Recent progress on transition metal dichalcogenide-based composites for cancer therapy

Abstract

Cancer remains a global health challenge, driving the need for advanced treatments. While transition metal dichalcogenides (TMDs) show promise in cancer therapy, their stability and efficacy require improvement. This study explores TMD-based composites as a solution to enhance their therapeutic potential. This review begins by providing an overview of TMDs and emphasizing their preparation techniques and fundamental properties. The focus is then shifted to categorizing TMD-based composites based on their constituent materials, delving into various types, such as TMD-organic, TMD-carbon, TMD-metal chalcogenide, TMD-metal, and TMD-oxide composites, as well as more complex ternary and multinary systems. We further explore key fabrication strategies, including hydrothermal/solvothermal methods and surface deposition/coating techniques. Subsequently, the focus shifted to their applications in cancer treatment, including chemotherapy, photothermal therapy, phototherapy, and integrated combination therapies. Finally, critical challenges in the field and perspectives on potential directions for future research are presented.

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Bo Chen

Bo Chen received his B.S. degree, M.S. degree, and Ph.D. degree from Lanzhou University (2009), Shandong University (2012), and Nanyang Technological University (2017), respectively. Then, he worked as a research fellow at Nanyang Technological University (2017–2020) before moving to the City University of Hong Kong as a research associate (2020–2023). Currently, he is a Professor at the School of Chemistry and Life Sciences, Nanjing University of Posts and Telecommunications. His current research interests include the synthesis, characterization, and applications of nanomaterials with unconventional phases.

Yue Dai

Yue Dai received a B.S. degree from Tongda College, Nanjing University of Posts and Telecommunications in 2022. She is currently pursuing her M.S. degree at the School of Materials Science and Engineering, Institute of Advanced Materials, Nanjing University of Posts and Telecommunications, under the supervision of Prof. Bo Chen. Her research interests include the preparation of TMD-based materials and their biomedical applications.

Chunhong Chen

Chunhong Chen received her Ph.D. from Zhejiang University in 2019, working on porous carbonaceous materials for application in catalysis and energy storge. She then joined the Institute for Basic Science, Korea, and the Hong Kong Polytechnic University as a postdoctoral fellow (2019–2023). She is currently a Professor at the Nanjing University of Posts and Telecommunications, and her research interests are mainly focused on the controllable preparation of functional carbonaceous materials and polyoxometalate-based micro-/nano-architecture.

Lianhui Wang

Lianhui Wang is a Professor at the State Key Laboratory of Flexible Electronics, Nanjing University of Posts and Telecommunications. He is a distinguished professor of Cheung Kong Scholars. He presided over more than 30 domestic and international scientific research projects, such as the National Outstanding Youth Fund, key projects of the National Natural Science Fund, the national major scientific research project, etc. He has long been engaged in teaching and research in the fields of photoelectric nanomaterials, bioptoelectronics, and nanobiological medicine.

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1. Introduction

Cancer therapy remains a pivotal focus in biomedicine.^1,2 As the global incidence of cancer continues to rise, the imperative for the development of pertinent diagnostic^3,4 and therapeutic methods^5–7 is escalating.⁸ In the course of treatment, researchers should not only assess the therapeutic effectiveness, but also prioritize the safety and feasibility of interventions. Hence, there is a pressing need to rationally design materials tailored for cancer therapeutics.

Over the last two decades, two-dimensional (2D) transition metal dichalcogenides (TMDs) have been drawing close attention from researchers^9–11 due to their unique electronic and optical properties,^12–14 establishing them as promising candidates for biomedicine.^15–17 Compared with some other 2D nanomaterials that have been utilized in cancer therapies, e.g., graphene,^18–20 layered double hydroxides (LDHs),^21–23 and black phosphorus (BP),^24–27 the tunable bandgap along with outstanding physicochemical properties endows TMDs with a wider scope of anti-tumor applications.^28–30 Their affordability and exceptional biocompatibility further contribute to their appeal.^31,32 For instance, MoS₂ nanomaterials have been extensively investigated as outstanding photothermal agents along with X-ray computed tomography (CT) imaging agents.³³ It is worthy of note that TMDs exhibit low toxicity when serve as therapeutic platforms, thanks to their rapid biodegradation and safe excretion.³⁴ Additionally, TMDs display superior near-infrared (NIR) light absorption, enhanced optical stability, and greater photothermal conversion efficiency compared to gold nanoparticles. These attributes make them more suitable for imaging-guided photothermal therapy (PTT).³⁵

Despite TMDs have plenty of prominent physicochemical properties, their limited serum stability and inefficient intracellular delivery efficiency may pose constraints on their biomedical applications.³⁶ To address these challenges, researchers have adopted various strategies of surface modifications for TMDs.^8,37,38 Through the decoration with biocompatible and nontoxic materials, TMDs have been shown to exhibit enhanced stability in phosphate-buffered saline (PBS).³⁹ Over and above, it has been demonstrated that it is an effective approach to combine TMDs with various other functional materials, forming unique hybrids that exhibit higher efficiency in anti-tumor treatment.^36,40,41

In this review, we present a succinct introduction of TMDs and their synthesis. The subsequent discussion focuses on categorizing the TMD-based composites based on their components. Detailed insights are provided for various composite types, including TMD-organic material composites, TMD-carbon composites, TMD-metal chalcogenide composites, TMD-metal composites, TMD-oxide composites, and TMD-based ternary and multinary compounds. Following this, we delve into the preparation methods of TMD-based composites, which typically involve hydrothermal/solvothermal methods or surface deposition/coating. Subsequently, the focus shifts to their applications in cancer therapy, including chemotherapy, PTT, phototherapy, and combination therapy. Finally, we present the challenges faced in this research direction and discuss the prospects for these endeavors.

2. Transition metal dichalcogenides

The chemical formula of TMDs is MX₂,⁴² indicating a hexagonal bonding structure with a sandwich-type X–M–X arrangement.^13,43,44 In this formula, X refers to the sulfur group elements while M denotes to the transition metal elements (Fig. 1A and B).⁴⁵ Due to the weak van der Waals forces governing the bonding between TMD layers, their monolayered flakes can be exfoliated via a strategy akin to that employed for graphene.¹³

Fig. 1 Composition and structure of TMDs. (A) The elemental composition of TMDs.⁴³ Reproduced with permission from ref. 43. Copyright 2013 Springer Nature. (B) Sandwich TMD structure (C) Phase structures of TMDs. Top view (top) and side view (bottom) depicting the octahedral (1T), hexagonal (2H), and rhombohedral (3R) phases. The black lines delineate the unit cells of these lamellar structures.⁴⁴ Reproduced with permission from ref. 44. Copyright 2020 Springer Nature. (D) Top and side views of the distorted 1T′ WS₂ phase. The upper panel illustrates the in-plane crystal structure of monolayer 1T′-WS₂, whereas the lower panel displays the zigzag chain of W atoms.⁴⁹ Reproduced with permission from ref. 49. Copyright 2023 American Association for the Advancement of Science (AAAS).

It should be noted that because of the diverse spherical coordination of transition metals elements, TMDs display a variety of phase structures.^9,44,46–48 The most common phase structures include the hexagonal 2H phase, as well as the octahedral 1T and rhombohedral 3R phases (Fig. 1C).⁴⁴ Besides, there is a variant known as the distorted phase 1T′ characterized by a distorted octahedral structure (Fig. 1D).⁴⁹

The preparation methods of 2D TMDs can be broadly classified into top-down and bottom-up strategies.^50–53 Top-down strategies can be further categorized based on force sources, including mechanical exfoliation, ultrasonic exfoliation, and electrochemical exfoliation. On the other hand, bottom-up strategies encompass chemical vapor deposition (CVD),⁵⁴ physical vapor deposition (PVD), and hydrothermal/solvothermal methods.⁵⁵

Fig. 2A shows a diagram of the preparation of few-layer MoTe₂ crystals through the CVD method.⁴² The metal precursor compounds, MoO₃ and NaCl, were placed in the center of a quartz tube and the Si/SiO₂ substrate was placed on an alumina boat with the polished side facing down. Another alumina boat containing tellurium (Te) powder was placed on one side of the quartz tube, and a mixture of H₂ and Ar was used as the carrier gas. After the reaction, the mixture was allowed to cool to room temperature. The obtained 1T_d phase MoTe₂ had an in-plane crystal structure and displayed vertical stacking.

Fig. 2 Schemes of methods for the preparation of TMDs. (A) Schematic representation of the CVD method for preparing few-layer MoTe₂ crystals.⁴² Reproduced with permission from ref. 42. Copyright 2019 Springer Nature. (B) Schematic illustration of the MBE method used to prepare TMDs. (C) Schematic illustration of the hydrothermal/solvothermal synthesis of TMDs. (D) Schemes of top-down strategies for TMDs.⁵⁵ Reproduced with permission from ref. 55. Copyright 2021 Elsevier. (E) Schematic illustration of Au-assisted exfoliation for synthesizing 2D MoS₂.⁶⁴ Reproduced with permission from ref. 64. Copyright 2020 Springer Nature.

PVD is another typical method used for preparing 2D TMDs. Under high vacuum conditions and appropriate temperatures, bulk TMDs (e.g., MoS₂ powder) can be evaporated into gaseous molecules, which are deposited onto the surface of the substrate with temperature drops.^56,57 As one of the most representative PVD methods, molecular beam epitaxy (MBE) (Fig. 2B) has received widespread attention. Generally, during epitaxial growth, the lattice structure of the substrate affects the orientation of the film. Therefore, if the substrate and synthesized end materials meet eutectic conditions or lattice matching, high-quality films can be obtained. Whereas, TMDs do not require the lattice matching condition in principle when epitaxial growing since they do not process dangling bonds.⁵⁸

Hydrothermal/solvothermal synthesis, as two similar synthesis methods,^59–61 can be used not only for the preparation of TMD dispersions, but also for the functionalization of TMDs simultaneously. These two methods are mainly conducted in sealed reactors lined with polytetrafluoroethylene, where precursors containing transition metals and sulfur group elements are mixed with water or organic solvents (Fig. 2C). As the temperature increases, high vapor pressure will be formed to promote the reaction.^62,63

In contrast to bottom-up strategies, the typical top-down strategy for 2D TMDs is usually regarded as exfoliating bulk TMDs with a layered structure (Fig. 2D).⁵⁵ An Au-assisted exfoliation of 2D MoS₂ can be seen in Fig. 2E.⁶⁴ A thin layer of Au was deposited on the substrate, which was first covered with a thin Ti or Cr adhesion layer. Because of the good contact between the Au and layered bulk MoS₂ crystal on the tape, one or several large-area monolayer MoS₂ flakes remained on the Au surface when the adhesive tape was peeled off. However, the size of the available bulk crystals is limited, and thus the obtained monolayer flakes usually have macroscopic dimensions.

3. Transition metal dichalcogenide-based composites

Because TMDs lack stability in the physiological environment^34,65 and have a relatively low intracellular delivery efficiency,³⁶ researchers have utilized various functional materials to modify TMDs to mitigate such difficulties. By integrating TMD materials with other functional materials, on one hand, the stability and biocompatibility of TMDs can be significantly enhanced, while on the other hand, this approach effectively addresses the limitations of low efficiency associated with single-component materials. In this section, we introduce TMD-based composites with constituent materials such as TMD-organic material composites, TMD-carbon composites, TMD-metal chalcogenide composites, TMD-metal composites, TMD-oxide composites, and TMD-based ternary and multinary compounds.

3.1. Transition metal dichalcogenide-organic material composites

As one of the most frequently employed materials for surface modification on TMDs, organic materials have the advantages of good biocompatibility and nontoxicity.³⁶ Organic materials commonly encompass polymers, for example, poly(ethylene glycol) (PEG)^66,67 and polyetherimide,^68,69 and small molecules, for example, chitosan (CS)^70,71 and L-cysteine.⁷²

In a typical example, Liu et al. synthesized PEGylated MoS₂ nanosheets (Fig. 3A) for photothermal-chemo cancer therapy.³⁹ In their experiment, lipoic acid conjugated polyethylene glycol (LA-PEG) was used to functionalize 2D MoS₂ nanosheets after chemical exfoliation. With a disulfide group of LA-PEG anchored to surface defects of MoS₂, the physiological stability of MoS₂ in aqueous solutions was remarkably enhanced. MoS₂-PEG showed no obvious agglomeration in the PBS solution after centrifugation, while aggregation occurred with MoS₂ alone under the same treatment (Fig. 3B). Additionally, PEGylated MoS₂ exhibited a decrease in the lateral size and an increase in the average thickness compared to pristine MoS₂ (Fig. 3C). However, the UV-to-NIR absorbance was still strong upon PEG modification, which can be verified by UV-vis-NIR absorbance spectra. Moreover, this study examined the photothermal conversion efficiency of the as-obtained nanocomposites. As the photothermal heating curves shown, the temperature rose with the increasing laser power in the case of a low and constant concentration (0.03 mg mL⁻¹) of MoS₂-PEG solution.

Fig. 3 Preparation and characterization of TMD-organic material composites. (A) Schematic diagram of the preparation of MoS₂-PEG nanosheets. (B) Photographs of MoS₂ (top) and MoS₂-PEG (bottom) after centrifugation at 3000 rpm in water, PBS, and cell medium. (C) Atomic force microscopy (AFM) images of MoS₂ (top) and MoS₂-PEG (bottom).³⁹ Reproduced with permission from ref. 39. Copyright 2014 Wiley-VCH. (D) Schematic illustration of the chemical structure of FA/LA-hPG. (E) Schematic illustration of the synthesis process of FP-MoS₂. (F) Photographs of MoS₂ (F₁) and FP-MoS₂ (F₂) dispersed in Milli-Q water, PBS, and Dulbecco's modified eagle's medium (DMEM) cell culture medium (containing 10% serum) for 7 days at 4 °C.⁶⁵ Reproduced with permission from ref. 65. Copyright 2021 Wiley-VCH.

To improve the biocompatibility and properties of MoS₂ nanosheets, Xu et al. utilized folic acid (FA) and lipoic acid (LA) functionalized hyperbranched polyglycerol (hPG) to conjugate on MoS₂ (FP-MoS₂, Fig. 3D and E).⁶⁵ With the existence of hPG and FA, the as-synthesized materials showed improved water dispersibility and higher cancer therapeutic efficiency. As shown in Fig. 3F, the stability of MoS₂ in PBS was significantly enhanced after FA/LA-hPG conjugation via disulfide bonds. The as-obtained FP-MoS₂ also displayed an excellent photothermal effect which could be adjusted by concentration and laser-power.⁶⁵

Moreover, small molecules have also attracted the interest of many researchers due to their simple structure and small site-blocking effect, which can make them easier and more controllable to biocouple on the surface of TMDs and improve the stability of TMDs during biochemical analysis.⁷³ Xie et al. chose egg yolk phospholipid, a representative of lipids, for modification on the surface of layered MoS₂ nanosheets so that it could offer a biocompatible protective barrier.⁷⁴ During the synthesis process, the lipid drew support from physical adsorption to coat on the as-prepared MoS₂ in order to obtain MoS₂-lipid nanocomposites following the rotary evaporation of liposomes. After a series of tests, it was found that the layered structure of MoS₂ did not change after modification (Fig. 4A). Clearly, MoS₂-lipid displayed better dispersibility in the three media than pristine MoS₂ (Fig. 4B). Meanwhile, the photothermal conversion efficiency of MoS₂ was not noticeably influenced by the lipid coating.

Fig. 4 Preparation and characterization of TMD-organic material composites. (A) Typical TEM image of the MoS₂-lipid. A₁–A₄ are bright-field scanning transmission electron microscopy (BF-STEM) images of the MoS₂-lipid and the corresponding energy dispersive X-ray (EDX) element mappings of P, S, and Mo, respectively. (B) Photographs of MoS₂ (upper) and MoS₂-lipid (bottom) incubated in water, PBS and cell culture medium (containing 10% fetal bovine serum) for 24 hours and 48 hours.⁷⁴ Reproduced with permission from ref. 74. Copyright 2020 Elsevier. (C) Scheme of HA-MoS₂ conjugates. (D) AFM images (upper) and the corresponding height profiles (bottom) of MoS₂ (left) and HA-MoS₂ (right). (E) TEM images of MoS₂ (top) and HA-MoS₂ (bottom) (scale bar = 500 nm). Insets: high-resolution TEM (HRTEM) images of MoS₂ and HA-MoS₂.³⁶ Reproduced with permission from ref. 36. Copyright 2019 Wiley-VCH.

In another case, Shin et al. conjugated hyaluronate with MoS₂ (hyaluronate-MoS₂) for cancer therapy.³⁶ As a biocompatible natural material, hyaluronate was demonstrated to be equally capable of solving the low stability problem of MoS₂ nanosheets. In this nanocomposite, the disulfide bond acted as a link between MoS₂ and hyaluronate (Fig. 4C). As shown in the AFM images (Fig. 4D), the thickness and particle size of MoS₂ were all slightly increased owing to surface modification. Moreover, the obtained conjugates retained their crystal structure, as verified by transmission electron microscopy (TEM) images (Fig. 4E). In addition to the changes in morphology, dynamic light scattering analysis also revealed that hyaluronate-MoS₂ exhibited a dramatic improvement in stability. After 7 days in the presence of PBS, the sample with hyaluronate conjugation showed less aggregation and a smaller increase in size.

Beyond that, Zheng et al. proposed the use of gallic acid (GA) to modify MoS₂ nanosheets.⁷⁵ Upon preparing MoS₂ nanosheets via ultrasonic exfoliation, MoS₂@GA could be synthesized through strong π–π stacking. The prepared MoS₂@GA retained its nanosheet structure, with an average size of approximately 101 nm. Since GA is a kind of Fe(III) ion chelating agent, Fe(III) can be introduced into MoS₂@GA by a chelation reaction to form MoS₂@GA-Fe, which has shown a high therapeutic efficiency.⁷⁵

3.2. Transition metal dichalcogenide-carbon material composites

Carbon materials with excellent photothermal properties are also used to modify TMDs for PTT.⁷⁶ Given that heterojunction structure can improve the separation and immigration efficiency of photoexcited charges, researchers often consider utilizing 0D and 2D carbon materials with matched bandgaps to fabricate hybrid heterojunctions which will enhance photothermal conversion performance.⁷⁷

Geng et al. designed carbon dot/WS₂ heterojunctions (CD/WS₂ heterojunctions) as NIR-II (near-infrared region II) agents for PTT of osteosarcoma and bone regeneration.⁷⁶ As illustrated in Fig. 5A, the preparation of CD/WS₂ heterojunctions can be divided into three procedures, and the binding between CD and WS₂ was mainly through electrostatic interactions. After CDs with a diameter of approximately 10 nm (Fig. 5B) were attached to the surface of WS₂ (Fig. 5C), the thickness showed a distinguishable increase, whereas the average size did not change. In addition, the CD/WS₂ heterojunctions exhibited improved photothermal properties and stability compared to pure CDs and WS₂, which can be verified in the temperature elevation figure.

Fig. 5 Preparation and characterization of TMD-carbon material composites. (A) Schematic illustration of the preparation procedures for the CD/WS₂ heterojunctions. (B) TEM image and Gaussian distribution (inset) of NIR-II responsive CDs. (C) HRTEM image of CD/WS₂ heterojunctions.⁷⁶ Reproduced with permission from ref. 76. Copyright 2020 Elsevier. (D) Schematic illustration of preparation procedures of CD/WS₂ nanorods. (E) SEM image of CD/WS₂ nanorods (scale bar = 0.5 μm).⁷⁸ Reproduced with permission from ref. 78. Copyright 2017 Wiley-VCH.

In addition to combining with WS₂, Geng et al. proposed CD-sensitized MoS₂ nanosheet heterojunctions (NIR-CD/MoS₂ HJs).⁷⁷ The preparation procedure can likewise be seen as three steps, which contained the synthesis of NIR-CDs and MoS₂-PEG nanosheets along with the surface charge-driven assembly for a 0D/2D/0D sandwich architecture. Upon loading NIR-CDs, dynamic light scattering analysis showed no obvious changes in the hydrodynamic size, and the photothermal conversion efficiency was proportional to the loading level. It can be observed that the MoS₂ nanosheets were almost wrapped in a layer of NIR-CDs. Such a structure, with a loading level as high as 200%, revealed enhanced photothermal effects.

In another typical example, Nandi et al. proposed conjugates composed of WS₂ nanorods and CDs (CD/WS₂ nanorods, Fig. 5D).⁷⁸ Followed by the addition of glucose gemini surfactant and probe-sonication; the aggregation in the aqueous solution of NH₂-functionalized WS₂ nanorods clearly disappeared. Subsequently, CDs were covalently attached to the surface of WS₂via carbonized amine residues. As shown in the scanning electron microscopy (SEM) image in Fig. 5E, the material exhibited a rod-shaped structure with a length of a few microns.

3.3. Transition metal dichalcogenide-metal chalcogenide composites

To enhance the anti-cancer efficiency, metal chalcogenides with narrow bandgaps are also chosen for combining with TMDs.¹⁷ For instance, Bi₂Se₃/MoSe₂ nano-heterostructure was successfully constructed by Wang et al. for cancer therapy.¹⁷ After preparing MoSe₂ nanosheets through ultrasound-assisted exfoliation, the cation-exchange strategy was utilized to partially replace Mo atoms with Bi atoms to form a novel sandwich nanostructure Bi₂Se₃/MoSe₂/Bi₂Se₃ (Fig. 6A). As illustrated in Fig. 6B and C, the morphology and size did not change significantly upon the introduction of Bi atoms. To further confirm the crystal structure of Bi2_Se₃/MoSe₂/Bi₂Se₃, selected area electron diffraction (SAED) patterns of MoSe₂ and Bi2_Se₃/MoSe₂/Bi₂Se₃ nanosheets were obtained and displayed in Fig. 6D and E, respectively. The additional diffraction spots (Fig. 6E, marked in blue circle) of Bi2_Se₃/MoSe₂/Bi₂Se₃ could be ascribed to the successful exchange between Bi ions and Mo ions. Similarly, Gao et al. adopted a one-pot solvothermal protocol to prepare polyvinyl pyrrolidone (PVP)-assisted Bi₂S₃-MoS₂ heterogeneous nanoparticles (BMNPs) as nano-radiosensitizers for triple-negative breast cancer (TNBC).⁷⁹ BMNPs presented a uniform morphology and clear crystal structure with an orderly arrangement of lattice fringes.

Fig. 6 Preparation and characterization of TMD-metal chalcogenide composites. (A) Side view of cation exchange during the preparation of Bi₂Se₃/MoSe₂/Bi₂Se₃ nanostructures. TEM images of (B) MoSe₂ and (C) Bi₂Se₃/MoSe₂/Bi₂Se₃. SAED patterns for (D) MoSe₂ and (E) Bi₂Se₃/MoSe₂/Bi₂Se₃.¹⁷ Reproduced with permission from ref. 17. Copyright 2019 Elsevier. (F) Schematic illustration of synthesis of MoSe₂/CoSe₂@PEG nanosheets. (G) TEM, (H) HRTEM, and (I) SAED images of MoSe₂/CoSe₂ nanocomposites. Inset: MoSe₂/CoSe₂ aqueous dispersion. (J) High-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) image and elemental mapping images of Mo, Se, and Co, respectively.⁸⁰ Reproduced with permission from ref. 80. Copyright 2020 Wiley-VCH.

In another study, Li et al. synthesized MoSe₂/CoSe₂@PEG nanosheets via a one-pot co-deposition strategy for NIR-enhanced chemodynamic therapy (CDT) (Fig. 6F),⁸⁰ in which Co-doping enhanced NIR harvesting. As shown in Fig. 6G, the size of the as-prepared MoSe₂/CoSe₂ nanosheets was close to 30–50 nm. In addition, the corresponding HRTEM image (Fig. 6H) can confirm the crystal structure of MoSe₂/CoSe₂ as it revealed typical lattice fringes of MoSe₂ and CoSe₂, matching well with the SAED pattern displayed in Fig. 6I. The well distribution of Co, Mo and Se elements in the sample was confirmed by elemental mapping analysis (Fig. 6J).

3.4. Transition metal dichalcogenide-metal composites

Metal nanostructures (e.g., Au and Pt) have unique surface plasmon resonances, and their decorations of semiconductor TMDs are also considered to be good candidates for cancer therapy.^81–83 In a typical example reported by Maji et al., gold nanobipyramids (Au NBPs, right image of Fig. 7A) with a positive charge were used as a substrate to combine MoS₂ nanosheets with a negative charge via a strong electrostatic interaction.⁸¹ As can be clearly seen in Fig. 7B–D, Au NBPs with average lengths and widths of approximately 110 nm and 36 nm, respectively, were successfully coated with a thin layer of MoS₂ nanosheets with a thickness of ∼1.5–2 nm. Importantly, Au NBPs endowed the hybrid with excellent peroxidase properties and impressive NIR absorbance.

Fig. 7 Preparation and characterization of TMD-metal composites. (A) Structural sketches of MoS₂ and Au NBPs. (B) Field-emission SEM (FESEM), (C) TEM, and (D) HRTEM images of AuNBPs@MoS₂.⁸¹ Reproduced with permission from ref. 81. Copyright 2018 American Chemical Society. (E) Schematic illustration of the preparation of MoS₂-AuNPs and Ab-MoS₂-AuNPs nanoprobes. TEM images of (F) MoS₂ nanosheets and (G) MoS₂-AuNPs nanocomposites. Inset: statistical data on the diameter of AuNPs. (H) Ultraviolet–visible (UV-vis) spectra of MoS₂ (a, black line) and MoS₂-AuNPs (b, red line). Inset: photos of MoS₂ and MoS₂-AuNPs.⁸⁴ Reproduced with permission from ref. 84. Copyright 2019 American Chemical Society.

Su et al. constructed a colorimetric sensor depending on highly catalytic gold nanoparticle-decorated MoS₂ nanocomposites (MoS₂-AuNPs, Fig. 7E).⁸⁴ It can be observed from Fig. 7F and G that the prepared MoS₂ nanosheets showed typical layered nanostructure and Au nanoparticles deposited uniformly on the surface. The UV-vis analysis was revealed in Fig. 7H, a new characteristic absorption peak belonged to Au nanoparticles can be observed at 538 nm in MoS₂-AuNPs, which could further confirm the successful synthesis of the nanocomposites. Moreover, the inset in Fig. 7H revealed the difference in color between MoS₂ nanosheets and MoS₂-AuNPs nanocomposites. Owing to the high catalytic activity of MoS₂-AuNPs, researchers have further combined anti-CEA (Ab1, Ab1-MoS₂-AuNPs) or anti-CEA (Ab2, Ab2-MoS₂-AuNPs) for the diagnosis of cancer (Fig. 7E).

Apart from Au, other metals, e.g., Pt, were also utilized for modifying TMDs.^85–87 For example, Meng et al. doped Pt nanoparticles on MoSe₂ nanoflowers for synergistic cancer therapies.⁸⁶ With the loading of Pt, the shape of MoSe₂ was not significantly affected along with their size, which could be verified by corresponding TEM images and dynamic light scattering analysis. Furthermore, it could be observed that Pt nanoparticles uniformly distributed on the surface of MoSe₂.

3.5. Transition metal dichalcogenide-oxide composites

In addition, many attempts have been made to combine TMDs with various types of oxides.^88,89 For example, to overcome the limited efficiency of the Fenton-like reaction in CDT, Pidamaimaiti et al. functionalized MoS₂ with Cu₂O (Cu₂O-MoS₂) for synergistic CDT and PTT against tumor cells.⁸⁸ In which MoS₂ nanosheets were first obtained through a facile solvothermal method, after which Cu₂O nanoparticles were decorated on the surface of MoS₂ nanosheets by electrostatic interactions (Fig. 8A). As presented in Fig. 8B and C, the average size of the nanosheets increased after introducing Cu₂O. As shown in Fig. 8D, Mo, S, Cu, and O coexist and are distributed homogeneously in Cu₂O-MoS₂. Notably, the Cu⁺ in Cu₂O can easily react with H₂O₂ to form highly toxic ˙OH, which can strongly promote the Fenton-like reaction in a weakly acidic environment.

Fig. 8 Preparation and characterization of TMD-oxide composites. (A) Schematic illustration of the synthesis of Cu₂O-MoS₂ nanosheets. TEM images of (B) MoS₂ and (C) Cu₂O-MoS₂. (D) Elemental mapping images of Mo, S, Cu, and O.⁸⁸ Reproduced with permission from ref. 88. Copyright 2021 Royal Society of Chemistry. (E) Structural sketch, (F) TEM, and (G) STEM images of UsMSND@MSN. Inset: enlarged TEM image of an individual UsMSND@MSN nanoparticle.⁸⁹ Reproduced with permission from ref. 89. Copyright 2021 Elsevier.

In another case, Chen et al. introduced ultra-small MoS₂ nanodots to incorporate in mesoporous silica nanospheres (UsMSND@MSN, Fig. 8E) since mesoporous silica nanomaterials are promising candidates for intelligent drug delivery platforms against tumors.⁸⁹ As can be seen in Fig. 8F, the uniformed nanosphere structure of UsMSND@MSN was distinguished displayed. Additionally, the dot-like surface of the prepared material was rough with ordered mesopores (Fig. 8G), suggesting the homogeneous incorporation of ultra-small nanodots in the MSN. UsMSND@MSN remained uniform in size (∼115 nm) and biocompatibility, which is in favor of its use as a carrier for anti-cancer drugs.

3.6. Transition metal dichalcogenide-based ternary and multinary compounds

Although so many types of individual materials are mentioned above to modify TMDs, the most common ones are actually TMD-based ternary and multinary compounds.⁵² For instance, Li et al. developed an anti-cancer drug carrier using MoS₂ modified with lipoic acid (LA)-polyethyleneimine and LA-PEG (MoS₂-PEI-PEG, MPP) to combine chemotherapy, gene therapy and PTT.³⁴ To obtain the well-dispersed products with flake-like shapes, the heating time during the hydrothermal process for preparing MoS₂ nanosheets was chosen to be 10 hours. Because the sulfur molecules in LA would bind to the defects of MoS₂, the LA-dominated thiol reaction could help couple PEI and PEG to the nanosheets. The TEM image obtained after coupling clearly demonstrated that the flake-like structure did not change and the core–shell structure appeared. As PEI and PEG are both hydrophilic, they were also proven to clearly improve the colloidal stability and dispersion of MoS₂ nanosheets.

Mussel-inspired chemistry, which takes advantage of polydopamine (PDA), provides another novel surface-modification strategy. Zeng et al. prepared MoS₂ nanosheets modified with PDA and poly((polyethylene glycol) methyl ether methacrylate) (PPEGMA) (MoS₂-PDA-PPEGMA) through mussel-inspired chemistry along with chain transfer free radical polymerization to conquer cancer, in which MoS₂ nanosheets were synthesized via lithium intercalation exfoliation.⁹⁰ It can be observed from TEM images that the thickness of the obtained nanocomposites significantly increased due to the successful coating of PDA thin films and PPEGMA on the surface of MoS₂.

To study the efficacy of rod-shaped MoS₂-based nanoplatform for PTT, Yang et al. synthesized MoS₂ nanosheets coated with mesoporous silica nanorods (MSNR) along with human serum albumin (HSA) modifying and chlorin e6 (Ce6) loading (MSNR@MoS₂-HSA/Ce6).³³ Utilizing silica nanorods as templates, MSNR@MoS₂ were prepared through a facile hydrothermal method. Moreover, HSA, which is defined as an endogenous protein, and Ce6, a hydrophobic photosensitizer, were introduced into MSNR@MoS₂ nanocomposites for more accurate targeted tumor therapy under NIR irradiation (Fig. 9A). As presented in TEM images (Fig. 9B and C), MSNR@MoS₂ displayed obscurer edges compared to pristine MSNR. Interestingly, MSNR@MoS₂-HSA exhibited smoother edges than MSNR@MoS₂. Furthermore, the loading of Ce6 could be verified by the existing quenching effect, as a new characteristic peak at 404 nm appeared in the UV-vis spectra of MSNR@MoS₂-HSA/Ce6, whereas MSNR@MoS₂-HSA did not. These results confirmed the successful realization of each procedure.

Fig. 9 Preparation and characterization of TMD-based ternary and multinary compounds. (A) Schematic illustration of the preparation of MSNR@MoS₂-HSA/Ce6. TEM images of (B) MSNR and (C) MSNR@MoS₂.³³ Reproduced with permission from ref. 33. Copyright 2019 Ivyspring International Publisher.

3.7. Others

There are also several other types of materials that have been used for surface functionalization of TMDs.⁹¹ For instance, rare earth element-based upconversion nanoparticles (UCNPs), which are considered difficult to combine with effective photothermal therapeutic materials into a small-sized structure. Wang et al. grew VS₂ directly on the surface of luminescent UCNPs to obtain oil-soluble UCNPs@VS₂ nanocomposites and then modified them with PEG (mPEG) for better water solubility (UCNPs@VS₂-mPEG).⁹¹ Such nanostructure provides an effective strategy for integrated materials based on UCNPs assessing nanoscale dimension. As illustrated in Fig. 10A, NaYF₄:Yb,Tm@NaGdF₄ (UCNPs) exhibited a core–shell structure, and UCNPs@VS₂-mPEG was synthesized successfully. TEM images presented in Fig. 10B–D verified the integration of VS₂ and mPEG with UCNPs, which was consistent with the results of elemental mapping images. Besides, growing VS₂ on the surface of UCNPs did not influence the average size (∼25 nm) of nanocomposites.

Fig. 10 Preparation and characterization of TMD-other material composites. (A) Schematic illustration of the preparation of UCNPs@VS₂-mPEG nanostructure. TEM images of (B) UCNPs, (C) UCNPs@VS₂, and (D) UCNPs@VS₂-mPEG.⁹¹ Reproduced with permission from ref. 91. Copyright 2020 Royal Society of Chemistry. (E) Schematic illustration of the synthesis procedure of LMM@BSA/Ce6 nanosheets. (F) SEM image of LMM nanosheets and (G) TEM image of LMM@BSA.¹⁶ Reproduced with permission from ref. 16. Copyright 2021 BioMed Central.

In another case, Zhao et al. proposed LDH-MoS₂ (LMM) clay nanosheets for cancer therapy. Beyond that, bovine serum albumin (BSA) was modified on the surface of LMM to improve the colloidal stability and biocompatibility of materials in both vitro and vivo together with Ce6, which acted as a photosensitizer beneficial for enhancing therapeutic efficacy (LMM@BSA/Ce6, Fig. 10E).¹⁶ It can be observed from SEM images (Fig. 10F) and TEM images (Fig. 10G) that LMM@BSA showed 2D structure as well as LMM.

3.8. Structure of transition metal dichalcogenide-based composites

TMD-based composites can be divided into four categories according to their structure: 0D/2D, core–shell, 2D/2D, and inorganic–organic. A scheme of the 0D/2D structure is shown in Fig. 11A, where 0D nanoparticles are explicitly embedded in 2D nanosheets. The adsorption of CDs on WS₂ nanosheets (CD/WS₂) is a typical example of 0D/2D structures. Through electrostatic interactions, CD/WS₂ nanocomposites with excellent photothermal effects and physiological stability were synthesized, which could be used for PTT against tumors.⁷⁶Fig. 11B shows a schematic diagram of the core–shell structure with the characterization that one material coats on another material. AuNBPs@MoS₂ fabricated by Maji et al. had such a core–shell structure, and it exhibited excellent photothermal effects that were efficient for anti-cancer treatment.⁸¹ The 2D/2D structure is an alternative type of representative structure as well. Wang et al. successfully combined NIR-CDs with MoS₂ nanosheets to synthesize NIR-CD/MoS₂ heterojunctions with a 2D/2D structure (Fig. 11C). During the preparation, ultrasonic exfoliation and cation exchange were the main preparation procedures, and the products had a high surface area to volume ratio along with superior photothermal performance.⁷⁷ Although the aforementioned structures have terrific NIR absorption energy for cancer therapy, their poor biocompatibility would limit the corresponding development to some extent. To address this issue, Yi et al. proposed an organic–inorganic structure (Fig. 11D) by encapsulating ultrathin WS₂ nanosheets with BSA. Through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and zebrafish embryo survival rate experiment, this organic–inorganic structure displayed excellent biocompatibility.⁹²

Fig. 11 Structure of TMD-based composites. Schematic diagrams of (A) 0D/2D, (B) core–shell, (C) 2D/2D, and (D) inorganic–organic structures.

4. Synthesis of transition metal dichalcogenide-based composites

Synthesis strategies for TMD-based composites generally involve hydrothermal/solvothermal methods^15,79 and surface deposition/coating.^93,94 In this section, we focus on the typical synthetic strategies for TMD-based composites.

4.1. Hydrothermal/solvothermal methods

Hydrothermal/solvothermal methods are commonly employed to prepare TMD-based composites with high crystallinity, thanks to their cost-effectiveness and simple operational procedures^95,96 As displayed in Fig. 12A, such Fe(III)@WS₂-PVP nanocapsules⁸⁷ were prepared via a one-pot solvothermal method by Wu et al., in which WS₂ nanosheets and Fe(III) species were transformed from ammonium tetrathiotungstate (H₈N₂S₄W) and ferric chloride hexahydrate (FeCl₃·6H₂O), respectively. During the preparation process, a plentiful inner space in nanocapsules formed because the Fe(III) species would roll up the WS₂ nanosheets, which could lead to an improved drug loading capacity of Fe(III)@WS₂-PVP. Moreover, the modification of PVP on the surface of nanocapsules has been demonstrated to greatly enhance their colloidal stability and biocompatibility. The SEM image in Fig. 12B shows the successful synthesis of Fe(III)@WS₂-PVP, and the red arrows indicate the Fe(III) species.

Fig. 12 Hydrothermal/solvothermal methods for preparing TMD-based composites. (A) Schematic illustration of the solvothermal synthesis of Fe(III)@WS₂-PVP nanocapsules. (B) SEM image of Fe(III)@WS₂-PVP nanocapsules.⁸⁷ Reproduced with permission from ref. 87. Copyright 2019 Wiley-VCH. (C) Schematic illustration of the hydrothermal synthesis of WS₂-PVP nanosheets. (D) TEM image of WS₂-PVP_{360 kDa} nanosheets.⁵¹ Reproduced with permission from ref. 51. Copyright 2017 Elsevier. (E) Schematic illustration of hydrothermal synthesis of MoSe₂ hetero-dimensional hybrid. (F) TEM image of the MoSe₂ hetero-dimensional hybrid.⁹⁸ Reproduced with permission from ref. 98. Copyright 2017 Tsinghua University Press.

Moses O. A. et al. produced PVP intercalated metallic 1T-WSe₂ nanosheets (1T-WSe₂@PVP) via a one-step solvothermal approach as well.⁹⁷ During the preparation, N,N-dimethylformamide (DMF) solvent was also utilized for the dissolution of materials which contained 0.5 mmol selenourea powder, 0.1 mmol WCl₆, and 0.5 g PVP. The as-prepared solution was then transferred into a sealed autoclave and heated at 220 °C for 24 hours. It can be seen from the SEM image that the obtained 1T-WSe₂@PVP exhibited a uniform nanosheet structure. Additionally, such ultrathin nanosheets consisted of 3–8 layers which can be confirmed by the high-magnification TEM image.

Likewise, Wang et al. proposed a PVP-mediated hydrothermal reaction to prepare WS₂-PVP_{360 kDa} (the weight average molecular weight of PVP is 360 kDa) nanosheets (Fig. 12C), and it could achieve synthesis and surface modification at the same time.⁵¹ During the synthesis process, 0.15 g (NH₄)₂WS₄ served as a source of S and W elements while 0.15 g PVP was selected as a modifier. A homogeneous solution was obtained by dissolving (NH₄)₂WS₄ and PVP in 30 mL of DMF with vigorous magnetic stirring. The as-obtained solution was then transferred into a 100 mL stainless-steel autoclave lined with polyphenylene and heated at 220 °C for 12 hours. The final products are displayed in Fig. 12D, and a uniform and regular disk shape with a nanosheet morphology can be observed clearly.

In another typical example, Mao et al. adopted a one-pot hydrothermal synthesis to prepare MoSe₂ hetero-dimensional hybrid which was self-assembled by MoSe₂ nanodots and small-sized MoSe₂ nanosheets (Fig. 12E).⁹⁸ Na₂MoO₄ and Se were utilized as precursors and PEG served as the capping agent. Furthermore, a solution with a Mo : Se molar ratio of 1 : 2 was transferred into an 80 mL autoclave lined with Teflon and then heated at 200 °C for 12 hours. As can be observed from TEM images, the obtained MoSe₂ hetero-dimensional hybrid had a flake-like structure. Moreover, large amounts of evenly sized MoSe₂ nanodots were dispersed on the surface of the MoSe₂ nanosheets (Fig. 12F). Such phenomenon above could be well explained by the capping effect of PEG.

4.2. Surface deposition/coating

Some materials, like organic compounds, are commonly combined with TMDs using surface deposition/coating techniques. These methods provide better control over preparation parameters, enabling faster reaction times.^99,100 Wang et al. coated PEG on the surface of MoSe₂ nanoflowers (MoSe₂@PEG), which could be served as an efficient nanoplatform for drug loading and delivery.¹⁰¹ The target product MoSe₂@PEG was obtained by dispersing 20 mg prepared MoSe₂ nanoflowers into PEG5000-NH₂ aqueous solution (1 mg mL⁻¹, 5 mL), followed by ultrasonication for 4 hours. Subsequently, the anti-cancer drug, Doxorubicin (DOX), could be loaded onto MoSe₂@PEG for cancer therapy (MoSe₂@PEG-DOX). From Fig. 13A and B, it can be clearly observed that the nanocarrier was successfully synthesized with the introduction of PEG and DOX. Additionally, PEG enhanced the stability and biocompatibility of the obtained compositions.

Fig. 13 Surface deposition/coating for preparing TMD-based composites. (A) TEM image of MoSe₂ nanoflowers. (B) Schematic illustration of the preparation process of MoSe₂@PEG-DOX nanocomposites.¹⁰¹ Reproduced with permission from ref. 101. Copyright 2018 Royal Society of Chemistry. (C) Schematic illustration of the synthesis process of MoSe₂(Gd³⁺)-PEG. (D) TEM image of MoSe₂(Gd³⁺) nanosheets. Inset: Magnified TEM image of an individual MoSe₂(Gd³⁺) nanosheet. (E) AFM image of MoSe₂(Gd³⁺) nanosheets. Inset: thickness profile of MoSe₂(Gd³⁺) nanosheets.¹⁰⁴ Reproduced with permission from ref. 104. Copyright 2018 Royal Society of Chemistry.

In addition to organic materials, metal ions have also been used to dope TMDs via a surface deposition approach.^102,103 Pan et al. utilized a facile liquid-phase strategy to synthesize Gd³⁺-doped MoSe₂ nanosheets (MoSe₂(Gd³⁺)) as a cancer therapeutic agent and a contrast agent.¹⁰⁴ To enhance the stability in physiological solutions, PEG was modified on the surface of MoSe₂(Gd³⁺) (MoSe₂(Gd³⁺)-PEG, Fig. 13C). During the preparation process, Gd³⁺ ions were introduced into MoSe₂ crystals by adding anhydrous ethanol with gadolinium chloride to a beaker containing 25 mL distilled water along with 1.645 g NaMoO₄·2H₂O, 1.549 g Se, 0.259 g NaBH₄, and GdCl₃·6H₂O. Besides, N-methyl-2-pyrrolidone could assist the exfoliation of MoSe2 nanosheets from bulk MoSe₂. As shown in Fig. 13D, the obtained MoSe₂(Gd³⁺) exhibited a sheet structure. From Fig. 13E, the AFM image well displays the doping of Gd³⁺ into the crystals.

5. Application for cancer treatments

As the incidence and mortality rates of cancer continue to rise in recent years,^105,106 researchers have explored many nanomaterials for tumor treatment, including lung cancer, prostate cancer, and breast cancer et al.^29,107,108 Among them, TMD-based composites have been gradually developed and used for effective tumor elimination^109,110 by virtue of their good photothermal conversion efficiency,³⁵ excellent biocompatibility³³ and large specific surface area.¹¹¹ In this section, we will elaborate on the application of TMD-based composites for cancer treatments.

5.1. Chemotherapy

Chemotherapy, a widely applied anti-cancer strategy, often uses chemically synthesized drugs (e.g., DOX) to treat tumor tissues. It functions by interfering with DNA and RNA in cells or proteins to inhibit the growth of cancer cells. However, such treatment still suffers from some problems like instability, poor solubility, and inefficiency of chemotherapeutic agents due to the non-specific uptake of cancer cells, which will result in distinct side effects. Therefore, 2D TMD-based composites, which can be excellent drug carriers, play an important role in reducing side effects and boosting the anti-cancer effects of chemotherapy.

Li et al. successfully prepared MoS₂ superstructures (layer-by-layer (LbL)-DNA/MoS₂ nanosheets) through the rapid self-assembly of complementary DNA oligonucleotides anchored on MoS₂ nanosheets to load DOX (DOX/DNA/MoS₂).¹¹² Specifically, DNA can bind to the surface of MoS₂ through interactions between its thiol groups and sulfur vacancies in MoS₂, allowing doxorubicin (DOX) to intercalate within the DNA duplex. In the presence of adenosine triphosphate (ATP), a crucial metabolic coenzyme, the DNA/MoS₂ complex responds by disassembling, triggering the controlled release of DOX. This ATP-sensitive mechanism facilitates targeted chemotherapy by ensuring drug release primarily in tumor regions, where ATP concentrations are higher (Fig. 14A). Additionally, DNA anchoring markedly prevented the aggregation of MoS₂ in the physiological environment, which enhanced its stability and drug delivery efficiency. To investigate the biodegradability of DOX-loaded DNA/MoS₂ during tumor cell killing, DOX/DNA/MoS₂ nanosheets were exposed to DNAase, and the MoS₂ nanosheets effectively protected DNA from degradation, indicating the excellent biocompatibility of DNA/MoS₂ nanosheets. As expected, this composite ultimately demonstrated the optimal tumor-suppressing effect, and its high degree of inertness protected DNA from enzymatic cleavage until it entered ATP-rich cancer cells, obviously enhancing the targeted DOX release from chemotherapy.

Fig. 14 TMD-based composites for chemotherapy. (A) Schematic illustration of the chemotherapy mechanism of multilayer DOX/DNA/MoS₂ nanosheets.¹¹² Reproduced with permission from ref. 112. Copyright 2017 American Chemical Society. (B) Body weight curves of mice in each group. (C) Tumor volume curves after 25 days of treatment in each group. (group 1: saline; group 2: saline + NIR; group 3: MoS₂-PEI-HA; group 4: free DOX; group 5: MoS₂-PEI-HA + NIR; group 6: DOX@MoS₂-PEI-HA; group 7: DOX@MoS₂-PEI-HA + NIR)¹¹³ Reproduced with permission from ref. 113. Copyright 2018 American Chemical Society. (D) Cell viabilities of human hepatocellular carcinomas (HepG2) cells treated with different concentrations of MS-CO-NH. (E) Cell viabilities of HepG2 cells treated with different concentrations of MS-P-D and free DOX.¹¹⁴ Reproduced with permission from ref. 114. Copyright 2020 Royal Society of Chemistry. (F) The live/dead cell images of HaCaT cells stained with Calcein AM and PI after various treatments of (i) control, (ii) TGA-WS₂-PPy-Fu nanocomposite, and (iii) drug-released solution from TGA-WS₂-PPy-FU.¹¹⁵ Reproduced with permission from ref. 115. Copyright 2020 Elsevier.

Beyond that, Dong et al. presented a PEI-assisted MoS₂ modified with hyaluronic acid (MoS₂-PEI-hyaluronic acid) and loaded DOX to combat chemoresistance in clinical oncology, where PEI was introduced by electrostatic interaction and the –COOH of hyaluronic acid was coupled with the –NH₂ of PEI.¹¹³ Hyaluronic acid, a biocompatible polysaccharide, is specifically broken down by hyaluronidase, an enzyme mainly found in the tumor microenvironment and lysosomes. This controlled degradation helps maintain MoS₂ stability in aqueous and physiological conditions, facilitating targeted tumor therapy. After investigating the DOX release ability of MoS₂-PEI-hyaluronic acid at tumor sites under different pH and laser irradiation conditions, the DOX cumulative release rate of MoS₂-PEI-hyaluronic acid was calculated to be as high as 77.4% under acidic conditions along with low-power density NIR laser irradiation due to the multi-stimuli-accelerated release of DOX and the improved accumulation of DOX depending on the downregulation of the expression of drug-resistance-related proteins in the tumor microenvironment. In vivo experiments showed that mice bearing tumors did not experience significant weight loss, but exhibited a substantial decrease in tumor volume under 808 nm NIR laser radiation, confirming that MoS₂-PEI-hyaluronic acid had excellent biocompatibility (Fig. 14B) and the ability to overcome drug resistance issues in chemotherapy (Fig. 14C).

Apart from these examples, Long et al. synthesized a pH-responsive drug delivery system through a straightforward approach for chemotherapy.¹¹⁴ They employed lithium-ion-assisted liquid-phase exfoliation to prepare multilayered nanoparticles, and the surface defects were modified with aldehyde-PEG (CHO-PEG) and thiolated methoxypolyethylene glycol to enhance the dispersibility, stability, and pH responsiveness. An anti-cancer drug, DOX, was then loaded onto the surface of nanoparticles (MoS₂-PEG-DOX, MS-P-D) via a pH-responsive oxime chemical bond (MoS₂-carbonyl-imino, MS-CO-NH) formed between the carbonyl group of CHO-PEG and the amine group of DOX. To evaluate the effectiveness of this system in eliminating cancer cells, MTT assays were conducted, which revealed the excellent biocompatibility of MS-CO-NH (Fig. 14D), along with the highest rate of DOX release under acidic conditions. Moreover, when tumor cells were co-cultured with the MS-P-D composite material, their cell viability significantly decreased (Fig. 14E), indicating that the capacity of MS-P-D to kill cancer cells was comparable to that of high concentrations of free DOX.

In a separate study, Hsiao et al. developed a novel drug delivery carrier, thioglycolic acid-WS₂-polypyrrole-5-fluorouracil (TGA-WS₂-PPy-FU), which utilized electrical stimulation for drug release.¹¹⁵ The incorporation of PPy, a representative polymer, enhanced the sensitivity to electrical stimuli, thereby improving drug delivery. To study the efficacy of TGA-WS₂-PPy-FU in cancer treatment, UV-vis spectroscopy was employed to monitor drug release and the result showed that such material exhibited the best drug release behavior under electrical stimulation. Subsequently, they assessed the viability of human keratinocyte (HaCaT) cells treated with non-electrically stimulated TGA-WS₂-PPy-FU using an MTT assay, which showed over 80% cell viability, indicating good biocompatibility. Furthermore, calcein acetoxymethyl ester (Calcein AM) and propidium iodide (PI) staining (Fig. 14F) were used for live/dead cell determination, during which TGA-WS₂-PPy-FU exhibited superior biocompatibility and could effectively release chemotherapy drugs under electrical stimulation. Moreover, both drug-loaded- and drug-free-TGA-WS₂-PPy-FU were applied onto patches, which were then affixed to the skin followed by electrical stimulation. Based on the Raman spectroscopy results, TGA-WS₂-PPy-FU was concluded to be the platform with the strongest drug release signal. These findings collectively demonstrate the potential of TGA-WS₂-PPy-FU for application in chemotherapy. Overall, TMD-based composites show non-negligible potential for loading chemical drugs, which significantly improves drug delivery rate and chemotherapeutic efficiency.

5.2. Photothermal therapy

PTT, one of the most promising treatments for tumors, which depends on converting light energy into heat energy, often results in localized hyperthermia that drives the death of cancer cells. It has attracted increasing attention recently thanks to its ability to precisely target lesions with a controllable dose of external laser irradiation, thus minimizing damage to the surrounding healthy tissue. However, pure TMDs lack stability and sometimes exhibit potential side effects, poor photothermal conversion efficiency, and inferior biocompatibility, which limits their clinical medical applications. Consequently, there is an urgent need to exploit TMD-based photothermal agents to address these issues.

For example, Ariyasu et al. synthesized a photothermal agent by coating MoS₂ with a thiolated CS. With CS coating, the aggregation of MoS₂ was distinctly prevented, thus the stability and dispersibility of the material in a biological context were enhanced.¹¹⁶ To inhibit heat shock protein 90 (Hsp90), which helps tumors resist thermal stress, a cyclic peptide sequence (Cype), an Hsp90 inhibitor analog, was loaded onto MoS₂-CS. The addition of CS and Cype had little effect on the thermal properties of composite, preserving its strong photothermal performance. Under 808 nm NIR irradiation, Cype specifically bound to the N-middle domain of Hsp90, disrupting its function and weakening cellular resistance to heat treatment (Fig. 15A). Additionally, the CS modification contributed to better biocompatibility and potential biodegradability, supporting safer therapeutic applications. Besides, experiments with human colon cancer (HCT-116) cells proved that MoS₂-CS-Cype showed more effective PTT efficacy and hypotoxicity (Fig. 15B) compared to pure MoS₂ and MoS₂-CS, which was attributed to the rapid release of Cype and the increase in the photothermally mediated apoptosis.

Fig. 15 TMD-based composites for PTT. (A) Schematic illustration of the PTT process-based on MoS₂-CS-Cype. (B) Fluorescence expression images of HCT-116 cells stained by Alexa Flour 488 labeled anti-Hsp70 antibody after various treatments of (B1) NIR only, (B2) MoS₂ + NIR, (B3) Cype + NIR, and (B4) MoS₂-CS-Cype + NIR.¹¹⁶ Reproduced with permission from ref. 116. Copyright 2017 American Chemical Society. (C) Temperature change curves of 100 μg mL⁻¹ MoS₂-Gd-BSA solution under the 808 nm laser at different power densities for 10 minutes. (D) Temperature changes in MoS₂-Gd-BSA as measured by on/off irradiation cycles. (808 nm laser, 50 μg mL⁻¹).⁹³ Reproduced with permission from ref. 93. Copyright 2017 American Chemical Society. (E) Tumor volume growth changes of tumor-bearing mice under different treatments.¹¹⁷ Reproduced with permission from ref. 117. Copyright 2021 Elsevier.

In another case, Chen et al. prepared MoS₂ nanosheets via a one-pot hydrothermal method, followed by surface coating with polyethyleneimine hydrochloride and polyacrylic acid (PAH/PAA).⁹³ Subsequently, an amination reaction between the amino groups of BSA-Gd composite and carboxyl groups of MoS₂ nanosheets yielded MoS₂-Gd-BSA nanosheets. The photothermal effect and stability of the modified MoS₂-Gd-BSA nanosheets were investigated by irradiating them with different laser frequencies and then examining the temperature curves upon repeated irradiation. As a result, BSA-Gd-MoS₂ displayed a good photothermal effect and stability (Fig. 15C and D). The toxicity of MoS₂-Gd-BSA was also assessed during the cell incubation using the Cell Counting Kit-8 (CCK-8) assay, which revealed that the materials had low toxicity. Encouraged by these conclusions, they conducted in vivo experiments on 4T1 (breast cancer) tumor-bearing mouse models and found significant tumor growth suppression under laser irradiation with MoS₂-Gd-BSA treatment, together with no observed tumor recurrence, which suggests its potential for cancer treatments.

To obtain nanostructures with high specificity for tumor cell recognition and effective enrichment at the tumor site, Pang et al. synthesized ∼10 nm MoS₂ nanosheets by a hydrothermal method, conjugated with BSA and a specific nuclear accounting adapter (Apt) to prepare MoS₂-BSA-Apt nanosheets.¹¹⁷ Upon examining the physical and chemical properties of the composite, they found that it exhibited outstanding photothermal effect and stability. MoS₂-BSA-Apt was then incubated with MCF-7 human breast cancer cells to assess their survival rate. Consequently, MoS₂-BSA-Apt exhibited low cell toxicity and excellent tumor-targeting capabilities. Given these excellent properties, in vitro/vivo experiments were conducted as well, which demonstrated the effective ablation of human breast cancer cells under the treatment of MoS₂-BSA-Apt + NIR 10 min (Fig. 15E). In summary, MoS₂-BSA-Apt has the potential to become a photothermal material for tumor precision treatments.

In summary, TMD-based composites exhibit superior photothermal conversion efficiency and stability, making them outstanding photothermal agents for killing tumor cells. Moreover, compared to gold nanoparticles, TMD-based composites provide a more practical and affordable option for PTT, benefiting from their low material costs and economical synthesis methods.^118–120

5.3. Phototherapy

Although PTT is effective, to a certain extent, the results of a single therapy are often suboptimal. Therefore, phototherapy, mainly including PTT and photodynamic therapy (PDT), is employed to further enhance the effectiveness of cancer treatments. In phototherapy, phototherapeutic agents absorb visible/NIR light, generating hyperthermia or cytotoxic substances such as reactive oxygen species (ROS), including singlet oxygen (¹O₂), superoxide radicals (˙O₂˙⁻), and hydroxyl radicals (˙OH) to induce cancer cell damage.

In 2019, Younis et al. absorbed positively charged Au nanorods onto negatively charged MoS₂ nanosheets through electrostatic interaction, and then loaded indocyanine green (ICG) to prepare an efficient, low-power irradiation nanoplatform (Au/MoS₂-ICG) for synergistic cancer phototherapy (Fig. 16A).⁸³ In the Au/MoS₂ nanoplatform, the photothermal conversion efficiency of dual plasmonic PTT nanoagent (Au/MoS₂) reached as high as 68.8% under 808 nm laser radiation. More importantly, the high temperature caused by PTT promoted the release of ICG (85%) and the production of ¹O₂, which was necessary for simultaneous PDT and PTT. Both in vitro and in vivo experiments showed the complete eradication of tumors, indicating that the synergistic therapeutic effect induced by Au/MoS₂-ICG was more significant than that induced by PDT or PTT alone. At the same time, the great biocompatibility of such composite has been verified as well.

Fig. 16 TMD-based composites for phototherapy. (A) Schematic illustration of Au/MoS₂-ICG nanoplatform for tumor treatment.⁸³ Reproduced with permission from ref. 83. Copyright 2019 American Chemical Society. (B) Temperature change curves of various groups of different treatments under 808 nm laser.¹²¹ Reproduced with permission from ref. 121. Copyright 2020 Elsevier. (C) Absorption intensity change of 1,3-diphenylisobenzofuran (DPBF) in various treatment groups after laser irradiation for a fixed time. (D) Infrared thermography of OSA-HPCS/BSA-MoS₂ with different BSA-MoS₂ concentrations under an NIR laser.¹²² Reproduced with permission from ref. 122. Copyright 2022 Wiley-VCH. (E) Heating and cooling curves of MoS₂ and MoS₂:5%Eu³⁺ at different times. (F) Cell viability changes of mice in each group at different concentrations.¹²⁴ Reproduced with permission from ref. 124. Copyright 2021 Elsevier.

However, ICG in the aforementioned nanoplatforms had poor stability and water solubility and accumulated well in tumors. Hence, Liu et al. used PDA and hyaluronic acid to modify ICG-loaded MoSe₂ nanoparticles and synthesized a highly stable nanosystem (MoSe₂@ICG-PDA-hyaluronic acid).¹²¹ With the modification of PDA and hyaluronic acid, the products would significantly enhance the stability and accumulation of ICG in tumors, thereby producing a large amount of ROS to inhibit cancer cell growth. Meanwhile, under the irradiation of NIR light, MoSe₂ would generate abundant heat energy to kill cancer cells (Fig. 16B). In summary, MoSe₂@ICG-PDA-hyaluronic acid exhibited an excellent ability to inhibit tumor growth and metastasis through synergistic PDT/PTT.

In another recent study conducted by Qi et al., MoS₂ nanosheets were modified with BSA (BSA-MoS₂) and loaded onto oxidized sodium alginate (OSA) and hydroxypropyl chitosan (HPCS) to synthesize an injectable and self-healing polysaccharide hydrogel (OSA-HPCS/BSA-MoS₂).¹²² Owing to the reversible Schiff base bond formed between OSA and HPCS, the composite could be directly injected into the tumor site to avoid the loss of BSA-MoS₂ in the blood. Subsequently, under 808 nm laser irradiation, BSA-MoS₂ effectively killed tumor cells through the generation of ROS (Fig. 16C) along with photothermal conversion (Fig. 16D). Both in vitro/vivo investigations proved that BSA-MoS₂ could effectively eradicate cancer cells under NIR irradiation and was highly biocompatible.

Li et al. used MoS₂ as a carrier to load ICG and curcumin (Cur), and synthesized an ICG@Cur@MoS₂ nanoplatform applied for phototherapy.¹²³ During the study, Cur was proven to be efficient in inhibiting the activity of P-glycoprotein (P-gp), which is highly expressed in liver cells and will significantly decrease the activity of ICG. Therefore, the activity of ICG increased together with the effect of PDT. Through in vitro/vivo investigations, the ICG@Cur@MoS₂ nanoplatform further exhibited excellent photothermal effects, low toxicity, and efficient anti-tumor effects.

In addition to these materials above, metal ions doped into TMDs for phototherapy have also been explored. Zhou et al. successfully developed Eu³⁺-doped MoS₂ (MoS₂:Eu³⁺) nanoflowers via a hydrothermal method.¹²⁴ Under 808 nm laser radiation, the photothermal conversion efficiency of MoS₂:Eu³⁺ was significantly higher than that of pristine MoS₂ (Fig. 16E), which thus promoted the generation of ROS. Besides, in vitro experiments conducted on 4T1 cells showed exceptional anti-cancer effects of MoS₂:Eu³⁺ (Fig. 16F) as well as great biocompatibility and high photostability. Overall, with the synergistic effects of hyperthermia and generation of cytotoxic substances, the efficacy of cancer treatments based on TMDs under NIR irradiation can be dramatically enhanced.

5.4. Other combination therapy

Apart from the synergistic PDT/PTT described above, there are also some other dual-modality (e.g., chemotherapy/PTT) and tri-modality (e.g., PTT/radiotherapy/checkpoint blockade immunotherapy) therapies for treating tumors or cancer cells. The related mechanism is schematically shown in Fig. 17A.¹²⁵

Fig. 17 TMD-based composites for combination therapy. (A) Schematic illustration of WO_2.9-WSe₂-PEG nanoparticles for combination therapy.¹²⁵ Reproduced with permission from ref. 125. Copyright 2020 American Chemical Society. (B) Cumulative DOX release curves from DOX@MSN-WS₂-HP under various pH conditions. (C) Temperature change of water and different concentrations of WS₂-HP under laser irradiation.⁹⁹ Reproduced with permission from ref. 99. Copyright 2017 American Chemical Society. (D) ROS levels in the cells after various treatments. (E) Survival rate of mice after various treatments of control, US only, Fe-VS₂, and Fe-VS₂ + US during 50 days of treatment.¹²⁶ Reproduced with permission from ref. 126. Copyright 2020 American Chemical Society. (F) Relative tumor growth and (G) average weight of mice in various treatment groups.¹²⁷ Reproduced with permission from ref. 127. Copyright 2018 Wiley-VCH. (H) Cell viability of L929 cells treated with MoS₂ nanoflowers modified with GOx (MPGFs) and MPGGFs for 24 hours or 48 hours, respectively. (I) Cell viability of 4T1 cells for the diverse treatment groups in control, CoCl₂, MPGFs + CoCl₂, MPGFs + CoCl₂ + β-D-glucose, MPGGFs + CoCl₂ + β-D-glucose.¹²⁸ Reproduced with permission from ref. 128. Copyright 2022 Tsinghua University Press.

Lei et al. successfully designed mesoporous silica nanoparticles (MSN) for DOX loading and blocked it with tumor-homing/-penetrating peptide tLyp-1 modified WS₂ quantum dots (WS₂-HP).⁹⁹ With the assistance of tLyP-1. DOX@MSN-WS₂-HP was delivered to the tumor site and released along with two other substances, DOX@MSN-NH₂ and WS₂-HP. DOX was responsible for the surface of tumor cells, while the penetrating WS₂-HP would kill deep cancer cells in the presence of the NIR laser. In brief, the DOX@MSN-WS₂-HP nanoplatform with synergistic effects of chemotherapy and PTT was a prospective candidate for anti-tumor therapy (Fig. 17B and C).

In another study, Lei et al. proposed a multifunctional therapeutic agent for synergistic sonodynamic therapy/CDT (SDT/CDT) by doping iron onto vanadium disulfide (VS₂) nanosheets with PEG modification (Fe-VS₂-PEG).¹²⁶ SDT always uses ultrasound and sonosensitizers to treat local tumors, whereas CDT depends on ˙OH produced by the Fenton reaction, which can achieve tumor-specific treatment. During the experiments, the Fe within the composite was found to be capable of extending the electron–hole recombination time and reducing the bandgap to enhance the SDT effect. Additionally, Fe-VS₂-PEG could trigger the Fenton reaction under H₂O₂ conditions to produce ˙OH (Fig. 17D) for CDT and consume glutathione (GSH), further enhancing the synergistic anti-cancer effect. In general, Fe-VS₂-PEG exhibited excellent cancer cell killing ability and low toxicity (Fig. 17E).

Beyond that, Yang et al. obtained WS₂-iron oxide/SiO₂@MnO₂-PEG (WS₂-IO/S@MO-PEG) nanoparticles by adsorbing iron oxide nanoparticles (IONP) onto the surface of WS₂ and coating them with SiO₂ together with MnO₂ for synergistic PTT/radiotherapy (PTT/RT).¹²⁷ The composite took advantage of the strong NIR absorption ability of WS₂ for PTT, and MnO₂ would accelerate the release of H₂O₂ to alleviate O₂ deficiency and enhance RT. As a result, in 4T1 tumor-bearing mouse models, such nanocomposites caused significant necrosis and apoptosis of tumor cells (Fig. 17F,G) without obvious toxicity.

Except for the aforementioned dual-modality treatments, triple-modality therapies are also widely used against cancer. Dong et al. prepared a WO_2.9-WSe₂ heterostructure (WSP nanoparticles) by selenizing WO_2.9 nanoparticles through a hydrothermal method.¹²⁵ These WSP nanoparticles were applied for PTT owing to their strong NIR absorption ability, high photothermal conversion efficiency, high temperature, and increased oxygen levels resulting from PTT, thereby promoting RT. Subsequently, the combined treatment of PTT/RT was demonstrated to enhance the sensitivity of tumor immune antigens to checkpoint blockade immunotherapy (CBT), which was mainly reflected in the fact that anti-PD-L1 antibodies blocked the combination of programmed death ligand-1 (PD-L1) and programmed death receptor-1 (PD-1) to restore the recognition of the immune system and attack cancer cells (Fig. 17A). In vitro experimental results showed that WSP nanoparticles had the most significant therapeutic effect under X-ray and NIR laser irradiation, with a cancer cell survival rate of only 3.9%. In vivo experiments further confirmed the most significant tumor inhibition effect of WSP nanoparticles under X-ray and NIR, together with primary tumors regressing by more than 90% and distant tumors regressing by more than 80%.

Xie et al. modified MoS₂ nanoflowers with 2-deoxy-D-glucose (2-DG) and glucose oxidase (GOx) to synthesize multifunctional nanocatalysts (MPGGFs) for PTT/CDT/immunotherapy.¹²⁸ Upon delivery to the tumor microenvironment, MPGGFs released GOx to consume glucose and oxygen, producing large amounts of H₂O₂. Then, MPGGFs catalyzed exogenous and endogenous H₂O₂ to generate ROS, leading to cell necrosis. At the same time, MPGGFs also had a high photothermal conversion efficiency, which amplified the CDT effect to a certain extent. Subsequently, CDT/PTT combination therapy-induced tumor cell apoptosis and tumor antigen release, along with specific T cells for immunotherapy. Finally, they further demonstrated the good biocompatibility (Fig. 17H) and anti-tumor effects of the composite (Fig. 17I) using 4T1 cell-bearing mouse models. Generally, MPGGFs exhibited great potential for cancer treatments.

6. Conclusions and outlook

In this review, we briefly introduced TMD-based materials and summarized their categorizations according to their components and structures, as well as preparation strategies of TMD-based composites. The enhanced performance and stability achieved through material modifications have positioned TMD-based composites as focal points for cancer therapy research. These composites have demonstrated significant therapeutic effects and are increasingly being utilized in multimodal therapies to achieve synergistic anti-cancer outcomes. Importantly, TMD-based composites show excellent biocompatibility, as they have a minimal impact on normal cells while targeting tumor cells through endocytosis. Compared to individual TMDs, these composites offer superior stability and therapeutic efficiency.

However, several challenges persist. First, the large-scale synthesis of TMD-based composites remains difficult, requiring advancements in scalable production techniques. Second, the systemic toxicity of these materials is not yet fully understood, raising concerns regarding their safe excretion and metabolism in vivo. Third, phase engineering has shown potential for developing materials with novel properties.^9,129–132 However, its application to TMD-based composites for cancer therapy is still in its infancy, necessitating further investigation. Finally, more in-depth studies are needed to unravel the mechanisms by which these composites interact with biological systems, thereby enabling the design of more effective therapeutic strategies. Addressing these issues is essential for transitioning TMD-based composites from laboratory research to clinical application.

In conclusion, TMD-based composites represent an exciting frontier in biomedical research. Their versatility and effectiveness in cancer therapy highlight their potential to drive advancements in cancer treatment strategies. Moving forward, combining TMDs with other materials to create more efficient composites will be the key to broadening their applications in cancer and other biomedical fields.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the Key Grant for Special Professors in Jiangsu Province (RK119STP23002), the Natural Science Research Start-up Foundation of Recruiting Talents of Nanjing University of Posts and Telecommunications (NY223016), the Project of State Key Laboratory of Organic Electronics and Information Displays, Nanjing University of Posts and Telecommunication (ZS030ZR24004 and ZS030ZR23034), 2024 Nanjing Science and Technology Innovation Program (NJKCZYZZ2024-06), and the Belt and Road “Innovation Cooperation Project of Jiangsu” (BZ2022011).

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