Recent advances in inorganic nanocomposites for the photothermal therapy of bone tumors

Abstract

Bone tumors represent a category of malignant diseases with high risks of recurrence and metastasis. Surgical resection, as the primary treatment modality, often fails to eliminate microscopic tumor foci, and the postoperative recurrence rate remains high. In recent years, photothermal therapy (PTT) has emerged as a novel, minimally invasive therapeutic strategy, demonstrating remarkable potential in suppressing tumor recurrence and metastasis. However, traditional PTT still faces challenges such as low photothermal conversion efficiency, insufficient tumor-targeting ability, and the limitations of monomodal therapy, which restrict its clinical applications. To address these issues, various inorganic nanocomposites have been developed that can integrate multiple functions, such as targeted drug delivery and imaging diagnosis, thereby enhancing treatment specificity while minimizing damage to healthy tissues. This review summarizes the current status and challenges of inorganic nanocomposites for PTT in bone tumors and explores their design, performance, and therapeutic mechanisms. Through the continuous optimization of material design and therapeutic strategies, this approach may pave the way for more effective, precise, and minimally invasive therapies in clinical oncology.

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1. Introduction

Bone tumors and bone metastatic tumors, including common types such as osteosarcoma and chondrosarcoma, are generally highly invasive, potentially fatal, difficult to treat, and have a high recurrence rate.¹ Primary malignant bone tumors occur predominantly in adolescents. The 5-year survival rate reaches 79% in the United States, while it is only 61.8% in Europe, making bone tumors the third most common cancer among minors.^2,3 In contrast, bone metastatic tumors are the most common malignant bone lesions; these are secondary tumors formed when malignant tumor cells from other parts of the body metastasize to bone tissue through the bloodstream (Fig. 1). Although traditional treatments (surgery, radiotherapy, and chemotherapy) are widely used clinically, they often fail to eradicate tumor tissues and are accompanied by significant side effects. Therefore, developing more precise and effective therapeutic strategies, especially those that simultaneously enhance efficacy, minimize side effects, and facilitate targeted therapy, has become a research focus in bone tumor treatment.

Fig. 1 Schematic of malignant tumor bone metastasis.

In recent years, the rapid evolution of nanotechnology has catalyzed significant advancements in photothermal therapy (PTT), positioning it as a highly promising modality for bone tumor treatment.^4,5 This approach offers several distinct advantages over conventional therapies, including precise spatiotemporal control, minimal invasiveness, and the potential for repeated applications without cumulative toxicity. Moreover, the thermal energy generated during PTT can induce immunogenic cell death, potentially stimulating antitumor immune responses that may help combat metastatic disease. This feature is particularly relevant for bone tumors, which are known for their aggressive metastatic behavior. However, enhancing PTT efficacy and overcoming existing technical limitations remain key challenges. The photothermal conversion efficiency of existing agents often proves insufficient for complete tumor ablation, particularly in larger or deeper-seated lesions. Targeting specificity remains another critical hurdle as nonspecific accumulation of photothermal agents in healthy tissues can lead to undesirable side effects. Furthermore, the complex and heterogeneous nature of bone tumors, combined with the unique physiological characteristics of bone tissue, including dense extracellular matrix and limited vascularity, presents additional barriers to effective drug delivery and uniform heat distribution. The design and development of inorganic nanocomposites have significantly improved PTT outcomes, enabling enhanced efficacy and reduced side effects. PTT ablates tumor cells by converting light energy into heat through the use of nanomaterials, thereby inducing localized hyperthermia.^6,7 Inorganic nanocomposites often combine photothermal agents with targeting moieties to enhance tumor specificity, imaging contrast agents for real-time monitoring, and drug-loading capabilities for combined therapeutic approaches. Some innovative designs incorporate stimuli-responsive elements that release their payload only upon exposure to specific tumor microenvironment cues or external triggers, thereby improving spatiotemporal control of treatment. These multifunctional systems not only enhance therapeutic efficacy but also provide valuable tools for treatment planning and response assessment through integrated imaging capabilities.^8,9 Nevertheless, the high production cost of nanomaterials and challenges in large-scale manufacturing remain bottlenecks for clinical translation.^10,11

This immunogenic cell death effectively activates dendritic cells and promotes the infiltration and activation of tumor-specific T cells, thereby stimulating systemic antitumor immune responses that can target potential micro-metastases, proteins, and damage-associated molecular patterns in tumor cells.

Additionally, issues such as operability and standardization in clinical applications, as well as poor targeting and inadequate control of drug release in traditional single nanomaterials, underscore the importance of inorganic nanocomposites as a critical area for development. This review focuses on the application of inorganic nanocomposites in PTT for bone tumors, exploring their multidimensional mechanisms and prospects. As these efforts progress, PTT-based approaches, particularly those employing advanced inorganic nanocomposites, hold tremendous potential to revolutionize the treatment paradigm for bone tumors, offering hope for improved outcomes in these devastating malignancies.

2. Principles of photothermal therapy and the role of inorganic nanocomposites

2.1. Photothermal mechanisms

As an emerging, minimally invasive treatment strategy for localized bone tumors, PTT has shown significant potential. Its core mechanism relies on nanomaterials with high photothermal conversion efficiency, which efficiently convert light energy into localized heat under precise near-infrared (NIR) irradiation.¹² The controllable thermal effect forms the basis of PTT for eradicating bone tumor cells.

When the temperature at the tumor site rapidly exceeds 42–45 °C, it induces irreversible protein denaturation, enzyme inactivation, altered membrane lipid bilayer fluidity, and mitochondrial dysfunction in tumor cells, ultimately leading to apoptosis or more severe necrosis (Fig. 2).^13–15 Notably, compared to normal bone tissue, tumor regions exhibit higher thermal sensitivity due to abnormal vascular structures and a “heat accumulation effect”, enabling selective tumor ablation.

Fig. 2 Schematic of the PTT principle.

Furthermore, PTT induces local hyperthermia that not only directly ablates primary lesions but also triggers the release of heat shock proteins. Additionally, the thermal effect of PTT disrupts the integrity of the tumor vascular endothelium, increases vascular permeability, improves the immunosuppressive tumor microenvironment, and enhances the synergistic effects of chemotherapy, radiotherapy, and other therapies.

2.2. Immunogenic cell death and microenvironment regulation

Accumulating evidence indicates that PTT reshapes the tumor immune microenvironment beyond direct thermal ablation.^16,17 Moderate hyperthermia induces immunogenic cell death, characterized by the release of DAMPs such as calreticulin, ATP, and HMGB1, leading to dendritic cell maturation and enhanced antigen presentation. In bone tumors, PTT reduces the prevalence of immunosuppressive myeloid-derived suppressor cells and promotes the infiltration of CD8⁺ T cells within the bone marrow niche (Fig. 3).¹⁸ Moreover, inorganic nanocomposites can be engineered to co-deliver immune adjuvants or checkpoint inhibitors, further amplifying PTT-triggered systemic antitumor immunity and reducing metastasis.

Fig. 3 Immunomodulatory effects of photothermal therapy in bone tumors.

2.3. Advantages of inorganic nanocomposites for enhancing PTT

Inorganic nanocomposites have emerged as powerful enhancers of PTT due to their tunable optical absorption, excellent thermal stability, and ability to integrate multiple therapeutic and diagnostic functionalities.¹⁹ These nanocomposites are engineered systems that combine photothermal-responsive materials with bioactive or pharmaceutical components to achieve efficient, targeted, and synergistic tumor therapy. Their advantages derive from the interplay between compositional diversity and functional integration. Representative photothermal cores include gold-based, GO-based, MXene-based, BP-based, and MoS₂-based nanocomposites (Fig. 4). These materials exhibit strong near-infrared absorption and high photothermal conversion efficiency, enabling rapid temperature elevation under low-power irradiation and effective thermal ablation of tumor cells.

Fig. 4 Examples of common inorganic nanocomposites.

Compared with organic nanocomposites, inorganic nanocomposites demonstrate several intrinsic benefits in the photothermal treatment of bone tumors. Their crystalline structures provide high photothermal conversion efficiency, exceptional thermal stability, and resistance to photobleaching, ensuring consistent heat generation within the mineralized bone microenvironment where dense tissue often restricts light penetration. In addition, inorganic nanomaterials offer distinctive physicochemical properties such as magnetic responsiveness, X-ray attenuation, and photoacoustic contrast, supporting multimodal imaging guidance that is generally unattainable with organic carriers.²⁰

The mechanical robustness and tunable surface chemistry of inorganic nanomaterials further promote their integration with hydroxyapatite and other bone-mimetic scaffolds, enhancing their applicability in treatment strategies that require both tumor ablation and bone regeneration. Although organic nanocomposites offer advantages in biodegradability and biocompatibility, the superior optical tunability, structural stability, and imaging compatibility of inorganic nanocomposites make them particularly well-suited for achieving precise, durable, and multifunctional photothermal therapy in bone tumor management.

3. Inorganic nanocomposites for photothermal therapy of bone tumors

The modern PTT system originated in 1995, when Chen's team first discovered that indocyanine green (ICG) produces a significant photothermal effect under 808 nm laser excitation, resulting in the selective killing of breast cancer cells in vitro.²¹ This breakthrough not only revealed the molecular mechanism of photothermal conversion but also laid the theoretical foundation for PTT. In 2003, Hirsch et al. systematically elaborated the principle of PTT, noting its similarity to magnetic hyperthermia in inducing localized thermal effects for precise tumor eradication, opening new avenues for the application of nanomaterials in PTT.²²

With the rise of nanotechnology, 2014 marked a critical turning point for PTT in bone tumor treatment. Liu et al. developed cysteine-modified copper sulfide nanoparticles, which effectively inhibited the growth of osteosarcoma (OS) in animal models.²³ This study significantly improved photothermal conversion efficiency by optimizing the material's light absorption cross-section and biocompatibility, representing a key step from basic research to clinical application. Subsequently, researchers have developed various novel photothermal agents, such as gold nanorods, black phosphorus quantum dots, and MXenes, gradually overcoming challenges like insufficient tissue penetration depth and poor control of thermal damage boundaries through surface functionalization and multimodal combination therapies (Fig. 5).^24–26

Fig. 5 Timeline of the development in the field of PTT for bone tumors from 2003 to 2024.

3.1 Metal-based nanocomposites

Metal-based nanomaterials have emerged as a key focus in PTT research due to their unique physicochemical properties, particularly their strong surface plasmon resonance (SPR) effects in the NIR regions (NIR-I: 650–950 nm and NIR-II: 1000–1350 nm). In bone tumor treatment, metal-based inorganic nanocomposites not only exhibit excellent photothermal conversion efficiency but also enable targeted delivery, imaging enhancement, and synergistic drug release through surface functionalization.

3.1.1 Gold-based nanocomposites. Gold (Au) nanomaterials are the most widely studied metal-based photothermal agents. These include Au nanorods (Au NRs), nanocages, and nanoshells, and are characterized by good stability, biocompatibility, and easily modifiable surfaces.^27,28 Studies have shown that Au NRs achieve efficient thermal conversion under 808 nm NIR irradiation, with their absorption wavelength and tissue penetration enhanced by optimizing the aspect ratio.^29,30 Liao et al. developed a bifunctional hybrid hydrogel system with excellent photothermal performance and osteogenic capacity via photo-induced polymerization (Fig. 6(a)). The hydrogel consists of a three-dimensional network of gelatin methacrylate and chondroitin sulfate methacrylate, incorporating Au NRs and nano-hydroxyapatite (nHA) as functional fillers. Transmission electron microscopy (TEM) images of polyethylene glycol (PEG)-modified gold nanoparticles (Au NPs) show uniform morphology with lengths and widths of 48 nm and 12 nm, respectively. In comparison, nHA exhibits a spindle-like morphology with a nanoscale diameter (Fig. 6(b) and (c)). Freeze-dried hydrogels have a porous structure with an average pore size of ∼76 µm, aiming to achieve photothermal elimination of residual postoperative tumors and promote regenerative repair of bone tissue (Fig. 6(d)). In vitro experiments demonstrated that the hybrid hydrogel efficiently induces apoptosis of K7M2wt OS cells under NIR laser irradiation while promoting osteoblast adhesion and differentiation. In a murine tibial OS model, implantation of the hydrogel not only achieved effective photothermal treatment of residual tumors but also significantly accelerated new bone formation at bone defect sites.³¹

Fig. 6 (a) Schematic of the preparation of the GNRs/nHA hybrid hydrogel. (b) TEM image of PEGylated GNRs. (c) SEM image of nHA. (d) SEM image of the cross-section of GNRs/nHA hybrid hydrogel.³¹ Copyright 2021, Bioact. Mater. Schematic of different synthesis procedures for the (e) MBG-xAg powder materials and (f) SC-MBG-xAg scaffolds. (g)–(i) TEM images of the MBG-xAg (x = 0, 0.15, and 0.3) powder samples.³⁷ Copyright 2023, Elsevier B.V.

To enhance tumor-killing efficacy, Ma et al. constructed a theranostic nanoplatform comprising an Au NPs core coated with a metal–organic framework and a mesoporous silica (MS) bilayer shell, designed for precise treatment of lung cancer spinal metastases.³² This nanosystem enables efficient co-loading of the anticancer drugs BYL719 and cisplatin, with pH-responsive release in the acidic tumor microenvironment, significantly improving spatiotemporal control of drug release. Crucially, surface modification with dYNH peptides endows the platform with excellent tumor-targeting ability, enhancing both drug delivery and PTT efficiency.

3.1.2 Silver-based nanocomposites. Silver nanoparticles (Ag NPs) are important noble metal nanomaterials with excellent antibacterial properties, as well as the ability to promote bone healing and wound repair.³³ Ag NPs play an indispensable role in bone tumor therapy due to their unique properties.^34,35 Ag NPs exhibit strong localized SPR, enabling efficient photothermal conversion under NIR irradiation, with their photothermal performance precisely tunable by regulating particle morphology and size. He et al. reported a PA–EG–Ag NPs composite with a thermal conductivity of 2.987 W (m K)⁻¹, demonstrating excellent heat conduction and a 20.1% improvement in photothermal conversion efficiency.³⁶ Compared to Au nanomaterials, Ag NPs offer cost advantages and broader-spectrum antibacterial activity, which is particularly significant for bone tumor patients at high risk of postoperative infection. Sánchez-Salcedo et al. synthesized mesoporous bioactive glass (MBGs) nanocomposites based on a silica–calcium oxide–P₂O₅ ternary system, with uniformly doped Ag NPs in the matrix (Fig. 6(e) and (f)).³⁷ TEM analysis of MBG-based materials revealed a “hexagonally ordered” mesostructure with electron beams aligned parallel and perpendicular to the mesopore channels (Fig. 6(g)–(i)). Antibacterial experiments demonstrated that Ag NPs significantly enhanced the inhibition of bacterial growth and biofilm formation, with efficacy positively correlated with the silver content. In vitro, coculturing MC3T3-E1 cells with Staphylococcus aureus further confirmed that Ag NPs are critical for antibacterial activity, with minimal impact on osteoblast proliferation.³⁷ Overall, the three-dimensional printed bioactive glass–silver nanocomposite scaffold, characterized by its hierarchical porous architecture and robust antibacterial activity, shows substantial promise for applications in bone tissue regeneration and may offer valuable insights for designing multifunctional scaffolds capable of addressing postoperative infection risks in bone tumor therapies.

Beyond gold- and silver-based nanocomposites, several other metallic systems have emerged as highly promising candidates for photothermal therapy in bone tumors.³⁸ Copper chalcogenides, such as copper sulfide, exhibit strong absorption in the near-infrared region and possess clear cost advantages, making them attractive for large-scale translational development. Iron oxide nanocomposites provide intrinsic magnetic resonance imaging capability, enabling magnetic guidance and highly precise MRI-assisted photothermal treatment.³⁹ Palladium nanostructures display tunable plasmonic absorption that can extend into the second near-infrared window, thereby facilitating efficient photothermal ablation at greater tissue depths. Titanium nitride and oxygen-deficient titanium dioxide nanoparticles also demonstrate excellent photothermal stability, favorable biocompatibility, and photothermal conversion efficiencies comparable to those of gold-based materials. Recent progress in metal sulfide nanomaterials for bone tumor therapy further highlights the translational potential of these platforms.⁴⁰ Collectively, these emerging metallic nanomaterials broaden the design space for next-generation photothermal platforms and offer new opportunities for addressing the unique therapeutic challenges associated with bone tumors.

3.2 Carbon-based inorganic nanocomposites

Carbon-based nanomaterials have become a research hotspot in PTT due to their excellent optical properties, high thermal conductivity, biocompatibility, and ease of functional modification.⁴¹ They primarily include graphene and its oxide (graphene oxide, GO), carbon nanotubes (CNTs), and carbon dots (CDs), all of which exhibit strong NIR absorption and efficient photothermal conversion.⁴²

3.2.1 Carbon nanotubes. CNTs, especially multi-walled CNTs (MWCNTs), exhibit excellent photothermal conversion in the NIR region, with their one-dimensional hollow structure enabling high drug-loading efficiency and tissue penetration. Due to the tendency of bare CNTs to aggregate in aqueous solutions, which affects in vivo stability, researchers widely use surface polymer modification to improve dispersibility and biocompatibility.⁴³ To enhance the stability of the MWCNTs, Lin et al. prepared PEG-MWCNTs, which remained stable in aqueous solutions for over a week and exhibited rapid temperature elevation under 808 nm laser irradiation, significantly inducing apoptosis in bone tumor cells. Additionally, MWCNTs can load antitumor drugs via covalent grafting or π–π stacking, enabling multimodal therapeutic platforms.⁴⁴ Recently, Elgamal et al. developed PEG-functionalized multi-walled carbon nanotubes as a nanocarrier for the proteasome inhibitor Ixazomib, aiming to improve drug delivery efficiency and reduce systemic toxicity. Ixazomib was covalently loaded onto PEG-modified MWCNTs through surface functionalization, forming a stable MWCNTs–PEG–Ixazomib conjugate with a high loading capacity of approximately 78% (w/w). In vitro assays using the RPMI 8226 multiple myeloma cell line demonstrated that the nanocomposite exhibited markedly lower cytotoxicity compared with free Ixazomib, with cell viability reaching 91% at the highest tested concentration, relative to 69% for the free drug. These results indicate that PEGylated MWCNTs effectively mitigate Ixazomib-associated toxicity while maintaining therapeutic activity, thereby enhancing drug tolerance and reducing dosage requirements.⁴⁵ Although this study was performed in a hematologic tumor model rather than a bone tumor model, the demonstrated improvements in drug loading, biocompatibility, and controlled delivery provide mechanistic insights that are highly relevant to the development of carbon-nanotube-based therapeutic platforms for bone malignancies.

3.2.2 Carbon dots. CDs are novel nanoscale carbon-based materials with excellent fluorescence properties, low toxicity, high stability, and favorable renal excretion.^46,47 Although their photothermal conversion efficiency is lower than that of GO and CNTs, it can be enhanced by doping with metals (Fe, Mn), nonmetals (N, S), or composite polymers.^48,49 In bone tumor treatment, researchers have combined CDs with bone-targeting drugs or scaffold materials to construct dual-functional systems for fluorescence imaging and PTT.^50–52 Lu et al. developed a novel CD-doped chitosan/nHA scaffold (CS/nHA/CDs) for bone tissue regeneration, with SEM images showing porous, highly interconnected structures in all scaffolds (Fig. 7(a)).⁵³ As shown in Fig. 7(b) and (c), CS/nHA/CDs scaffolds reached temperatures of 68.4 °C, 65.6 °C, and 62.8 °C in the wet state, while pure CS/nHA scaffolds only reached 31.4 °C after 10 min of 808 nm irradiation. In vivo, the CS/nHA/CDs + NIR group reached a maximum temperature of 51.4 °C at the tumor site after 10 min of 808 nm irradiation, whereas the pure CS/nHA + NIR group only reached 36.1 °C. Studies have shown that incorporating CDs enhances rBMSC adhesion and osteogenic differentiation on the scaffold while promoting vascularized bone tissue formation. In addition, it enables simultaneous PTT under NIR irradiation with effective antibacterial properties, highlighting its potential for clinical application.

Fig. 7 (a) SEM images of the CS/nHA/CDs and the CS/nHA scaffolds. (b) Quantitative temperature changes of the CS/nHA/CDs and the CS/nHA scaffolds in a wet state under 1 W cm⁻². (c) Quantitative temperature changes of the mouse tumor site under 1 W cm⁻².⁵³ Copyright 2018, the American Chemical Society.

3.2.3 Graphene oxide

Graphene oxide (GO) has attracted recent attention due to its excellent photothermal conversion efficiency and abundant surface functional groups.⁵⁴ GO nanosheets exhibit good thermal response in the NIR-I window (808 nm), with abundant hydroxyl, carboxyl, and epoxy groups enabling high modifiability.^55,56 GO synthesis dates back to Brodie's nitric acid oxidation method in 1859, later optimized by Staudenmaier (concentrated sulfuric acid-assisted) and Hummers’ (potassium permanganate system), leading to the current mainstream Hummers’ method and its modifications.^57–60 The in vivo metabolism and biological effects of graphene and its derivative, GO, are regulated by factors such as material size, administration route, biodistribution, toxicity, and interactions with biological systems.⁶¹ Li et al. developed a stable non-covalent complex of trastuzumab (TRA) and GO (TRA/GO) for targeting OS cells, providing important insights for GO-based nanomaterials in targeted tumor therapy.⁶² Recently, Zeng et al. designed a mitochondria-targeted GO nanocomposite: triphenylphosphine (TPP) and ICG were co-loaded onto PEGylated GO nanosheets (TPP-PPG@ICG), enabling specific accumulation in mitochondria of MG-63 OS cells.⁶³ Under NIR excitation, this system induces targeted tumor cell death by inhibiting ATP synthesis and mitochondrial function, offering an efficient synergistic mechanism for drug-resistant tumor therapy.

Additionally, GO can be functionalized with metal nanoparticles such as Fe₃O₄ to enhance imaging performance and magnetic targeting capability. Gonzalez-Rodriguez et al. developed multifunctional GO–Fe₃O₄ nanocomposites by integrating graphene oxide with superparamagnetic iron oxide nanoparticles, enabling simultaneous magnetic targeting, drug delivery, and dual-modality imaging (Fig. 8(a)). The resulting GO–Fe₃O₄ conjugates exhibited an average size of approximately 250–260 nm, low cytotoxicity comparable to pristine GO, and pronounced superparamagnetic behavior that supported efficient magnetic guidance and enhanced T₂-weighted MRI contrast. Moreover, the platform preserved the intrinsic pH-responsive fluorescence of GO, allowing optical discrimination between cancerous and healthy microenvironments. As a drug carrier, GO–Fe₃O₄ demonstrated high loading efficiency for hydrophobic doxorubicin through non-covalent interactions. They achieved more than a 2.5-fold improvement in therapeutic efficacy at markedly reduced drug doses, with progressive internalization visualized through fluorescence tracking (Fig. 8(b) and (c)). Collectively, these findings indicate that Fe₃O₄ functionalization significantly improves the imaging capability, magnetic responsiveness, and therapeutic performance of GO-based nanocomposites, underscoring their potential for targeted delivery and multimodal imaging-guided cancer therapy.⁶⁴

Fig. 8 (a) Representative schematic of the GO–Fe₃O₄ conjugate formation. (b) Cell viability of HeLa cells subject to: GO–Fe₃O₄ (black squares), DOX–GO–Fe₃O₄ (blue squares) and DOX (red squares) and (c) GO–Fe₃O₄ internalization fluorescence imaging in HeLa cells.⁶⁴ Copyright 2019, PLOS ONE.

3.3 Transition-metal chalcogenides nanocomposites

Transition-metal dichalcogenides (TMDs) are semiconductor materials with typical layered 2D structures, with the general formula MX₂. TMDs show broad application prospects in PTT due to their tunable bandgap, excellent optical absorption, high thermal conductivity, and large surface area.⁶⁵ Their strong absorption in the NIR region makes them promising candidates for next-generation photothermal agents. By combining with polymers, biological ligands, or bone-targeting factors, TMDs enable precise bone tumor therapy with integrated imaging, drug delivery, and bone repair functions.⁶⁶

3.3.1 Molybdenum disulfide nanocomposites. Molybdenum disulfide (MoS₂), a typical 2D TMD, has gained increasing attention in PTT, especially for bone tumors, due to its unique layered structure, excellent NIR absorption, and good biocompatibility.⁶⁷ MoS₂ nanomaterials exhibit high photothermal conversion efficiency and possess a large specific surface area and abundant surface-active sites, offering significant advantages in drug loading, functional modification, and composite construction.^68,69 Their unique electronic structure and photothermal properties enable effective thermal response in both NIR-I and NIR-II, facilitating precise thermal ablation of tumor cells in deep bone tissues. Notably, MoS₂ nanomaterials also show osteogenic potential, promoting osteogenic differentiation of bone marrow mesenchymal stem cells and providing new insights for postoperative bone defect repair. To address the dual challenges of tumor elimination and bone defect repair in bone tumor treatment, Wang et al. developed a novel bifunctional scaffold by integrating 3D printing and hydrothermal technology.⁷⁰ The MS-AKT scaffold exhibits a distinct core–shell structure, consisting of an akermanite core and a ∼5 µm thick MoS₂ shell (Fig. 9(a)–(c)). Energy-dispersive spectroscopy mapping of the scaffold cross-section revealed an increase in Mo and S, along with a decrease in Ca, Mg, Si, and O signals, from the interior to the strut surface (Fig. 9(d)–(f)). When the scaffold size increased from 6 mm to 11 mm, the final temperature reached 107 °C to 120 °C in dry conditions and 38 °C to 55 °C in wet conditions (Fig. 9(g) and (h)). In dry environments, the final temperature of the MS–AKT scaffolds could be adjusted from 73 °C to 144 °C by varying the laser power density (0.2–0.6 W cm⁻²) (Fig. 9(i)). The MoS₂ nanosheets grew in situ on the bioceramic framework via hydrothermal treatment, endowing it with precisely controllable photothermal properties.

Fig. 9 Fracture morphologies of 0.2 MoS₂-modified akermanite (MS–AKT) scaffolds at different magnifications (a)–(c). The formed core/shell structures with an akermanite (AKT) core and MoS₂ shell of ∼5  µm thickness were observed. EDS elemental mapping of the cross-section of MoS₂–AKT interface: all elements (d), Mo (e), and S (f). Photothermal heating curves of the MoS₂-modified akermanite (MS–AKT) scaffolds with different sizes (diameter: 6.0 mm, 8.5 mm, and 11.0 mm) in dry (g) and wet (h) environments under an 808-nm laser irradiation at a power density of 0.50 W cm⁻²; photothermal heating curves of the MS–AKT scaffolds (diameter: 8.5 mm) at different laser power density (0.2, 0.3, 0.4, 0.5 and 0.6 W cm⁻²) in dry environment (i).⁷⁰ Copyright 2017, Nature.

The scaffold exhibited rapid temperature elevation under NIR irradiation, which could be tuned by the MoS₂ content, scaffold size, and laser power density. Experiments confirmed that the photothermal effect significantly inhibited the viability of OS/breast cancer cells and suppressed in vivo tumor growth. Simultaneously, the scaffold effectively supported the adhesion, proliferation, and osteogenic differentiation of BMSCs, inducing in vivo bone regeneration. This scaffold, which integrates antitumor and bone regeneration functions, provides an innovative strategy for addressing tumor-induced bone defects. Recently, Dai et al. modified the surface of PEEK scaffolds with MoS₂ nanosheets and hydroxyapatite (HA) nanoparticles using hydrothermal technology, thereby constructing a novel synergistic implant.⁷¹ The scaffold's photothermal performance was precisely regulated by molybdenum ion (Mo²⁺) concentration and laser power density, significantly outperforming traditional PEEK materials under NIR irradiation. In vitro, experiments confirmed that the modified scaffold effectively killed MG63 OS cells, while surface HA nanoparticles promoted MC3T3-E1 cell proliferation, adhesion, and mineralization. Micro-CT and in vivo studies in a rat femoral model showed that the scaffold exhibited excellent photothermal antitumor efficacy and osteogenic activity, achieving both bone tumor elimination and bone defect repair, and providing an innovative solution for clinical bone tumor treatment after 4 weeks of treatment.

Additionally, the potential of MoS₂ nanomaterials in responding to the tumor microenvironment has attracted significant attention. Their surfaces can be loaded with enzymes or responsive polymers, enabling the specific release of drugs in acidic tumor environments or regions with high glutathione concentrations, thereby improving therapeutic precision and efficiency. Beyond experimental advances, theoretical studies have further clarified the fundamental mechanisms underlying the exceptional photothermal behavior of MoS₂. Theoretical calculations demonstrate that the photothermal performance of MoS₂ is intimately linked to its layer number, defect type, and strain state. Density-functional-theory (DFT) results show that bulk MoS₂ has an indirect bandgap of 1.2 eV, whereas monolayer MoS₂ transitions to a direct-gap semiconductor with a bandgap of 1.8 eV, leading to a pronounced increase in exciton oscillator strength and a markedly enhanced absorption cross-section at 808 nm.⁷² Moreover, the introduction of sulfur vacancies creates defect levels within the bandgap; DFT calculations confirm that these defect-induced states act as intermediate energy levels, substantially lowering the excitation barrier for electrons in indirect-gap configurations and further improving the efficiency of photothermal conversion.⁷³ These theoretical insights complement the experimental findings and collectively highlight the structural, electronic, and defect-driven origins of the superior photothermal performance of MoS₂ nanomaterials in bone tumor therapy.

3.3.2 Tungsten disulfide nanocomposites. Tungsten disulfide (WS₂), a typical TMD, has been widely explored for tumor PTT in recent years due to its unique layered crystal structure, efficient NIR absorption, and excellent photothermal conversion performance; it shows particularly promise in bone tumor treatment.⁷⁴ WS₂ nanomaterials exhibit high photothermal conversion efficiency and can rapidly generate localized hyperthermia under low-power NIR laser irradiation (808–1064 nm), effectively inducing tumor cell apoptosis and necrosis.^75,76 Cheng et al. developed WS₂ nanosheet-based photothermal materials with strong NIR absorption, enabling multimodal imaging and efficient in vivo photothermal ablation of tumors in murine models.⁷⁷ Surface modification with PEG via thiol chemistry significantly enhanced the stability and biocompatibility under physiological conditions. Tests in multiple cell lines showed that PEG-modified WS₂ nanosheets (WS₂–PEG) exhibited minimal toxicity and effectively induced cancer cell death under NIR irradiation, demonstrating the potential of light-absorbing TMDC nanosheets in cancer theranostics and providing a theoretical and practical basis for their biomedical applications. To maximize photothermal efficacy for OS and deep bone tissue regeneration, Geng et al. constructed a novel, low-toxicity CDs/WS₂ heterojunction material that exhibits excellent photothermal conversion under 1064 nm laser irradiation.⁷⁶ Even when covered by 10 mm thick tissue, the material achieved complete elimination of deep bone tumors under low-power-density laser irradiation. Under low-intensity laser exposure, CDs/WS₂ not only ablated tumors via local hyperthermia but also promoted osteogenic differentiation through photothermal effects. Specifically, periodic low-intensity 1064 nm laser irradiation significantly accelerated osteogenic differentiation of human mesenchymal stem cells, with upregulated heat shock protein expression playing a key role. Studies demonstrated that the CDs/WS₂ heterojunction can eliminate bone tumors via PTT, prevent recurrence, and enhance bone regeneration to repair treatment-induced bone defects, showing broad prospects in cancer therapy and bone tissue engineering.

3.4 MXene-based nanocomposites

MXenes are 2D transition metal C/N obtained by selective etching of MAX phase precursors (where M is a transition metal, A is a group IIIA/IVA element, and X is C or N). They have attracted widespread attention in nanobiomedicine due to their unique layered structure, excellent photothermal conversion, large surface area, and abundant surface functional groups.⁷⁸ Especially in PTT, MXene materials such as Ti₃C₂, Nb₂C, and Mo₂C exhibit strong NIR absorption and rapid photothermal response, showing great potential for treating deep solid tumors like bone tumors. Their unique electronic structure and SPR properties enable high photothermal conversion efficiency in both NIR-I and NIR-II, with some studies reporting efficiencies exceeding 45%.⁷⁹ Bone tumor recurrence and postoperative failure primarily result from residual malignant cells and insufficient bone tissue integration. To address this, Pan et al. combined 2D Ti₃C₂–MXene nanosheets with 3D-printed bioactive glass scaffolds, constructing a composite scaffold with integrated antitumor and bone regeneration functions.⁸⁰ The scaffold utilizes Ti₃C₂–MXene's excellent photothermal conversion to achieve efficient thermal ablation of bone tumors under NIR irradiation, successfully eliminating xenografted bone tumor tissues in vivo. Additionally, Ti₃C₂–MXene significantly promoted new bone formation in vivo, accelerating bone tissue repair and reconstruction. This composite scaffold, which integrates PTT and bone regeneration, provides an efficient strategy for treating bone tumors and expands the applications of 2D MXene materials in tissue engineering and biomedicine. Subsequently, Yin et al. proposed integrating photon-responsive 2D ultrathin niobium carbide MXene nanosheets into 3D-printed biomimetic bone scaffolds for OS treatment (Fig. 10(a)).⁸¹ SEM images showed that niobium aluminum carbide ceramics prepared by solid-phase sintering have a dense layered microstructure (Fig. 10(b)). Treatment of MAX phase solids with hydrofluoric acid formed a multilayered structure (Fig. 10(c)), and further intercalation with TPAOH yielded few-layer Nb₂C nanosheets, observed via TEM (Fig. 10(d)). The Nb₂C–MXene nanosheets in the scaffold exhibit good photoresponsiveness and tissue penetration in the NIR-II, efficiently killing deep bone cancer cells. Biodegradation products of Nb₂C–MXene in vivo effectively promote angiogenesis: significant honeycomb-like lumen formation was observed in NBGS scaffolds after 24 h coculture with HUVECs (Fig. 10(e)–(g)), indicating strong pro-angiogenic capacity. This process enhances local oxygen, nutrient, and immune cell delivery, accelerating tissue repair and scaffold degradation. Quantitative assessment of bone regeneration via micro-CT-based histomorphometry showed superior osteogenic capacity of NBGS compared to BGS scaffolds (Fig. 10(h)–(j)).

Fig. 10 (a) Schematic of the fabrication process for NBGS. (b) SEM image of the Nb₂AlC ceramics. (c) SEM image of the multilayered Nb₂C MXene. (d) TEM image of the one-layered or few-layered Nb₂C MXene NSs. (e)–(g) Tube formation of HUVECs stimulated by BGS and NBGS for 24 h. (h)–(j) Bone regeneration capability, as evaluated by the quantitative analysis of fundamental parameters of two different scaffolds.⁸¹ Copyright 2021, Springer Nature Link.

Furthermore, calcium and phosphate released during scaffold degradation promote new bone mineralization and reconstruction. To further enhance in vivo stability and targeting, MXenes are often constructed as composite nanoplatforms. Zhang et al. designed a novel multifunctional composite scaffold material for simultaneous efficient bone tumor therapy and postoperative bone tissue repair.⁸² The scaffold composed of nano-hydroxyapatite, MXene nanosheets, and graphitic carbon nitride exhibits excellent antitumor performance and osteogenic capacity. Under NIR irradiation, the scaffold significantly inhibits the proliferation of bone tumor cells, rapidly eliminates residual tumor cells, and reduces the risk of postoperative recurrence. Meanwhile, n-HA and functional nanomaterials synergistically enhance osteoblast activity, promoting new bone formation and tissue reconstruction. With its excellent photothermal therapeutic and osteoregenerative properties, this multifunctional scaffold provides robust support for comprehensive post-resection bone tumor treatment, demonstrating broad prospects in bone tissue engineering and oncology.

3.5 Black phosphorus-based nanocomposites

Black phosphorus, an emerging 2D layered nanomaterial, has garnered extensive attention in biomedicine, particularly in tumor PTT, due to its exceptional photothermal conversion capabilities, biodegradability, and unique optical/electrical properties.^83,84 The tunable bandgap of BP (0.3–2.0 eV) enables strong absorption across the NIR region and high photothermal conversion efficiency.

Additionally, BP gradually degrades into non-toxic, metabolizable phosphate in physiological environments, offering inherent biocompatibility advantages over other inorganic photothermal agents.^85,86 Leveraging its excellent photothermal properties, Yang et al. integrated 2D BP nanosheets into 3D-printed bioactive glass scaffolds, constructing a novel bifunctional therapeutic platform to synergize PTT for OS and in situ bone regeneration (Fig. 11(a)).⁸⁷ Elemental mapping of strut surfaces and fracture cross-sections showed uniform distribution of Si, O, and Ca. At the same time, P was concentrated on the BG scaffold surfaces rather than the fracture cross-sections due to the adhesion and diffusion of BP nanosheets (Fig. 11(b)), enabling the regulation of photothermal performance and osteogenic capacity. Under 808 nm laser irradiation, the BP–BG scaffold temperature increased from 32.4 °C to 68.7 °C within 5 min (Fig. 11(c)), facilitating surface modification of BG scaffolds. In contrast, pure BG scaffolds showed negligible photothermal effect, with only ∼3.6 °C rise under the same power density (Fig. 11(c) and (d)), confirming BP nanosheets as the primary contributor to PTT. The study also evaluated the effect of laser power density on photothermal performance (Fig. 11(e)), supporting the feasibility for in vivo tumor treatment. Notably, ripple-like structures resembling Haversian canals were observed in new cranial bone tissue of Sprague–Dawley rats, enhancing our understanding of osteogenic mechanisms and providing new insights for bone tissue engineering. Due to the excellent surface activity and drug-loading capacity of BP, Xu et al. proposed a combined PTT-chemotherapy strategy using a platelet–OS hybrid membrane-coated delivery platform.⁸⁸ The hybrid membrane significantly extends in vivo circulation time and enables specific targeting of OS cells. The system encapsulates drug-loaded nanoparticles within an OPM shell, thereby achieving controlled release of doxorubicin. NIR irradiation further accelerates drug release, enabling photoresponsive delivery. In vitro and in vivo experiments showed that the BPQDs-DOX@OPM system efficiently accumulates at tumor sites, prolongs circulation, enhances targeting, and exhibits superior antitumor activity compared to single chemotherapy, with good biocompatibility. This combined strategy presents a novel and safe approach for treating clinical osteosarcoma.

Fig. 11 (a) Schematic of the fabrication process for the BP–BG scaffold. (b) Fracture morphologies of the BP–BG scaffold (scale bar: 300 µm), and the corresponding elemental mappings of Si, O, Ca, and P (scale bar: 75 µm). Photothermal heating curves of the BP–BG scaffolds in vitro (c) at different BP concentrations and (d) at different NIR laser power densities. (e) Viability assay of Saos-2 cells at different NIR power densities.⁸⁷ Copyright 2018, Wiley.

Crucially, BP shows significant potential in bone tissue engineering, as its degradation products promote osteogenic gene expression and induce the osteogenic differentiation of BMSCs, enabling the dual functions of tumor photothermal ablation and bone defect regeneration. Additionally, the photosensitivity of BP enables photodynamic therapy (PDT) by generating reactive oxygen species (ROS) under laser irradiation, thereby facilitating a combination therapy of PTT and PDT. Studies have integrated BP with chemotherapeutic drugs or immune agonists to develop multimodal nanoplatforms combining photothermal, photodynamic, chemotherapeutic, and immunomodulatory functions, achieving deep tumor killing and synergistic inhibition of distant metastases.⁸⁹

Beyond these experimental advances, theoretical investigations have provided fundamental insights into the electronic structure and photothermal behavior of BP, offering a mechanistic basis for its excellent therapeutic performance. Density functional theory (DFT) calculations show that the bandgap of BP widens linearly as the number of layers decreases, reaching approximately 2.0 eV in its monolayer form. This size-dependent modulation enhances excitonic absorption and promotes efficient non-radiative recombination within the 808–1064 nm spectral range, thereby supplying abundant pathways for photothermal conversion.^90,91 Moreover, synergistic strain–defect engineering has been demonstrated to further enhance the photothermal response of BP. DFT studies reveal that a 3% biaxial tensile strain lowers the conduction-band minimum by 0.18 eV, narrowing the bandgap and intensifying absorption in the NIR-II region.⁹² Concurrently, the introduction of a single phosphorus vacancy generates a mid-gap defect level at approximately 0.9 eV, which acts as an electronic intermediate state that facilitates carrier transitions and improves photothermal conversion efficiency.⁹³ These theoretical findings complement the experimental evidence and collectively deepen our understanding of how structural, electronic, and defect-related factors govern the photothermal properties of BP, supporting its continued development for multimodal bone tumor therapy.

4. Multimodal photothermal synergistic applications of inorganic nanocomposites

4.1 Targeted precision therapy

Targeted therapy is a key strategy in modern medicine for enhancing treatment efficiency and precision. In PTT, targeted delivery concentrates therapeutic energy on tumor cells, maximizing efficacy while minimizing damage to normal tissues.⁹⁴ Traditional PTT relies on the passive accumulation of nanomaterials in tumors; however, achieving specific targeting remains a key challenge. Inorganic nanocomposites can acquire active targeting capabilities through surface functionalization, thereby enhancing tumor-selective accumulation and therapeutic efficacy.

Nano-drug preparation technology is well-established, with significant progress in combining non-specific tumor targeting with PTT. Folic acid specifically binds to folate receptors that are overexpressed in various human tumors, making it a valuable tool for tumor targeting.^95,96 Based on this, Deng et al. developed a hybrid nanoplatform functionalized with bovine serum albumin and folic acid.⁹⁷ The platform uses zeolitic imidazolate framework-8 as a carrier to load IrO₂ and Ce6, enabling PTT-PDT synergy, with BSA–FA as an active targeting agent (Fig. 12(a)). Experiments showed 42.7% Ce6 release under pH 5.0 conditions, with IZBFC exhibiting good biocompatibility and drug delivery potential. Additionally, IZBF NPs achieved a photothermal conversion efficiency of ∼62.1% in vitro and in vivo, significantly enhancing the antitumor effects of PTT and PDT. In another study, Li et al. synthesized FA–Fe₂O₃@PDA-miRNA inorganic nanocomposites that target OS cells via folate receptors, achieving synergistic anticancer effects of gene therapy and PTT.⁹⁸ The system delivers miR-520a-3p to modulate the Jak-Stat signaling pathway, downregulate interleukin-6 receptor (IL6R) expression, and promote OS cell apoptosis. The FA–Fe₂O₃@PDA structure enhances the stability of miR-520a-3p, thereby prolonging its in vivo efficacy and significantly improving PTT conversion efficiency. Experiments demonstrated superior anticancer efficacy compared to single PTT.

Fig. 12 (a) Peptide-based semiconducting polymer nanoparticles permit efficient NIR-II fluorescence/NIR-I PA dual-modal imaging and targeted PTT/PDT for OS.⁹⁷ Copyright 2022, Drug Delivery. (b) Photothermal conversion behavior of different concentrations of SPN-PT under laser irradiation (635 nm, 0.45 W cm⁻²).¹⁰³ Copyright 2022, J. Nanobiotechnol.

Triphenylphosphine (TPP), a mitochondria-targeting molecule, is widely used to modify nanocomposites for the active targeting of OS cells. Hu et al. developed a drug delivery system based on hollow mesoporous MnO₂ nanostructures: AIBI@H-mMnO₂-TPP@PDA-RGD (AHTPR).⁹⁹ The system uses polydopamine to seal H-mMnO₂ pores, enabling acid-responsive drug release, while the azo initiator AIBI decomposes into highly reactive alkyl radicals under mild thermal stimulation. Intravenous injection of AHTPR enables pH/NIR dual-responsive drug release, with TPP-mediated mitochondrial targeting enhancing synergistic anticancer effects. In vitro and in vivo experiments showed effective cancer cell killing and complete tumor eradication, validating the synergistic therapeutic efficacy.

Recent advances in OS-specific targets have provided new insights into the photothermal inhibition of OS cells, with CD271, CD133, and OS-targeting peptides attracting significant attention. CD271 is a surface marker of OS stem cells. Tian et al. developed PEGylated multifunctional hollow gold nanospheres conjugated with CD271 monoclonal antibodies (HGNs-PEG-CD271) via bifunctional SH-PEG-COOH.¹⁰⁰ Experiments showed that HGNs-PEG-CD271 significantly inhibited cell viability under NIR irradiation, confirming CD271 targeting. CD133 is a key marker for screening tumor stem cells. Xiong et al. developed gold nanoparticles co-loaded with CD133, ICG, and hyaluronic acid. In this system, CD133 specifically targets OS stem cells, whereas HA facilitates tumor targeting and protects photosensitive drugs.¹⁰¹ In murine models, low-power single-wavelength laser irradiation significantly inhibited tumor growth. These studies provide important theoretical and technical support for precise PTT of OS. OS-targeting peptides, capable of rapidly recognizing patient-specific ligands, offer new avenues for personalized treatment. Lin et al. used a phage display to screen patient-specific OTP, which was conjugated with Cy7-TCF supramolecular 2D nanodiscs.¹⁰² Although Cy7-TCF primarily relies on EPR for passive tumor targeting, OTP modification enables active targeting. A single-dose intravenous injection demonstrated that OTP-modified T-ND complexes precisely recognize and deeply penetrate OS tissues, with retention lasting up to 24 days, thereby significantly enhancing the efficiency of PTT and tumor inhibition. Additionally, bone-targeting peptides that mimic natural osteocalcin exhibit high bone affinity and active targeting. Yuan et al. developed PT-based semiconductor polymer nanoparticles via nanoprecipitation, encapsulating PEGylated PT in the semiconductor polymer PCPDTBT (Fig. 12(b)).¹⁰³ As an efficient photothermal agent, PCPDTBT exhibits excellent NIR-II photothermal conversion, enables PT-mediated active targeting of OS cells, and supports high-resolution NIR-II fluorescence imaging for early, precise diagnosis.¹⁰⁴

4.2 Drug loading and release

Drug loading and release are key functions of inorganic nanocomposites, particularly in PTT, where combined drug delivery and targeted therapy enable multimodal strategies.^105,106 Nanomaterials efficiently load chemotherapeutic drugs and anticancer molecules due to their small size and large surface area, with external stimuli triggering timed drug release during PTT for synergistic therapy.

One important strategy relies on structural design to maximize drug-loading capacity. Nanomaterials with mesoporous architectures, hollow interiors, or high surface areas facilitate efficient encapsulation of therapeutic molecules. For example, Lu et al. designed mesoporous silica-coated bismuth sulfide NPs with a unique mesopore distribution and a large surface area, achieving 98.5% DOX encapsulation.¹⁰⁷ This porous structure enabled substantial drug loading and provided a suitable carrier framework for subsequent controlled release under low-power NIR irradiation, thereby reducing systemic side effects while enhancing delivery efficiency.

Surface modification represents another major approach to improving drug loading and modulating drug–carrier interactions. Curcumin (CM), a polyphenolic compound with antioxidant, anti-inflammatory, and anticancer properties, inhibits OS cells by regulating the HMOX1, JAK-STAT, and Smad signaling pathways, as well as microRNA/gene expression.^108–112 Sun et al. developed two CM-based nanomaterials: CM–CS nanoparticles and CM-PDA/SF/n-HA nanofibers.^113,114 The abundant functional groups in these materials promote interactions with CM, allowing high loading levels and extended retention. In vitro experiments showed that MG-63 cell viability decreased from 60% to 20% when cocultured with CM-PDA/SF/1% n-HA under NIR irradiation. NIR not only directly inhibits tumor growth via hyperthermia but also enhances CM permeability and release efficiency, demonstrating the combined benefits of surface-engineered loading and triggered release.

Triggered and stimuli-responsive release constitutes an additional strategy that improves therapeutic precision. Tan et al. embedded CM and ICG in PLGA hydrogels to form injectable formulations.¹¹⁵ In an orthotopic OS model (Fig. 13(a)), the hydrogel + NIR group showed significant tumor elimination, with live/dead staining (green/red) confirming efficacy (Fig. 13(b)). Tumor cell viability was 115.1% (MC hydrogel), 96.0% (Cur-MPs hydrogel), 55.8% (IR820 hydrogel + laser), and 23.9% (Cur-MP/IR820 hydrogel + laser) (Fig. 13(c)). Drug release studies showed prolonged CM release from microspheres/hydrogels for sustained therapy (Fig. 13(d)), with NIR-induced local hyperthermia accelerating release (Fig. 13(e)). After the treatment concluded, continued observation was conducted on tumor growth (Fig. 13(f)) and body weight changes (Fig. 13(g)). Post-treatment monitoring revealed rapid tumor growth in the control and MC gel groups, slower growth in the Cur-MP solution groups, and delayed growth in the Cur-MP/IR820 groups. Hydrogel-enabled sustained local drug concentrations, combined with IR820-mediated PTT, achieved strong tumor ablation, especially in the Cur-MP/IR820 + laser group, where hyperthermia accelerated CM release for synergistic elimination of OS. By day 17, tumors in the IR820 gel + laser and Cur-MP/IR820 + laser groups were significantly smaller than those in the other groups (Fig. 13(h)). These results highlight the importance of NIR-responsive systems for on-demand drug release and synergistic therapeutic outcomes.

Fig. 13 (a) Scheme of antitumor experiment. (b) Live and dead staining of tumor cells (2 h) after treatment with control MC gel, Cur-MPs gel, IR820 gel + laser, and Cur-MP/IR820 gel + laser (scale bar, 250 µm; border view, hydrogel boundary; central view, the center area of the hydrogel). (c) Cell survival rate of tumor cells cocultured and in direct contact with hydrogels in different groups. (d) Cumulative in vitro drug release studies of Cur-free, Cur-MPs, and Cur-MP-gel for 72 h and (e) cumulative drug release studies of Cur-MP/IR820 gel + laser for 192 h (red arrow: laser irradiation). (f) Recorded body weight of the Balb/c mice after the implantation of materials. (g) Tumor volumes recorded during the 17-day treatment period. (h) Weight evaluation of tumor and bone tissue (G1, control; G2, MC gel; G3, Cur-MPs solution; G4, IR820/Cur-MPs gel; G5, IR820 gel + laser; G6, Cur-MP/IR820 gel + laser). p < 0.05, p < 0.01.¹¹⁵ Copyright 2021, ACS Applied Materials Interfaces.

Through structural engineering, surface functionalization, and the integration of stimuli-responsive mechanisms, inorganic nanocomposites can achieve high drug-loading efficiency and precise spatiotemporal release. The studies discussed above collectively demonstrate how these strategies enhance the therapeutic performance of curcumin, doxorubicin, and related agents in bone tumor PTT, enabling more effective and controlled multimodal treatment.

4.3 Imaging-assisted monitoring

Imaging technologies significantly enhance PTT precision and real-time controllability, advancing theranostic nanoplatforms for bone tumors.¹¹⁶ Traditional PTT relies on external thermal feedback, lacking real-time monitoring and precise tumor localization, which is particularly limiting for deep-tissue therapy. Researchers have developed inorganic nanocomposites that integrate imaging and photothermal properties, enabling visual, controllable, and precise therapy via photoacoustic imaging, magnetic resonance imaging, and other modalities.

4.3.1 The combination of photoacoustic imaging and photothermal therapy. PAI, a hybrid imaging technique that combines optical contrast with ultrasound's high spatial resolution and tissue penetration, has gained attention in tumor diagnosis, treatment monitoring, and the visualization of nano-drugs. PAI works by irradiating tissues with short-pulse lasers. Light energy is absorbed by endogenous or exogenous dyes and converted into heat, causing local thermoelastic expansion and generating ultrasonic signals, which are received by transducers and reconstructed into images. Sun et al. developed a bone-targeted nano-platform by encapsulating gold nanorods in mesoporous silica nanoparticles (Au@MSNs) and conjugating them with zoledronic acid (ZOL).¹¹⁷ Gold nanorods function as both NIR thermal agents and photoacoustic contrast agents, while mesoporous silica provides excellent biocompatibility and drug-loading capacity.¹¹⁸ ZOL, as a bone-targeting agent, promotes nanoparticle accumulation in bones, enhancing anticancer efficacy and inhibiting bone resorption. Using photoacoustic imaging and in vivo thermal infrared imaging, Sun et al. evaluated the bone-targeting ability of Au@MSNs-ZOL and analyzed the nanoparticle distribution in the liver and kidney via ex vivo tissue fluorescence imaging.¹¹⁷ Experiments showed that Au@MSNs-ZOL combined with NIR irradiation significantly inhibited tumor growth, alleviated pain, and reduced bone resorption by inducing cancer cell apoptosis and improving the bone microenvironment (Fig. 14(a)). Fluorescence intensity of Au@MSNs-ZOL-FITC in ex vivo tissues showed that nano-particles primarily accumulated in the liver at 4 h post-injection, with significantly reduced levels at 24 and 48 h. Minimal accumulation was observed in the kidney (Fig. 14(b)). Compared to controls, tumor volume was significantly smaller in the Au@MSNs-ZOL treatment group and drastically reduced to 21.25 ± 16.4 mm³ in the Au@MSNs-ZOL + NIR group (Fig. 14(c)). Tumor weight showed a similar trend, with no significant differences in mouse body weight among the groups (Fig. 14(d)).

Fig. 14 (a) Timeline of the treatment schedule. A mouse model of breast cancer bone metastasis was established by directly injecting MDA-MB231 cells into the left hindlimb of nude mice. Nanoparticles and NIR irradiation were administered as indicated. (b) Representative fluorescence images of the ex vivo heart, lung, spleen, liver, kidney, and bone at 4, 24, and 48 h after administering the intravenous injection of Au@MSNs-ZOL-FITC. The colored scale represents the fluorescence signal, which quantifies the number of Au@MSNs-ZOL-FITC. (c) Tumor volumes. (d) Tumor weights.¹¹⁷ Copyright 2019, ACS Nano. (e) 1064 nm laser activatable semiconducting polymer-based nanoparticles used as all-in-one phototheranostic nanoplatforms for dual-modal NIR-II fluorescence/NIR-II photoacoustic imaging-guided orthotopic tumoral treatment. (f) Photothermal conversion of P2NPs under a laser irradiation of 1064 nm (1.0 W cm⁻²). (g) Cellular uptake behavior of P2NPs in 143B cells under an NIR-II imaging setup. (h) In vitro PAI of diverse levels of laser irradiation at 1064 nm.¹¹⁹ Copyright 2022, Elsevier B.V.

Recently, Li et al. developed a novel 1064 nm-activated semiconductor polymer-based nano-platform (P2NPs) integrating NIR-II fluorescence imaging, NIR-II photoacoustic imaging-guided PTT (Fig. 14(e)).¹¹⁹ At the maximum permissible exposure (MPE: 1.0 W cm⁻²), P2NPs at concentrations of 0.02, 0.04, and 0.08 mg mL⁻¹ reached temperatures of 50.0 °C, 55.1 °C, and 68.4 °C under 1064 nm laser irradiation, compared to an 8.5 °C rise in pure water (Fig. 14(f)). PAI brightness and signal intensity increased linearly with P2NPs concentration (Fig. 14(g)). NIR-I imaging showed efficient uptake of P2NPs by 143B human OS cells due to the DSPE-mPEG2000-RGD coating, laying a foundation for subsequent therapy (Fig. 14(h)). This study confirmed P2NPs’ specific binding to OS cells and efficient PTT efficacy under 1064 nm irradiation, providing a new strategy for bone tumor theranostics and treatment tracking.

4.3.2 The combination of magnetic resonance imaging and photothermal therapy. MRI, a non-invasive imaging method with high spatial resolution, has been increasingly applied in PTT. Zhang et al. synthesized Fe₃O₄ NPs via the hydrothermal method using ferric chloride as a precursor, then coated them with PDA to prepare Fe₃O₄@PDA nanocomposites.¹²⁰ This material exhibits excellent biocompatibility and low toxicity in human and animal models, significantly enhancing the signal-to-noise ratio of T₂-weighted MRI and improving OS imaging quality. In mice, 6 hours after tail vein injection of Fe₃O₄@PDA solution (5 mg kg⁻¹), the SNR of T₂-weighted MRI in tumor regions decreased from 4.92 ± 1.61 to 3.23 ± 1.39, with a contrast enhancement of 34.34% ± 2.78%. This improvement is primarily attributed to the enhanced permeability of tumor vessels and the EPR effect, which enables the long-term accumulation of Fe₃O₄@PDA in tumor regions, supporting the potential for early diagnosis and PTT.

Recently, Du et al. developed a dopamine-multivalently modified polyaspartic acid-chelated superparamagnetic iron oxide and iron ion nano-photothermal agent (SPIO@PAsp-DAFe/PEG) for MRI-guided NIR thermal therapy.¹²¹ Experiments showed that MRI can monitor the accumulation of nanocomposites in tumor regions in real-time after intravenous injection and determine the optimal time window for PTT. Under MRI guidance, SPIO@PAsp-DAFe/PEG demonstrated excellent therapeutic efficacy, significantly inhibiting mouse tumor growth without observable toxicity, thereby confirming its potential as a high-efficiency T₂-weighted MRI/PTT agent. Although this study was not performed in a bone tumor model, its demonstration of MRI-monitored biodistribution and image-guided photothermal intervention provides mechanistic insights and methodological strategies that are directly relevant to the development of multifunctional nanotheranostics for precise and minimally invasive treatment of bone malignancies.¹²¹

4.4 Combination of photothermal therapy and photodynamic therapy

The combination of PTT and PDT offers an efficient and precise multimodal approach for treating bone tumors.¹²² Inorganic nanocomposites enable the synergistic combination of PTT and PDT within a single system, significantly enhancing therapeutic efficacy. Studies have shown that combined PTT–PDT is more effective than single modalities: PDT increases tumor cell thermal sensitivity, which enhances PTT, while PTT improves tumor perfusion and oxygenation, which promotes the generation of PDT-induced reactive oxygen species.^123–125 This synergy reduces photosensitizer dosage and associated side effects, offering a promising approach for precise bone tumor therapy. Metal oxides can act as photothermal agents under NIR irradiation. However, their limited catalytic activity restricts therapeutic efficacy. To address this, Liang et al. loaded RhRu bimetallic hybrid nanoenzymes onto 2D Ti₃C₂ nanosheets, thereby constructing a RhRu/Ti₃C₂ composite system that significantly enhances the catalytic activity of nanoenzymes. In vitro and subcutaneous OS xenograft models showed that the system achieves synergistic PDT and PTT under 808 nm NIR irradiation, demonstrating significant therapeutic advantages.¹²⁶

Bismuth-based nanomaterials exhibit synergistic PTT–PDT potential, efficiently generating ROS under NIR irradiation.¹²⁷ Cheng et al. synthesized AgBiS₂ nanoparticles via a simple solvothermal method, achieving a high photothermal conversion efficiency of 36.51% under NIR irradiation and significantly promoting ROS production.¹²⁸ In vitro experiments demonstrated that the material effectively kills tumor cells through synergistic PTT/PDT. In vivo experiments confirmed significant growth inhibition of highly malignant OS. In animal studies, tumor temperature rapidly reached ∼51 °C after intratumoral injection of AgBiS₂ nanoparticles (5 mg kg⁻¹) followed by NIR irradiation (808 nm, 1 W cm⁻², 10 min) (Fig. 15(a)), enabling effective thermal ablation. To verify PDT efficacy, H₂O₂, singlet oxygen, and ROS production were measured in UMR-106 OS cells, revealing a significant elevation of H₂O₂ only in the AgBiS₂ + NIR group over time (Fig. 15(b)), with no apparent changes in the material-only or NIR-only groups, confirming that ROS generation depends on their synergy. In OS-bearing mice, AgBiS₂ or NIR alone had no significant effect on tumor growth (Fig. 15(c)). In contrast, the AgBiS₂ + NIR group significantly inhibited tumor progression, with live/dead staining showing nearly all tumor cells were dead (red fluorescence) compared to predominantly live cells (green fluorescence) in other groups (Fig. 15(d)). Histopathological analysis further validated the efficacy: H&E staining showed severe disruption of tumor tissue structure with no intact cells in the AgBiS₂ + NIR group, while other groups retained intact tumor structures (Fig. 15(e)); no significant differences in primary organ morphology were observed, indicating good biosafety (Fig. 15(f)). In summary, AgBiS₂ nanoparticles achieve precise, efficient OS treatment via synergistic photothermal and photodynamic effects, with promising prospects and tissue compatibility.

Fig. 15 (a) IR images of the OS-bearing mice captured every 2 min (from left to right), showing the temperature changes at the tumor site under NIR (808 nm, 1 W cm⁻²) irradiation. (b) H₂O₂ concentration released by the UMR-106 cells after different treatments. H₂O₂ was generated over time only in the AgBiS₂ + NIR group. (c) Tumor volume growth curves of different treatment groups. (d) Fluorescence images after live/dead staining of the UMR-106 cells in different groups. (e) H&E staining of tumors after different treatments. (f) H&E staining of the principal organs of different treatment groups.¹²⁸ Copyright 2020, Elsevier B.V.

Recently, Zhang et al. developed a 3D porous n-HA/g-C₃N₄/MXene scaffold with a hierarchical structure and nano-surface morphology, which enables simultaneous in situ treatment of bone tumors and repair of bone defects.¹²⁹ Studies showed that the scaffold rapidly heats to 45 °C within ∼3 min under 808 nm laser irradiation, exhibiting excellent photothermal performance. The combination of Ti₃C₂ and g-C₃N₄ promotes electron generation and reduces the bandgap width, significantly increasing ROS production. Additionally, n-HA enhances the inhibition of OS cells, enabling rapid tumor eradication within 10 min of NIR irradiation. Meanwhile, n-HA in the scaffold promotes the proliferation of bone marrow mesenchymal stem cells, their osteogenic differentiation, and the expression of osteogenic-related genes, thereby accelerating new bone formation. This multifunctional scaffold offers an efficient photothermal–photodynamic synergistic strategy for treating bone tumors while creating a favorable microenvironment for bone defect repair, providing a new clinical solution.

5. Conclusion and outlook

With the integration of nanomedicine and PTT, inorganic nanocomposites have demonstrated unprecedented multifunctional potential and therapeutic advantages in the treatment of bone tumors. These materials not only exhibit excellent photothermal conversion efficiency but also enable tumor targeting, imaging guidance, controlled drug release, immune activation, and bone regeneration through multi-component synergistic design. This multifunctionality provides novel approaches for the precise treatment of deep bone tumors. From metal-based (Au, Ag), carbon-based (CNTs, GO, CDs), and transition-metal sulfides (MoS₂, WS₂) to emerging MXenes and black phosphorus, diverse material platforms have enriched PTT technologies for bone tumors, accelerating the implementation of theranostic concepts.

Although the current review provides a comprehensive summary of recent achievements, several critical challenges remain insufficiently emphasized. A major unresolved issue is the limited targeting efficiency of many inorganic nanocomposites, which restricts their ability to achieve precise accumulation within deep or heterogeneous bone tumor tissues. Another significant concern lies in the absence of standardized approaches for evaluating long-term biosafety. Systematic investigations into chronic toxicity, metabolic pathways, and immunological responses are still lacking, which hinders the reliable assessment of clinical suitability. Furthermore, the translation of inorganic nanocomposite-based photothermal therapy into clinical practice faces substantial barriers. These include difficulties in large-scale, reproducible manufacturing, high production costs, variability in therapeutic response due to tumor heterogeneity, and the limited penetration depth of near-infrared light in dense osseous structures. Addressing these challenges is essential for advancing the clinical application of photothermal therapy and guiding the next stage of material design and translational research.

However, clinical translation of inorganic nanocomposites faces multiple challenges. First, long-term in vivo metabolism, cumulative toxicity, and immune responses remain unclear and require systematic toxicological evaluation. Second, balancing photothermal efficiency with biodegradability, environmental responsiveness, and tissue selectivity remains a key design challenge. Additionally, bone tumor heterogeneity, microenvironmental complexity, and limited light penetration in deep tissues pose higher technical barriers for PTT. Therefore, the efficient and precise construction of multifunctional nano-platforms, the development of biodegradable multifunctional materials, the optimization and development of new photothermal materials, and the acceleration of clinical translation and application will become important research directions in the future (Fig. 16).

Fig. 16 Prospects of inorganic nanocomposites for the PTT of bone tumors.

In summary, composite nanomaterial-enabled PTT presents a transformative approach for treating bone tumors. Through interdisciplinary collaboration and advancements in materials technology, inorganic nanocomposites are expected to accelerate the translation of basic research into clinical applications, facilitating the development of precise, personalized, and synergistic bone tumor therapies and improving patient outcomes with safer, more effective treatments.

Author contributions

Yanliang Jiao: writing–original draft, writing–review and editing. Yan Zhang: writing–review and editing. Chuanhui Dong: editing. Jing Zhu: editing. Wenjian Chen: conceptualization, funding acquisition, project administration. Tao Xu: conceptualization, funding acquisition, project administration. Sheng Ye: conceptualization, funding acquisition, project administration. Yibin Du: conceptualization, funding acquisition, project administration, supervision.

Conflicts of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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.

Acknowledgements

This work received financial support from the National Natural Science Foundation of China (22372001), Anhui Natural Science Foundation for Outstanding Young Scholars (2408085Y008), the Starting Fund for the Scientific Research of High-Level Talents at Anhui Agricultural University (rc382108), and Fengyang County Science and Technology Planning Project (2024SF–02). The authors acknowledge the financial support from the National Natural Science Foundation of Department of Education of Anhui Province Outstanding Young Teacher Training Project (YQZD2023023), Anhui Province University Outstanding Youth Research Project (2024AH020006), Anhui Provincial Health Research Program (AHWJ2022b113), the Basic and Clinical Collaboration Program of Anhui Medical University (2022sfy004), Anhui Province Traditional Chinese Medicine Inheritance and Innovation Research Project (2024CCCX287), and the Major Project of Scientific Research in Universities of Anhui Province (2023AH040087).

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Footnote

† These authors contributed equally to this work.

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