thakur, M. K. Kumawat and R. Srivastava, RSC Adv., 2017, 7, 5251–5261.
121. Z. M. Markovic, B. Z. Ristic, K. M. Arsikin, D. G. Klisic, L. M. Harhaji-Trajkovic, B. M. Todorovic-Markovic, D. P. Kepic, T. K. Kravic-Stevovic, S. P. Jovanovic, M. M. Milenkovic, D. D. Milivojevic, V. Z. Bumbasirevic, M. D. Dramicanin and V. S. Trajkovic, Biomaterials, 2012, 33, 7084–7092.
122. S. Y. Choi, S. H. Baek, S. J. Chang, Y. Song, R. Rafique, K. T. Lee and T. J. Park, Biosens. Bioelectron., 2017, 93, 267–273.
123. B. Z. Ristic, M. M. Milenkovic, I. R. Dakic, B. M. Todorovic-Markovic, M. S. Milosavljevic, M. D. Budimir, V. G. Paunovic, M. D. Dramicanin, Z. M. Markovic and V. S. Trajkovic, Biomaterials, 2014, 35, 4428–4435.
124. S. P. Jovanovic, Z. Syrgiannis, Z. M. Markovic, A. Bonasera, D. P. Kepic, M. D. Budimir, D. D. Milivojevic, V. D. Spasojevic, M. D. Dramicanin, V. B. Pavlovic and B. M. T. Marković, ACS Appl. Mater. Interfaces, 2015, 7, 25865–25874.
125. M. Nafiujjaman, M. Nurunnabi, S. H. Kang, G. R. Reeck, H. A. Khan and Y. K. Lee, J. Mater. Chem. B, 2015, 3, 5815–5823.
126. J. D. Monroe, E. Belekov, A. O. Er and M. E. Smith, Photochem. Photobiol., 2019, 95, 1473–1481.
127. A. M. Derfus, W. C. W. Chan and S. N. Bhatia, Nano Lett., 2004, 4, 11–18.
128. H. Zhu, T. Yu, H. Xu, K. Zhang, H. Jiang, Z. Zhang, Z. Wang and S. Wang, ACS Appl. Mater. Interfaces, 2014, 6, 21461–21467.
129. K. Li, W. Liu, Y. Ni, D. Li, D. Lin, Z. Su and G. Wei, J. Mater. Chem. B, 2017, 5, 4811–4826.
130. K. Liu, R. Xing, Q. Zou, G. Ma, H. Mohwald and X. Yan, Angew. Chem., Int. Ed., 2016, 55, 3036–3039.
131. Y. Y. Li, D. Du, H. Dong, D. Shi, Y. Y. Li, Z. Wu, D. Du, H. Dong, D. Shi and Y. Y. Li, RSC Adv., 2016, 6, 6516–6522.
132. H. M. Meng, D. Zhao, N. Li and J. Chang, Analyst, 2018, 143, 4967–4973.
133. C. Wu, X. Guan, J. Xu, Y. Zhang, Q. Liu, Y. Tian, S. Li, X. Qin, H. Yang and Y. Liu, Biomaterials, 2019, 205, 106–119.
134. J. V. Jokerst, T. Lobovkina, R. N. Zare and S. S. Gambhir, Nanomedicine, 2011, 6, 715–728.
135. K. Habiba, J. Encarnacion-Rosado, K. Garcia-Pabon, J. C. Villalobos-Santos, V. I. Makarov, J. A. Avalos, B. R. Weiner and G. Morell, Int. J. Nanomed., 2016, 11, 107–119.
136. W. S. Kuo, C. Y. Chang, H. H. Chen, C. L. Hsu, J. Y. Wang, H. F. Kao, L. C. Chou, Y. C. Chen, S. J. Chen, W. T. Chang, S. W. Tseng, P. C. Wu and Y. C. Pu, ACS Appl. Mater. Interfaces, 2016, 8, 30467–30474.
137. K. Kholikov, S. Ilhom, M. Sajjad, M. E. Smith, J. D. Monroe, O. San and A. O. Er, Photodiagn. Photodyn. Ther., 2018, 24, 7–14.
138. W. S. Kuo, H. H. Chen, S. Y. Chen, C. Y. Chang, P. C. Chen, Y. I. Hou, Y. T. Shao, H. F. Kao, C. L. L. Hsu, Y. C. Chen, S. J. Chen, S. R. Wu and J. Y. Wang, Biomaterials, 2017, 120, 185–194.
139. J. Ju, S. Regmi, A. Fu, S. Lim and Q. Liu, J. Biophotonics, 2019, 12, e201800367.
140. J. Sun, Q. Xin, Y. Yang, H. Shah, H. Cao, Y. Qi, J. R. Gong and J. Li, Chem. Commun., 2018, 54, 715–718.
141. D. Zhang, L. Wen, R. Huang, H. Wang, X. Hu and D. Xing, Biomaterials, 2018, 153, 14–26.
142. Y. Liu, Y. Xu, X. Geng, Y. Huo, D. Chen, K. Sun, G. Zhou, B. Chen and K. Tao, Small, 2018, 14, e1800293.
143. Z. Tian, X. Yao, K. Ma, X. Niu, J. Grothe, Q. Xu, L. Liu, S. Kaskel and Y. Zhu, ACS Omega, 2017, 2, 1249–1258.
144. Y. Xuan, R. Y. Zhang, X. S. Zhang, J. An, K. Cheng, C. Li, X. L. Hou and Y. D. Zhao, Nanotechnology, 2018, 29, 355101.
145. X. Yao, X. Niu, K. Ma, P. Huang, J. Grothe, S. Kaskel and Y. Zhu, Small, 2017, 13, 1602225.
146. X. Yao, Z. Tian, J. Liu, Y. Zhu and N. Hanagata, Langmuir, 2017, 33, 591–599.
147. F. Wo, R. Xu, Y. Shao, Z. Zhang, M. Chu, D. Shi and S. Liu, Theranostics, 2016, 6, 485–500.
148. X. Wang, X. Sun, H. He, H. Yang, J. Lao, Y. Song, Y. Xia, H. Xu, X. Zhang and F. Huang, J. Mater. Chem. B, 2015, 3, 3583–3590.
149. J. Fang, Y. Liu, Y. Chen, D. Ouyang, G. Yang and T. Yu, Int. J. Nanomed., 2018, 13, 5991–6007.
150. F. Xia, H. Wang and Y. Jia, Nat. Commun., 2014, 5, 4458.
151. H. Liu, A. T. Neal, Z. Zhu, Z. Luo, X. Xu, D. Tomanek and P. D. Ye, ACS Nano, 2014, 8, 4033–4041.
152. Z. Sun, H. Xie, S. Tang, X. F. Yu, Z. Guo, J. Shao, H. Zhang, H. Huang, H. Wang and P. K. Chu, Angew. Chem., Int. Ed., 2015, 54, 11526–11530.
153. J. Shao, H. Xie, H. Huang, Z. Li, Z. Sun, Y. Xu, Q. Xiao, X. F. Yu, Y. Zhao, H. Zhang, H. Wang and P. K. Chu, Nat. Commun., 2016, 7, 12967.
154. H. Wang, X. Yang, W. Shao, S. Chen, J. Xie, X. Zhang, J. Wang and Y. Xie, J. Am. Chem. Soc., 2015, 137, 11376–11382.
155. Y. Li, Z. Liu, Y. Hou, G. Yang, X. Fei, H. Zhao, Y. Guo, C. Su, Z. Wang, H. Zhong, Z. Zhuang and Z. Guo, ACS Appl. Mater. Interfaces, 2017, 9, 25098–25106.
156. T. Guo, Y. Wu, Y. Lin, X. Xu, H. Lian, G. Huang, J. Z. Liu, X. Wu and H. H. Yang, Small, 2018, 14, 1702815.
157. S. Lan, Z. Lin, D. Zhang, Y. Zeng and X. Liu, ACS Appl. Mater. Interfaces, 2019, 11, 9804–9813.
158. X. Chu, K. Li, H. Y. Guo, H. B. Zheng, S. Shuda, X. L. Wang, J. Y. Zhang, W. Chen and Y. Zhang, ACS Biomater. Sci. Eng., 2017, 3, 1836–1844.
159. X. X. Wu, L. Y. Yang, L. Luo, G. H. Shi, X. B. Wei and F. Wang, ACS Appl. Bio Mater., 2019, 2, 1998–2005.
160. D. W. Zheng, B. Li, C. X. Li, J. X. Fan, Q. Lei, C. Li, Z. Xu and X. Z. Zhang, ACS Nano, 2016, 10, 8715–8722.
161. X. Chu, K. Li, H. Y. Guo, H. B. Zheng, S. Shuda, X. L. Wang, J. Y. Zhang, W. Chen and Y. Zhang, ACS Biomater. Sci. Eng., 2017, 3, 1836–1844.
162. M. Yao, L. Ma, L. Li, J. Zhang, R. Lim, W. Chen and Y. Zhang, J. Biomed. Nanotechnol., 2016, 12, 1835–1851.
163. X. X. Wu, L. Y. Yang, L. Luo, G. H. Shi, X. B. Wei and F. Wang, ACS Appl. Bio Mater., 2019, 2, 1998–2005.
164. J. Ji, X. Song, J. Liu, Z. Yan, C. Huo, S. Zhang, M. Su, L. Liao, W. Wang, Z. Ni, Y. Hao and H. Zeng, Nat. Commun., 2016, 7, 13352.
165. W. Tao, X. Ji, X. Xu, M. A. Islam, Z. Li, S. Chen, P. E. Saw, H. Zhang, Z. Bharwani, Z. Guo, J. Shi and O. C. Farokhzad, Angew. Chem., Int. Ed., 2017, 56, 11896–11900.
166. G. Song, J. Shen, F. Jiang, R. Hu, W. Li, L. An, R. Zou, Z. Chen, Z. Qin and J. Hu, ACS Appl. Mater. Interfaces, 2014, 6, 3915–3922.
167. D. Ding, W. Guo, C. Guo, J. Sun, N. Zheng, F. Wang, M. Yan and S. Liu, Nanoscale, 2017, 9, 2020–2029.
168. H. R. Zu, Y. X. Guo, H. Y. Yang, D. Huang, Z. M. Liu, Y. L. Liu and C. F. Hu, New J. Chem., 2018, 42, 18533–18540.
169. M. Ghidiu, M. R. Lukatskaya, M. Q. Zhao, Y. Gogotsi and M. W. Barsoum, Nature, 2014, 516, 78–81.
170. H. Lin, X. Wang, L. Yu, Y. Chen and J. Shi, Nano Lett., 2017, 17, 384–391.
171. X. Yu, X. Cai, H. Cui, S. W. Lee, X. F. Yu and B. Liu, Nanoscale, 2017, 9, 17859–17864.
172. J. K. Tee, L. X. Yip, E. S. Tan, S. Santitewagun, A. Prasath, P. C. Ke, H. K. Ho and D. T. Leong, Chem. Soc. Rev., 2019, 48, 5381–5407.
173. F. Peng, M. I. Setyawati, J. K. Tee, X. Ding, J. Wang, M. E. Nga, H. K. Ho and D. T. Leong, Nat. Nanotechnol., 2019, 14, 279–286.
174. M. I. Setyawati, C. Y. Tay, S. L. Chia, S. L. Goh, W. Fang, M. J. Neo, H. C. Chong, S. M. Tan, S. C. Loo, K. W. Ng, J. P. Xie, C. N. Ong, N. S. Tan and D. T. Leong, Nat. Commun., 2013, 4, 1673.
175. M. I. Setyawati, C. Y. Tay, B. H. Bay and D. T. Leong, ACS Nano, 2017, 11, 5020–5030.
176. C. Y. Tay, M. I. Setyawati and D. T. Leong, ACS Nano, 2017, 11, 2764–2772.
177. J. K. Tee, M. I. Setyawati, F. Peng, D. T. Leong and H. K. Ho, Nanotoxicology, 2019, 13, 682–700.
178. J. Wang, L. Zhang, F. Peng, X. Shi and D. T. Leong, Chem. Mater., 2018, 30, 3759–3767.
179. E. Tan, B. L. Li, K. Ariga, C. T. Lim, S. Garaj and D. T. Leong, Bioconjugate Chem., 2019, 30, 2287–2299.

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