Two-dimensional photonic MXene nanomedicine

2.1.1 Selective etching strategies

The selective etching strategies, including direct hydrofluoric acid (HF) etching, HF-forming etching, HF-containing etching, molten-slats etching, and alkali etching, play a critical role in acquiring single- or few-layer MXenes from MAX phases. Starting from the etching of the Ti₃AlC₂ MAX phase to obtain Ti₃C₂ MXenes [54], HF etching is widely used as a convenient and effective method for the etching MAX phase bulks. It is well-known that the preparation of a large number of MXenes requires the participation of the HF etching process, such as Ti₂CT _x , Ta₄C₃T _x , Nb₂CT _x , V₂CT _x , Nb₄C₃T _x , Mo₂CT _x , Zr₃C₂T _x , Hf₃C₂T _x [61], etc. HF etching not only etches the MAX phase effectively and selectively but also endows MXenes materials with an accordion-like morphology. Specifically, different MAX phases need the distinct etching conditions. For example, it takes more than three days to obtain Nb₂C MXenes by immersing the Nb₂AlC MAX phase into a 50 wt% HF solution at room temperature [62], whereas the complete etching of Ti₃AlC₂ MAX phase needs only about one day in a 5 wt% HF solution [63]. In addition, the etching conditions are related to the strength of the A-bond. In general, it is easier to obtain MXenes from MAX phases that are attached to relatively weak ionic bonds via Al, Si, or Ga [64]. Furthermore, diverse HF concentrations can yield MXenes with different surface terminations (e.g., –O, –OH, and/or –F) and distinguishable defects density. A lower concentration of HF solution generally results in the acquisition of MXenes with more –O and less –F terminations, whereas a higher concentration of HF solution provides MXenes with stronger interlayer interactions and more defects. Besides, both mono-metal or double-metal MXenes (e.g. Cr₂TiC₂T _x , Mo₂Ti₂C₃T _x , and Mo₂TiC₂T _x ) have been successfully synthesized in a varied concentrations of HF solution by etching their MAX phase bulks [65]. It can be concluded that selection of suitable etching conditions signifies the pivotal role of obtaining MXenes materials with high yield and purity features.

Considering that a trace amount of HF is harmful to biological organisms, a series of alternative approaches have been exploited and developed to avoid HF-related security issues. For instance, in 2014, Ghidiu et al. figured out a milder selective etching strategy to fabricate MXenes by mixing Ti₃AlC₂ powders, fluoride salts (e.g., NaF, KF, LiF, and CsF) with HCl or H₂SO₄ [66]. Subsequently, Lipatov et al. improved the selectively etching method by changing the molar ratio of LiF to MAX and the concentration of HCl, aiming to produce high-quality monolayer MXenes with high O/F ratio, few defects, low resistivity, and excellent environmental stability. It is worth mentioning that the synthetic MXenes materials could remain stable after being exposed to air for even 70 h [67]. Intriguingly, Halim et al. successfully prepared MXenes with hydrogen ammonium bifluoride ((NH₄HF₂) instead of LiF [68], further broadening the variety of fluorine-based etchants.

Despite different strategies had been developed and proposed to avoid or reduce the utilization of HF, there are still inevitable problems regarding safety and environmental pollution. In view of this situation, Li et al. demonstrated that a fluorine-free strategy, namely the alkali etching strategy, is capable of obtaining MXenes from MAX phase bulks [69]. In this procedure, the typical Ti₃C₂T _x (T = –OH, –O) was synthesized at 270 °C in a 27.5 M NaOH solution with 92 wt% purity [69]. The temperature and NaOH concentration are two important factors in this reaction, in which the temperature control determines the successful production of Ti₃C₂T _x , while the NaOH concentration is closely related to the purity of the product. In addition, Li et al. prepared various MXenes through etching MAX-phase precursors with a elements (Si, Zn, and Ga) by Lewis acidic molten salts (e.g., CuCl₂, NiCl₂, AgCl, FeCl₂, CdCl_2, and CoCl₂) [70]. This generic selective etching strategy based on Lewis acidic molten salts enlarges the range of MAX phases and the potential properties of MXenes via tailoring the surface chemistry.

2.1.2 Delamination strategies

Weakening the interaction force between the adjacent layers plays a crucial role of the delamination of MXenes since multilayer MXenes synthesized by selective etching are held together by van der Waals interactions and/or hydrogen bonding. It is well-known that intercalating large organic molecules or ions, shanking, and/or sonication are effective approaches to obtain single- or few-layer MXenes [71]. Moreover, the delamination route depends on etching conditions. Spontaneous intercalation of cations (e.g., Li⁺, Na⁺, K⁺, Mg²⁺, and NH₄ ⁺) was used to intercalate into the multilayered MXenes because the van der Waals force can be weakened by the subsequent negative surface charges of MXenes [72]. Apart from this, Ghidiu et al. made the Li⁺ ions intercalate between the adjacent MXenes sheets through the HCl/LiF approach and utilized simple shaking or sonication to facilitate the exfoliation process [66]. It is vital to note that the successful delamination of MXenes via HF etching strategy can only intercalate ions or organic molecules among the layers. Otherwise, the chemical compositions are related to the delamination strategy as well. For instance, when the exfoliation process of Ti₃C₂ [73] and (Mo_2/3Ti_1/3)₃C₂ [65] MXenes is insensitive for etching reagent with different compositions, it was reported that dimethyl sulfoxide could be employed instead.

2.3.1 Non-covalent strategies

In general, MXenes that have been synthesized in the past typically perform poorly in terms of stability and dispersibility in physiological solutions. MXenes must undergo the proper surface modification, such as non-covalent interaction, in order to be feasibly used in biomedicine. Some natural molecules, for instance, soybean phospholipid (SP) with the features of sufficient surface area and favorable biodegradability could modify MXenes by means of physical absorption. According to these characteristics, our team created a Ti₃C₂-SP nanosystem for intravenous injection that has sufficient stability, permeability, and biocompatibility in order to increase the effectiveness of tumor-thermal therapy [35]. Electrostatic attraction, in addition to physical absorption, is a successful tactic for non-covalent interactions, because the negative charge on MXenes’ surface makes it simple for positively charged molecules to adhere. Both polyethylene glycol (PEG)-modified Ti₃C₂ MXene [82] and polyvinylpyrrolidone (PVP)-modified Nb₂C MXene [37] exhibited exceptional stability under different physiological conditions. Moreover, it turns out that polyethyleneimine (PEI) [83] and poly (dopamine) (PDA) [84] also show satisfactory results in inhibiting the aggregation and deposition of MXenes nanosheets.

2.3.2 Covalent modifications

In addition to non-covalent methods, covalent modification is a prominent way to improve the biocompatibility of MXenes. In the past few years, self-initiated photographing-photopolymerization (SIPGP) has been demonstrated to effectively modify the surface of miscellaneous materials (e.g., graphene, diamond, carbon nanotubes, and silicon-based materials) [85–87]. Intriguingly, SIPGP can be branched straightly to the surface of materials under ultraviolet (UV) irradiation at room temperature, while other polymerization methods require catalysts, ligands, and other reaction conditions. In 2015, Chen et al. synthesized MXenes with dual response properties of CO₂ and temperature via grafting poly (2-(dimethylamino) ethyl methacrylate) (PDMAEMA) on the surface of V₂C MXene through SIPGP, opening the door for their use in biological applications [88]. Additionally, there seems to be a consensus on the ability of aryl diazonium to construct covalent bonds on the surface of various materials such as metal nanoparticles, metal oxides, carbon materials, and semiconductors [89, 90]. Wang et al. utilized the aryl diazonium salt to modify the surface of as-prepared Ti₃C₂ MXene nanosheets by forming powerful Ti–O–C bonds [91]. These nanosheets are improved in terms of dispersion, stability, and specific surface area through this method. Moreover, this modification method allows for the covalent modification of additional functional molecules on the surface of MXenes by employing aryl diazo ions as surface modifiers and inserters, thus opening up a wide range of potential applications for 2D materials. However, to our knowledge, the use of aryl diazo to functionalize the surfaces of MXene-related biomaterials is still in its early stages of development.

3.2.1 PA imaging

PA imaging, as one of the emerging imaging techniques, is a specific biomedical imaging modality that has been used in disease monitoring, drug delivery, and surgical guidance [105]. As a rapidly developing technology with high contrast and large penetration depth, it combines the outstanding contrast of optical biomedical imaging with the extremely deep tissue penetration capability of ultrasound imaging, overcoming the shortcomings of conventional optical imaging to produce label- and speckle-free images, especially in deep biological tissues [106]. PA imaging contrast agents (CAs) with outstanding photothermal conversion are indispensable for obtaining significant PA signals, therefore, further studies of CAs are needed to improve the resolution and sensitivity of this technique. In general, MXenes nanosheets exhibit a semi-metallic-like energy band structure that readily induces the LSPR effect, enabling them to exhibit excellent absorption properties and high conversion efficiency under broad spectra light irradiation [35]. Consequently, MXenes including Ti₃C₂ and Ta₄C₃ could serve as effective CAs for PA imaging [24, 25]. Especially, deep-tissue PA imaging is particularly feasible with MXenes because of their wide and dense NIR absorption spectra.

So far, several kinds of MXenes including Ti₃C₂, Ta₄C₃, Ti₃N, V₂C, and Nb₂C have been applied for in vitro and in vivo PA imaging under the NIR laser irradiation [100]. On top of that, we have fabricated the MnO _x /Ta₄C₃ composite nanosheets, which can achieve multiple imaging-guided photothermal tumor ablation and tumor growth inhibition [24]. Furthermore, Tang et al. constructed Ti₃C₂@Au nanocomposites with remarkable photothermal conversion, as shown in Figure 5A, which showed stronger photoacoustic signals than the same concentration of Ti₃C₂ alone for imaging and quantitative measurements from 680 to 970 nm [47]. More recently, Shao et al. have prepared Ti₂N QDs with a diameter of about 5 nm that exhibit high photothermal conversion efficiency in both NIR-I and NIR-II laser excitation (Figure 5B–D) [26]. As a result of the characteristic enhanced permeability and retention (EPR) effect, Ti₂N QDs quickly accumulated, which quickly increased the PA signal in the tumor tissue following the initial phase of circulatory delivery (Figure 5E and F).

Figure 5:

PA imaging of MXene. (A) Schematic diagram of Ti₃C₂@Au synthesis and PA/CT dual-modality imaging-guided treatment [47]. Copyright 2019, American Chemical Society. (B) Schematic diagram of Ti₂N QDs synthesis and the role of PTT guided by PA imaging in NIR-I/II biological windows. (C) PA signals of Ti₂N QDs in NIR-I/II regions by taking different samples (water, skin, tissue, and blood of mice) as the control group. (D) In vitro PA images of Ti₂N QDs at various concentrations (from 0 to 500 ppm) irradiated by 808 and 1280 nm laser. (E–F) In vitro PA images in tumor tissue after intravenous injection [26]. Copyright 2020, Elsevier.

It is noted that the development of MXenes for PA imaging is encouraged by their superior optical qualities, distinctive biological characteristics, and top performance even if the use of MXenes in PA imaging is still in the research stage.

3.2.2 Fluorescent imaging

Fluorescence imaging is frequently employed in biomedical research due to its excellent imaging sensitivity and straightforward operation. In the past few years, 2D biomaterials and their corresponding quantum dots (QDs) possessing tunable wavelength, high photostability, and desirable quantum yields have attracted considerable attention in fluorescence imaging [52]. As demonstrated by Xue et al., Ti₃C₂ QDs with defect-induced luminescence and size-effect induction formed by hydrothermal fracture can be effectively used for cellular fluorescence imaging [27] (Figure 6A). Similarly, other MXene QDs including Nb₂C [30, 31] and V₂C [107] can also serve as imaging contrast agents for bioimaging.

Figure 6:

Fluorescence imaging of MXene. (A) Diagram of the preparation of Ti₃C₂ QDs [27]. Copyright 2017, Wiley-VCH. (B–C) PL emission spectra (B) of Nb₂C QDs and normalized PL intensity (C) corresponding to three aqueous solutions (Nb₂C QDs, FITC, and RhB) at different durations of irradiation with a 350 W xenon lamp. (D–E) UV spectra (D) and PL emission spectra (E) of Nb₂C QDs after different degradation treatments [30]. Copyright 2018, Elsevier.

As previously mentioned, Xue et al. fabricated Ti₃C₂ MXene QDs by a simple hydrothermal method and successfully tailored their size by adjusting the reaction temperature [29]. They found that the MXenes are capable of readily entering cells for in vitro bioimaging by endocytosis without causing genetic damage. Wang et al. created the Ti₃C₂ QDs by simultaneously stacking cleavage and layer cutting in tetramethylammonium hydroxide [28]. The resulting monolayer Ti₃C₂ QDs exhibit distinct and tunable fluorescence with powerful photoluminescence and excitation-dependent behavior. Importantly, the authors suggested that additional ultra-small MXene nanosheets, such Nb₂C or Ti₂C, can also be obtained using this all-encompassing and gentle method, which broadens the use of MXene materials in optical-related domains. Except for Ti₃C₂ QDs, Yang et al. have effectively employed Nb₂C QDs for fluorescence sensing and fluorescent imaging of heavy metal ions. They successfully produced Nb₂C QDs with high photostability, biodegradability, and strong resistance to photobleaching (Figure 6B and C) [30]. Nb₂C QDs can be degraded by human myeloperoxidase (hMPO) (Figure 6D and E). As another example, Yan et al. have prepared nitrogen and sulfur co-doped Nb₂C MXene QDs with significant green fluorescence through the hydrothermal method [31]. The obtained Nb₂C MXene QDs possessed the characteristics of anti-photobleaching, high dispersion stability, and photostability, which led to their successful application in copper ion detection with a detection limit of 2 μmol/L and Caco-2 cell imaging.

3.2.3 Multiple bio-imaging

Generally speaking, the MXene family with high atomic number metallic elements, such as tantalum (Ta) (Z = 73) and tungsten (W) (Z = 74), is a promising candidate contrast agent for CT imaging with exceptional X-ray attenuation. For instance, our group has successfully synthesized 2D ultrathin Ta₄C₃ MXene nanosheets with SP modification through HF etching and probe sonication, and they are successfully applied in dual-mode PA/CT imaging for the first time by taking advantage of their strong X-ray attenuation ability and high NIR optical absorbance (Figure 7) [32]. More importantly, greater Ta concentrations resulted in a higher Hounsfield unit (HU) value for Ta₄C₃ MXene nanosheets than the clinically utilized iopromide. As another paradigm, our group reported W_1.33C-based i-MXene nanosheets with ordered exfoliation via selective etching of Al and yttrium (Y) elements [33]. Thanks to the strong X-ray attenuation capability of W, the outstanding absorbance of the NIR region, and the excellent photothermal conversion capability, the CT/PA/photothermal tri-mode imaging is successfully achieved. Similarly, experimental results showed that both PA image signals and the HU values of CT images increased linearly with increasing W_1.33C MXene concentration. The photoacoustic signal intensity was 10 times greater after the medicine was injected intravenously for 4 h, and the CT signal intensity of the tumor tissue was dramatically improved from 37.5 to 98.2 HU.

Figure 7:

Multiple imaging capabilities of MXene. (A) Schematic representation of Ta₄C₃ nanosheet synthesis and in vivo PA/CT dual-mode imaging-guided photothermal tumor ablation. (B) PA images of tumor tissues after 0, 0.5, 1, 2, 4, 12, 24 and 48 h injections. (C) Schematic illustration of Ta₄C₃-SP enabling in vivo CT imaging. (D) In vivo 3D reconstructed CT (left) and CT comparison (right) images of mice before and after 24 h intravenous injection [33]. Copyright 2018, Wiley-VCH.

Except for CT-related photonic imaging, Cao and co-workers fabricated V₂C QDs with significant MR imaging capability packed with RGD modification [34]. The as-prepared nanocomplexes had multimodal imaging capabilities including PAI, fluorescence imaging, and MR imaging (Figure 8). In addition, the V₂C-TAT@Ex-RGD also exhibited good biocompatibility, long cycle time, and endosome escape capability. Furthermore, MnO _x /Ta₄C₃ and MnO _x /Ti₃C₂ nanocomposites with multimodal imaging properties have been constructed by inducing redox reactions between oxidized MnO _x and the surface groups of MXenes [24, 25]. MnO _x /Ti₃C₂ composite MXenes have a strong photothermal conversion, which makes them desirable for PA imaging. Mn, a regularly utilized paramagnetic agent, is also present in these materials, which allows them to accomplish T₁-weighted MR imaging. With regard to MnO _x /Ta₄C₃ composite nanosheets, PA, CT, and MR tri-mode imaging are made possible by their excellent photothermal conversion performance, potent X-ray attenuation ability of Ta, and T₁-weighted MRI capability of integrated Mn.

Figure 8:

Multiple imaging capabilities of MXene. (A) Scheme of the synthesis and surface modification of V₂C-TAT@Ex-RGD and multimodal imaging in NIR-II biological window combined with low-temperature PTT. (B) In vivo PA images of mice at different times after i. v. injection of V₂C-TAT@Ex-RGD (V₂C-TAT, 10 mg/kg). (C) MR images of mice after intravenous injection of PBS (left) and V₂C-TAT@Ex-RGD (right) [34]. Copyright 2019, American Chemical Society.

3.3.1 Photodynamic therapy (PDT)

PDT is a technique in which localized tumor tissue is exposed to particular light wavelengths to activate multifunctional photosensitizers that release ROS to kill cancer cells [108]. PDT provides some noteworthy advantages over traditional tumor therapy methods, such as weak aggressiveness, non-toxic reproducibility, low side effects, remarkable treatment effects, and low long-term morbidity. Basically, PDT uses light with specific wavelengths to activate multifunctional photosensitizers that aggregate at the tumor site, and the activated photosensitizers transfers energy to surrounding oxygen molecules, leading to the production of ROS and oxygen reduction, thereby oxidizing the biomolecules that cause cancer cell death [108, 109]. Owing to the distinctive optoelectronic properties and electronic structure of MXene, it is suggested by theoretical studies that MXene itself can be employed as a photosensitizer for PDT [39].

In 2017, the Ti₃C₂ MXene was firstly demonstrated to produce ROS upon irradiation with specific light wavelengths, implying its great possibility as a photosensitizer for PDT [44]. Experiments showed that this multifunctional Ti₃C₂ MXene nanoplatform modified by doxorubicin (DOX) and hyaluronic acid (HA) exhibits excellent photothermal conversion and sufficient ¹O₂ generation under 808 nm laser irradiation. It has been found that using 1,3-diphenylisobenzofuran (DBPF) as an oxygen detector, the absorption peak of DPBF at 420 nm decreased significantly after 10 min of laser irradiation, indicating a significant amount of ROS production. This might be a result of the LSPR effect brought on by its large specific surface area and the photoexcited electron transfer effect. Subsequently, Zhang et al. constructed Mo₂C nanospheres with negligible blood and tissue toxicity and excellent biocompatibility for cancer therapy [43]. Similarly, the absorption peak of DPBF in aqueous solution decreased after laser irradiation, confirming the generation of ROS. Due to the disappointing results of single-modality therapy, PDT is less frequently used alone to treat tumors; instead, it is frequently used in conjunction with chemotherapy and PTT for photonic theranostics.

3.3.2 Photothermal therapy (PTT)

PTT is a strategy of converting photonic energy into thermal energy enabled by the photothermal transduction agents at the tumor site, thus producing heat to cause cell death. Since the original discovery of PTT, it has received significant interest because of its ease of surgery, short treatment time, low invasiveness, few side effects, and low recurrence rate [92]. Therefore, PTT can be a distinct alternative or complementary approach to conventional cancer treatments.

Generally, the photothermal agent and external light are the two key contributors to the PTT effect. For photothermal agents, the light absorption capacity, revealed by the extinction coefficient (ε), and the photothermal conversion efficiency (η), which measures their capability to convert light into heat, are two crucial characteristics that mainly affect their PTT results [35]. Typical 2D MXenes, including Ti₃C₂ [35], Ta₄C₃ [32], Nb₂C [37], Mo₂C [40], V₂C [49], and Ti₂C [42], have been shown to feature remarkable photothermal properties and are frequently utilized in PTT in vivo and in vitro.

In 2016, our team synthesized the SP-modified Ti₃C₂ MXene nanosheets by a classical two-step exfoliation strategy that involved HF etching and TPAOH intercalation for the first time (Figure 9) [35]. The biosafe Ti₃C₂ exhibited photothermal conversion of up to 30.6% when exposed to a NIR laser irradiation (808 nm), which was significantly better than the majority of currently available photothermal materials like gold nanorods (21%) [110], FeS nanosheets (15.5%) [111] and Bi₂S₃ nanosheets (20.5%) [112]. Subsequently, we synthesized SP-modified MnO _x /Ti₃C₂ nanocomposites through in situ growth for PTT against cancer [25]. The results showed that the tumor temperature in the MnO _x /Ti₃C₂-SP NIR group increased from about 25 °C to 60 °C at 10 min of laser irradiation, which could entirely lead to the destruction of cancer cells. In addition, our team constructed superparamagnetic 2D Ti₃C₂ MXenes with high photothermal conversion efficiency (48.6%), which ensured effective photothermal killing of cancer cells and ablation of tumor tissue as demonstrated by in vitro and in vivo experiments (Figure 10A) [113]. The experimental results demonstrated the high biocompatibility of the magnetic Ti₃C₂-IONPs MXene composites as manufactured indicating their potential for further clinical applications.

Figure 9:

MXene for PTT. (A) Schematic representation of treatment with intravenous injection of Ti₃C₂-SP and intratumoral injection of PLGA/Ti₃C₂ implants under NIR laser irradiation. (B) Schematic illustration of the synthesis process of Ti₃C₂ nanosheet. (C) H&E staining of major organs (heart, liver, spleen, lung and kidney) in the control group and three treatment groups with different Ti₃C₂-SP doses (5, 10, and 20 mg/kg, respectively) [35]. Copyright 2017, American Chemical Society.

Figure 10:

MXene for PTT. (A) Schematic representation of the exfoliation and surface modification process of magnetic 2D Ti₃C₂-IONPs-SPs nanosheet and its PTT under T₂-weighted MRI guidance [113]. Copyright 2019 The Royal Society of chemistry. (B) Schematic representation of the synthesis process of Nb₂C and in vivo PTT in NIR-I and NIR-II biological windows [37]. Copyright 2017 American Chemical Society. (C) Schematic representation of the preparation of Mo₂C MXenes [40]. Copyright 2018 John Wiley and Sons.

As a PTT agent with high photothermal conversion efficiency, Ta₄C₃ has made fast progress in tumor therapy. The 2D SP-modified Ta₄C₃ nanosheets with 44.7% photothermal conversion efficiency exhibited high in vivo photothermal ablation of tumor xenografts [32], which were synthesized by two-step liquid phase stripping. More importantly, both in vitro cellular and in vivo mouse experiments demonstrated that the SP-modified Ta₄C₃ nanosheets have no discernible toxicity. On this basis, we applied MnO _x /Ta₄C₃ composite nanosheets (η = 34.9%) fabricated by activating redox reactions on the surface of Ta₄C₃ for multi-target photothermal tumor ablation [24]. Under 808 nm laser irradiation, the MnO _x /Ta₄C₃ exhibited concentration/laser power-dependent photothermal properties and significantly inhibited tumor growth. Additionally, our group reported the Ta₄C₃ nanosheets (η = 32.5%) modified with Fe₃O₄ nanoparticles (IONPs) and SP applied for multiple imaging-guided tumor therapy [36]. Experimental results showed that Ta₄C₃-IONP-SPs composite nanosheets completely eradicate tumors without recurrence, which further broadens the biomedical applications of MXene nanoplatform.

Since the original discovery of Nb₂C, surface engineering has played an important factor in determining how it is used in the biological field. Nb₂C nanosheets prepared by a two-part liquid exfoliation method showed high photothermal performance in the first and second biological windows with photothermal conversion efficiencies of 36.4 and 45.65%, respectively [37]. PVP-modified Nb₂C was capable of effective in vivo photothermal ablation of tumor xenografts in the first and second biological windows, as shown by both in vitro cellular investigations and in vivo experiments. It also exhibited high biocompatibility and minimal toxicity (Figure 10B). Moreover, our team created a “therapeutic mesoporous” layer on the surface of 2D Nb₂C MXenes using multifunctional sol–gel chemistry [38]. Nb₂C MXenes exhibited a photothermal conversion capacity of 28.6% in the NIR-II biological window and performed strong inhibitory effects on both U87 brain cancer cells and subcutaneous tumors in nude mice.

More recently, we reported the construction of emerging PVA-modified 2D Mo₂C MXene (Figure 10C) [40]. The Mo₂C-PVA nanosheets had a wide absorption band of NIR in both I and II regions, as well as a desirable photothermal conversion efficiency (24.5% for NIR I and 43.3% for NIR-II), which could allow for effective photothermal tumor ablation. In addition, Zhang and his co-worker prepared 50 nm Mo₂C nanospheres with excellent biocompatibility and minimal toxicity for both tumor treatment and imaging [43]. The photothermal conversion efficiency of 24.95% indicated the significant photothermal tumor ablation effect of Mo₂C MXene.

Two other MXene materials, V₂C and Ti₂C, are thought to be viable photothermal agents for PTT to treat cancer because of their high photothermal conversion efficiency. Zada et al. constructed V₂C nanosheets using the algae extraction method for the insertion and stacking of the V₂AlC MAX phase bulks (Figure 11A–D) [49]. The photothermal conversion efficiency of this material was 48%, which is on par with other top photothermal agents including carbon-based materials and gold-based nanostructures. This work not only demonstrated the strong tumor ablation ability of V₂C nanosheets but also provided an efficient, productive, and environmentally friendly method of disintegrating MAX, exploiting a new avenue for developing MXene with anticipated properties. Szuplewska’s group elaborated on the usage of PEG-coated Ti₂C sheets as an emerging, effective, and selective photothermal agent, with a photothermal conversion efficiency of 87.1% under 808 nm laser irradiation [42]. It was discovered that PEG-modified Ti₂C flakes had a negligible effect on healthy cells and tissues and may efficiently induce cancer cell ablation at a dose 24 times lower than other MXene photothermal treatments.

Figure 11:

MXene for PTT. (A) Schematic diagram of the synthesis of V₂C nanosheets by algae extraction and their application in tumor ablation. (B) Cytotoxicity analysis of MTT after control (PBS pH 7.4), algae extraction, and V₂C treatment. MTT (C) and Calcein AM/PI double staining (D) cell viability analysis after different treatments (control, laser only, V₂C only, and V₂C + laser) [49]. Copyright 2020, Wiley-VCH. (E) Schematic diagram of the Mo₂C nanosphere-mediated tumor treatment protocol [43]. Copyright 2019, The Royal Society of Chemistry. (F) Schematic illustration of the synthesis process of Ti₃C₂ nanosheet and multimodal tumor therapy [44]. Copyright 2017, American Chemical Society.

Apart from MXene flakes, MXene QDs have garnered considerable attention from researchers on account of their intriguing physicochemical properties, such as improved dispersion, photoluminescence, and ease of modification or doping [114]. Tetrabutylammonium hydroxide (TBAOH, (C₄H₉)₄NOH) was used as an etchant by Yu’s team to create F-free Ti₃C₂ QDs with excellent biocompatibility and high PTT effectiveness against cancer [41]. They adopted the F-free method to modify a large number of alumina anions on the surface of MXene QDs, resulting in a strong and widespread NIR absorption. The photothermal conversion efficiency of Ti₃C₂ MXene QDs as prepared was found to be as high as 52.2%. Cao et al. constructed 2D V₂C-QDs and loaded them into engineered arginine-glycine-aspartate exosomes after surface modification with cell nucleus-target TAT peptides (V₂C-TAT) [34]. In this way, they were able to acquire the dual-targeting diagnostic and therapeutic vector V₂C-TAT@Ex-RGD that targets the tumor cell membrane and nucleus. In vivo and in vitro studies had shown that V₂C-TAT@Ex-RGD almost completely killed tumors under laser irradiation in the NIR-II region. This nucleus-target low-temperature PTT approach in the NIR-II region had the benefit of adequate penetration depth and few side effects.

3.3.3 Synergistic photonic therapy

The variety, heterogeneity, and complexity of malignancies make single-modality therapeutic approaches frequently ineffective. Researchers have shown a great deal of interest in a synergistic treatment that combines two or more therapeutic techniques in order to increase the effectiveness of cancer treatment, decrease medication toxicity, and inhibit multidrug resistance. As an important component of phototherapy, photoactive substances are usually used for the single purpose of producing ROS as photosensitizers or generating heat as photothermal agents. MXenes have the potential to develop into multifunctional nanomaterials with photothermal effects and ROS generation properties under NIR radiation as a result of their distinctive features.

As previously described, the PEG-modified Ti₂C with photothermal transition properties was able to selectively ablate cancer cells [42]. This phenomenon may be caused by the production of ROS in tumor cells triggered by MXenes, which exactly demonstrated the synergistic effect of PTT/PDT. Furthermore, Mo₂C nanospheres can trigger both thermal therapy and ROS generation during NIR irradiation, which results in synergistic PTT and PDT (Figure 11E) [43]. Results from cellular experiments showed that PDT/PTT was more effective in killing tumor cells than either PDT or PTT. Furthermore, by surface modifying Ti₃C₂ nanosheets with DOX and HA, Liu’s team constructed a multifunctional nanoplatform that enables PDT/PTT/chemotherapy [44]. The as-prepared Ti₃C₂-DOX proved effective in killing tumor cells and tissues due to its stimulated responsive drug release, tumor-specific accumulation, and excellent biocompatibility (Figure 11F). Additionally, Bai’s team established Ti₃C₂@Met@CP, a nanoconforming drug delivery system capable of PTT/PDT/chemotherapy, by layer-by-layer adsorbing metformin (Met) and complex polysaccharides (CP) on the surface of Ti₃C₂ nanosheets [45]. In addition to its high photothermal conversion efficiency (59.6%) and efficient ROS producer, the CP contained in this composite nanosheet system was also a novel immunomodulator that can restrain tumor recurrence and metastasis by triggering the immune system. More recently, Ti₃C₂ nanosheets modified by IR780 were used to achieve synergistic treatment of laryngeal cancer with PTT and PDT, which has an excellent ability to generate ROS and disrupt mitochondrial function, according to data from both electron spin resonance and molecular biology results [46]. After 21 days of treatment, the experimental group showed an 88.1% reduction in tumor microvessel distribution and a 92% suppression of tumor growth compared to the control group.