1. Introduction

Cancer remains a major threat to human health in the 21st century. Fortunately, a multitude of cancer treatment strategies are clinically accessible, including chemotherapy and radiotherapy. Nevertheless, conventional treatment approaches frequently result in acute adverse effects on normal tissues, imposing additional suffering on patients. Moreover, these methods typically trigger the development of drug resistance in cancer cells, giving rise to tumor cell deterioration, recurrence, and metastasis. One major cause of drug resistance is the development of genetic mutations in cancer cells. These mutations can affect genes that are targeted by drugs, such as enzymes or receptors that control cell growth or survival. Also, changes in genes that repair DNA damage can make cancer cells better at fixing drug-induced damage, allowing them to survive and grow even with drug treatment. Furthermore, mutations in genes related to cell death pathways can render cancer cells resistant to drug-induced apoptosis, thereby promoting their survival^[1]. Consequently, there is a pressing requirement for novel therapeutic modalities to address cancer and mitigate these side effects.

In the past few decades, photodynamic therapy (PDT) and photothermal therapy (PTT) have emerged as novel cancer treatment methods^[2,3]. PDT relies on the combined effects of excitation light, photosensitizer (PS), and molecular oxygen^[3]. Photosensitizers are photosensitized to decompose H₂O/O₂ in tissues, generating reactive oxygen species (ROS) to damage tumor cells^[4]. Unlike PDT, the main mechanism of PTT is that photothermal agents absorb near-infrared (NIR) light and convert it into heat energy (raising the local temperature of tumors to 40-45 ℃) to kill tumor cells^[3]. In fact, TiO₂ nanoparticles (NPs) simultaneously possess PDT and PTT effects and can be potentially used for cancer treatment.

Recently, titanium dioxide (TiO₂), one of the most vital and classical metal oxides, has been thoroughly investigated and extensively used in many fields of science and technology owing to its outstanding photoactivity^[5]. Notably, with high absorption in the ultraviolet (UV) light region, TiO₂ can act not only as a PS to generate cytotoxic ROS, but also as a photothermal agent (PTA) to convert light energy into hyperthermia^[6]. However, the relatively wide energy band gap of TiO₂ enables it to absorb energy only in the ultraviolet light region. In practical applications, it still has limitations such as insufficient utilization of visible light and low quantum efficiency^[7]. In 2011, Chen et al. constructed a disordered structure on the surface of the TiO₂ lattice through a hydrogenation method and successfully prepared black TiO₂ nanomaterials for the first time (Figure 1a). The band gap is significantly reduced (Figure 1b), which enhanced the visible-light response performance and quantum efficiency of the materials. In PDT/PTT, “high UV absorption” underpins the UV-driven PDT performance of conventional TiO₂, and yet UV suffers from poor tissue penetration. The primary merit of black TiO₂ is that it preserves this feature while extending spectral absorption into the NIR region, thus achieving efficient therapy by utilizing the superior tissue penetration of NIR. Since then, a research upsurge on black TiO₂ nanomaterials has been sparked^[7].

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Figure 1. (a) Photographs of white TiO₂ and black TiO₂ (B-TiO₂); (b) Comparison of the band structures and band gaps of black TiO₂ and white TiO₂^[8]. TiO₂: Titanium dioxide.

Numerous studies have been conducted on the use of black TiO₂ in cancer treatment. Therefore, a comprehensive review is required to systematically summarize its applications in PDT, PTT, and their combined treatment strategies with other methods. This review first introduces the characteristics and preparation of black TiO₂. It then presents the current research on black TiO₂ in PDT and PTT. Finally, it discusses current advances in combined treatment strategies involving black TiO₂ and other methods, and provides a prospect.

2. Characteristics and Preparation of Black TiO₂

2.1 Characteristics of black TiO₂

Similar to TiO₂, black TiO₂ mainly exists in three crystalline structures: rutile^[9], anatase^[10], and brookite^[11]. The rutile phase, belonging to the hexagonal crystal system, is the most stable crystal form of black TiO₂, exhibiting high catalytic activity and stability^[9]. The anatase phase, also a member of the hexagonal crystal system, has a relatively unstable crystal structure yet exhibits a large specific surface area and photocatalytic activity, making it one of the most commonly observed crystal forms of black TiO₂^[10]. The brookite phase of black TiO₂ belongs to the orthorhombic crystal system with relatively low structural stability; however, it features high electron mobility and is often blended with the anatase phase for photocatalytic applications^[11]. Black TiO₂ is similar to titanium dioxide in terms of crystal structure, but differs in composition, optical properties, electronic properties, and surface properties.

Black TiO₂ actively incorporates defects, such as oxygen vacancies and low-valence ions, resulting in marked differences from ordinary TiO₂ in optical, electronic, and surface properties^[12]. In terms of optical properties, the light absorption of ordinary TiO₂ is limited to the ultraviolet region, while black TiO₂, through defect engineering, enables efficient absorption in the near-infrared region. Regarding electronic properties, the energy band structure of ordinary TiO₂ is fixed. However, the intrinsic defects in black TiO₂ reduce the band gap from 3.2 eV to approximately 1.5 eV, extending the photoresponse to the near-infrared region. Meanwhile, a core-shell structure with a disordered surface and an ordered interior is formed, and oxygen vacancies are introduced simultaneously^[7].

In terms of surface properties, ordinary TiO₂ has a regular surface with relatively low reactivity. The defects in black TiO₂ decrease the adsorption energy an activation energy of reactants. Moreover, broadening the light response range improves the efficiency of active sites. For instance, low-valence ions and oxygen vacancies can trap photogenerated charge carriers, enhance the separation of photogenerated electrons (e^-) and holes (h⁺), and thus achieve efficient catalytic activity under visible or near-infrared light^[13].

2.2 Preparation of black TiO₂

Currently, the methods for preparing black TiO₂ are mainly classified into atmosphere roasting method^[14], metal reduction method^[13], chemical reduction method^[15], femtosecond pulse method^[15], and sol-gel method^[16]. The preparation methods and synthesis conditions can induce changes in physical and chemical properties of black TiO₂, including morphology, structure, optical properties, and electrical properties, which are summarized in Table 1.

2.2.1 Atmosphere roasting method

The atmosphere roasting method involves roasting the TiO₂ precursor under specific gas atmospheres (either non-air or air-controlled) and heating conditions to ultimately prepare black TiO₂. The commonly used gases are primarily hydrogen and nitrogen. The hydrogen atmosphere method has the drawbacks of high cost, great safety risks, and limited suitability for large-scale production^[7]. For example, Chen et al.^[7] synthesized black TiO₂ via calcination in a hydrogen atmosphere. The high-temperature, high-pressure conditions and H₂ environment induce lattice disorder on the surface of white TiO₂, leading to the formation of a core-shell structure with a crystalline core and an amorphous shell. This structural transformation alters the band gap width of TiO₂, reducing it to an initial absorption band gap of 1.0 eV, while hydrogen further stabilizes the lattice disorder by passivating dangling bonds. Currently, hydrogenation remains the mainstream synthesis method for black TiO₂; however, this method still suffers from the mentioned-above drawbacks.

2.2.2 Metallothermic reduction method

The synthesis of black TiO₂ by the metallothermic reduction method makes use of the strong reducibility of active metals^[20]. Under specific conditions (high temperature and/or an inert atmosphere), an oxidation-reduction reaction occurs between the active metals and the lattice oxygen in TiO₂. By “seizing” the lattice oxygen in TiO₂, a large number of oxygen vacancies and low-valence ion defects are directionally introduced. For example, Song et al.^[13] synthesized black TiO₂ nanostructures with an ultrathin hollow sphere morphology, high crystallization quality, small grain size, and ultra-high surface area through the aluminothermic reduction method. Different from the atmosphere roasting method, the reaction by this method is more intense, making it easier to achieve multi-metal doping during the reduction process. In 2015, Sinhamahapatra et al.^[21] first reported the synthesis of TiO₂ via magnesiothermic reduction in the coexistence of H₂/Ar, followed by acid washing to prepare black TiO₂ nanoparticles. The study indicated that in the high-resolution X-ray photoelectron spectroscopy (XPS) spectra, the peak intensity corresponding to black TiO₂ increased with the increase in the dosage of Mg reductant. Specifically, as the amount of Mg increased, more oxygen vacancies were formed on the surface of black TiO₂, which further enhanced the visible light absorption capacity and photocatalytic activity of the samples. Therefore, the key to this method lies in the reasonable control of the reducing agent quantity during the reaction.

2.2.3 Chemical reduction method

The chemical reduction method involves the use of reductive agents to generate the reductive condition to produce black TiO₂^[22]. Under mild temperature conditions, the oxidation-reduction reaction can occur with TiO₂. By injecting electrons into the TiO₂ lattice, low-valence ion and oxygen vacancies are induced. Jiang et al.^[15] synthesized black TiO₂ with a mesoporous hollow shell structure by the evaporation-induced self-assembly method. In this work, the authors fabricated silica (SiO₂) colloidal particles via a modification experiment. These SiO₂ colloidal particles were repeatedly dispersed and coated onto the surface of TiO₂ followed by high-temperature calcination to prepare SiO₂@TiO₂@SiO₂ core-shell-shell particles. Subsequently, the particles were subjected to NaOH etching and NaBH₄ reduction to obtain mesoporous black TiO₂ hollow spheres. It was found that this unique hollow mesoporous structure endows black TiO₂ with a higher specific surface area and more active reaction sites, significantly enhancing its photocatalytic activity and light absorption capacity. Compared with the metallothermic reduction method, the mild temperature condition results in the limited reducing ability, confining the reduction reaction mostly to the particle surface^[15].

2.2.4 Femtosecond laser pulses

Recent studies have demonstrated that a femtosecond laser filament-based far-field technique can remotely and rapidly fabricate nano/microstructures on crystalline silicon, as well as on irregularly shaped organic and metals surfaces for improved light absorption^[23]. Su et al.^[18] irradiated TiO₂ particle using femtosecond laser pulses, leading to the a large number of oxygen vacancies generated in the particle surface. However, compared with other methods, this method is costly and unsuitable for large-scale production.

2.2.5 Sol-gel method

The sol-gel method uses precursors containing highly chemically active components and hydrolysis (as well as other reactions) in the liquid phase to form a stable sol system^[19]. After aging, the colloidal particles slowly polymerize and transform into a gel state with a three-dimensional network structure. The gel can be further processed through drying, calcination, and other techniques to obtain functional materials with a porous structure. Currently, this method has also been applied to the construction of black TiO₂^[19]. Patil et al.^[19] prepared S, C, Ti³⁺ co-doped black TiO₂ nanoparticles using the sol-gel method. However, the synthesis of black TiO₂ by the sol-gel method has a long cycle and poor process stability.

3. BT in Cancer Treatments

Before being applied to cancer treatment, black TiO₂ was widely used in various fields, such as photocatalytic hydrogen production, air purification, water treatment, and photoelectrochemical cells^[24]. Based on excellent broad-spectrum properties and biocompatibility of black TiO₂, in 2015, Ren et al.^[17] first used black TiO₂ to treat cancer under near-infrared light irradiation. Since then, endeavor on the application of black TiO₂ in cancer treatment has been boosted. In this section, the applications of black TiO₂ in PDT, PTT, and the combined PDT and PTT are introduced (Figure 2).

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Figure 2. Therapeutic approaches for cancer using black TiO₂. PTT: photothermal therapy; PDT: photodynamic therapy; NIR: near-infrared; ROS: reactive oxygen species.

3.1 BT in PDT therapy

As early as 2017, Ni et al.^[25] first reported that black TiO₂ could be used as a photosensitizer for the phototherapy of bladder cancer cells at 808 nm, which established a basis for further research on PDT anti-cancer treatment. With the development of PDT for anti-cancer treatment, Estefanía et al.^[26] developed photoactive nanomaterials with drug-encapsulating properties. This study employs cervical cancer HeLa cells as the model, and mesoporous black TiO₂ nanorods prepared via sodium borohydride (NaBH₄) reduction as both drug carriers and photodynamic platforms. The Ti³⁺ sites and oxygen vacancies within the nanorods enable visible light-responsive generation of hydroxyl radicals (HO•). The material efficiently loads the chemotherapeutic drug doxorubicin (encapsulation efficiency: 92%). Through the synergistic effect of chemotherapy and photodynamic therapy, it also inhibits cancer cells via DNA/RNA damage, lipid peroxidation, and apoptotic pathways, reducing the cell viability to 30% at a concentration of 400 μg/mL. This work provides a novel strategy for the combined therapy of cervical cancer.

3.2 BT in PTT therapy

In 2015, Ren et al.^[17] pioneered the application of black TiO₂ for tumor PTT, with polyethylene glycol (PEG) modification to enhance biocompatibility and stability. In this study, black TiO₂-PEG was intravenously administered to mice bearing 4T1 breast cancer xenografts, followed by irradiation of the tumor region with an 808 nm NIR laser. Tumor ablation was achieved through local hyperthermia, and the material exhibited low toxicity and high photothermal conversion efficiency, which were fully validated by experimental results. Building on this foundational work, subsequent studies have continued to innovate while retaining these core advantages. In recent years, mesoporous silica-coated black TiO₂ photothermal nanoparticles have not only been shown to enhance the anti-cancer effect of PTT, but also been found to elicit tumor-associated antigens after PTT, which can stimulate the body to generate a tumor-specific immune response^[27]. This provides a typical example for photothermal immunotherapy.

3.3 BT in combined PDT/PTT therapy

Based on the excellent performance of black TiO₂ in PDT and PTT, combined PDT and PTT have attracted significant attention. In 2019, Saeed et al.^[28] designed an Fe₃O₄-black TiO₂ nanocomposites, which exhibited strong broadband light absorption, high photothermal conversion efficiency, and good magnetic resonance imaging properties. In 2021, Guo et al.^[29] designed a novel titanium-based targeting agent and proposed a nano-theranostic system with strong near-infrared-II absorption. In this study, black TiO₂ was subjected to hydrogenation reduction with NaBH₄ to introduce oxygen vacancies and boron doping, narrowing its band gap for NIR-II responsiveness. Its surface was coated with SiO₂ and grafted with hyaluronic acid (HA) to obtain black TiO₂@SiO₂–HA, which possesses both the functions of targeting CD44-overexpressing tumors and NIR-II photoacoustic imaging guidance. Under 1,064 nm laser irradiation, this system synchronously mediates PDT and PTT, achieving tumor ablation through a synergistic effect in vitro (4T1 and HeLa cells) and in vivo (4T1 tumor-bearing mice). Guided by real-time NIR-II photoacoustic imaging, combined PTT-PDT effects act on the tumor cells apoptosis, showing great potential in targeted PTT-PDT.

3.4 Comparison of BT with conventional PDT/PTT agents

Traditional PDT requires the synergistic use of photosensitizers (PSs) and light of specific wavelengths. Porphyrin-based compounds are the mainstay of PSs, such as hematoporphyrin derivative (HpD, trade name: Photofrin) and 5-aminolevulinic acid (5-ALA), with excitation wavelengths mostly ranging from 630 to 689 nm. Conventional PTT primarily relies on noble metal nanomaterials, including gold nanospheres, gold nanorods, gold nanoshells, and gold nanocages, all of which can efficiently generate heat through the localized surface plasmon resonance effect, with excitation wavelengths adapted to theNIR region^[30].

Compared with traditional agents, black TiO₂ features excitation wavelengths precisely matched to the NIR region, achieving a tissue penetration depth of 1-2 cm. This effectively overcomes the limitation of conventional PDT photosensitizers (excited by red light with a penetration depth < 1 cm). Furthermore, in contrast to gold-based photothermal agents that suffer from high preparation costs and potential in vivo accumulation toxicity, black TiO₂ boasts more universal preparation processes and lower risks of clinical translation. However, its photothermal conversion efficiency, ranging from 32%-40%^[26] and sufficient for clinical therapeutic needs, is lower than that of morphologically optimized traditional photothermal agents (e.g., gold nanoshells and gold nanocages with a photothermal efficiency of 35%-50%)^[31].

In addition, although traditional inorganic phosphorus materials (such as violet phosphorus quantum dots (VPQDs) and black phosphorus nanosheets (BPNSs)) exhibit excellent photoresponsive activity, they possess inherent drawbacks: the weak van der Waals forces between layers render them prone to degradation in oxygen- or water-containing environments, leading to diminished photoresponsive performance. Despite the production of metabolites (e.g., phosphate ions) capable of inducing calcification during degradation, their insufficient short-term stability restricts the long-term synergy of PDT/PTT. Moreover, the photothermal conversion efficiency of traditional inorganic phosphorus materials depends on specific morphological regulation (e.g., the two-dimensional sheet structure of BPNSs and the quantum size effect of VPQDs)^[32-35]. In contrast, the defect state structure of black TiO₂ exhibits low dependence on morphology, endowing it with more universal preparation processes.

In terms of therapeutic safety, the biocompatibility of black TiO₂ has been validated in preclinical studies, with its degradation product (titanium ions) showing extremely low toxicity. In contrast, the degradation of phosphorus materials may be accompanied by an abnormal local increase in phosphate ion concentration, necessitating strict control of the administration dose to avoid potential tissue damage^[27]. In summary, black TiO₂ demonstrates a balanced advantage between stability and photoresponsive efficiency in synergistic PDT/PTT therapy. To facilitate its further development and clinical translation, Table 2 summarizes the key technical parameters of the black TiO₂ system.

4. Summary and Prospects

This review systematically elaborates on the research progress of black TiO₂ in the field of cancer treatment. As a novel functional material, it possesses unique crystal core-disordered shell structure, which endows it with excellent broadband absorption, and notably enhances its light absorption in the near-infrared region. Black TiO₂ has become increasingly popular in the medical field due to its unique broadband absorption, high near-infrared light penetration, and tunable defect structure characteristics. Its unique properties underpin nearly all its current applications. Black TiO₂ can act as an efficient photosensitizer to generate reactive oxygen species, and a photothermal agent to achieve local thermal ablation. Moreover, by compounding with other functional materials (such as Au nanoclusters, Fe₃O₄, mesoporous silica, etc.), it shows great potential for applications in integrated strategies, such as imaging-guided therapy and immunotherapy. However, our understanding of the complexity of black TiO₂ are still incomplete. At the defect level, the existence forms, stability of low-valence ions and oxygen vacancies, as well as their regulatory mechanisms on PDT/PTT efficiency, remain unclear. The limitations in detection techniques further hinder precise defect optimization. In terms of biosafety, the issues of long-term in vivo accumulation risk and insufficient biodegradability have not been fully resolved, which may induce chronic inflammation. Regarding therapeutic efficacy, improvements in visible-light activity are limited, and deep-tissue therapeutic effects relying on near-infrared light still requires optimization. Future research should focus on the practical needs of cancer treatment. It is necessary to further deepen the research on the defect regulation mechanism and biological interactions of black TiO₂. Specifically, advanced characterization techniques should be integrated to clarify the defect-efficacy relationship, stimuli-responsive systems need to be designed to enhance biosafety, and standardized synthesis and evaluation systems should be established. Additionally, efforts should be made to promote the synergistic integration of black TiO₂ with immunotherapy and gene therapy, while strengthening the complementary advantages with other phototherapeutic materials. Ultimately, these strategies will facilitate the translation of black TiO₂ from basic research to clinical applications in precise, combined cancer therapy.

Authors contribution

Pei YF: Writing-original draft, investigation, formal analysis.

ao XY, Wen XM: Methodology, data curation, investigation

Chen LY: Writing-review & editing, validation.

Conflicts of interest

Liangyu Chen is an Editorial Board Member of BME Horizon. The other authors declare no conflicts of interest.

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Copyright

© The Author(s) 2026.