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Review

Application of Metal-Doped Nanomaterials in Cancer Diagnosis and Treatment

by
Xinhao Jin
1,2,3,4,5 and
Qi Sun
1,2,3,4,5,*
1
Department of Pharmaceutics, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
2
Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing 100069, China
3
Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing 100069, China
4
Beijing Laboratory of Biomedical Materials, Beijing 100069, China
5
Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
*
Author to whom correspondence should be addressed.
J. Nanotheranostics 2025, 6(4), 35; https://doi.org/10.3390/jnt6040035
Submission received: 19 October 2025 / Revised: 29 November 2025 / Accepted: 15 December 2025 / Published: 17 December 2025
(This article belongs to the Special Issue Feature Review Papers in Nanotheranostics)
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Abstract

Cancer remains a severe global health threat, with traditional therapies often plagued by limited efficacy and significant side effects. The emergence of nanotechnology, particularly metal-doped nanomaterials, offers a promising avenue for integrating diagnostic and therapeutic functions into a single platform, enabling a theranostic approach to oncology. This article explores the design and application of various metal-doped nanosystems, including gadolinium-doped selenium molybdenum nanosheets for magnetic resonance/photoacoustic dual-mode imaging and photothermal therapy, and metal-doped hollow mesoporous silica nanoparticles that leverage the tumor’s acidic microenvironment to release ions for catalytic generation of reactive oxygen species. Despite their promise, the limited enzyme-like activity of some nanozymes, insufficient endogenous hydrogen peroxide in tumors, and the tumor microenvironment’s defensive mechanisms, such as high glutathione levels, can restrict therapeutic efficacy. Looking forward, the outlook for the field is contingent upon advancing material engineering strategies. Future research should prioritize the development of intelligent, multifunctional nanoplatforms that can dynamically respond to and remodel the tumor microenvironment. Innovations in surface modification for enhanced targeting, alongside rigorous preclinical studies focused on safety and standardized manufacturing, are crucial for bridging the gap between laboratory research and clinical application, ultimately paving the way for personalized cancer medicine.

1. Introduction

Cancer remains one of the most formidable challenges in modern medicine, affecting millions of lives globally. The Global Burden of Disease Study 2023 estimates that there were approximately 18.5 million new cancer cases (excluding non-melanoma skin cancer) and 10.4 million cancer deaths worldwide in 2023, consolidating cancer’s position as the second leading cause of death globally, behind only cardiovascular disease [1]. While traditional therapeutic modalities, including chemotherapy, surgery, radiotherapy and hormonal therapy, have made significant strides but are often limited by their non-specific toxicity, acquired drug resistance, and substantial inter-patient heterogeneity [2]. These limitations underscore the urgent need for more precise, less invasive, and biologically informed treatment strategies.
In response, nanotechnology has ushered in a transformative approach through cancer theranostics, which integrates diagnostic imaging and therapeutic functions within a single agent. Among these advancements, metal-doped nanoplatforms represent a cutting-edge advancement in the field of cancer theranostics. Transition metals (Mn, Fe, Cu, Ru) and lanthanides (Gd, Tb, Yb) possess partially filled d- or f-orbitals, endowing them with superparamagnetism, X-ray attenuation, and Fenton/Fenton-like catalysis—properties unattainable with purely organic carriers [3]. By integrating these dopants into silica, scintillator, or metal–organic-framework (MOF) matrices, researchers have created all-in-one agents that provide real-time anatomical/molecular feedback, amplify oxidative damage inside tumors, and convert external energy (light, ultrasound, X-ray, radiofrequency) into cytotoxic heat or radicals [4,5,6,7,8].
This review aims to critically analyze the development of metal-doped nanoplatforms from a unique perspective: their evolving capacity for functional integration within the complex tumor microenvironment (TME). We propose a systematic framework to evaluate these platforms based on three critical dimensions: functional complexity (from single imaging or therapy to synergistic multi-modal approaches), TME-responsive intelligence (from passive targeting to active stimulus-responsive reactions), and systemic biological impact (from localized tumor eradication to the induction of sustained antitumor immunity). For instance, Wang, S. et al. [9] demonstrated a manganese-doped liquid-metal/silica nanoplatform (Mn-LMOP) with tunable stiffness for enhanced cellular uptake. Under near-infrared (NIR) irradiation, it not only mediated photothermal therapy (PTT) but also released Mn2+ ions to deplete glutathione (GSH) and catalyze hydroxyl radical production for augmented chemodynamic therapy (CDT), effectively eliminating primary tumors and stimulating systemic immunity. Similarly, Jiang et al. [10] developed Ti-Zr bimetallic-organic nanosheets (TiZr-MOLs) with Ru(III) catalysts that, upon ultrasound activation, amplified oxidative stress and triggered robust immunogenic cell death, leading to complete tumor regression in murine models. These examples underscore a paradigm shift from simple drug carriers to sophisticated, multi-functional systems that actively interact with and modulate the TME.
Despite their promise, the clinical translation of metal-doped nanoplatforms faces several challenges. Biodistribution profiling consistently reveals rapid and long-lasting sequestration in liver and spleen, primarily due to uptake by the reticulo-endothelial system (RES) [11,12,13]. Additionally, repeated dosing often elicits anti-PEG antibodies, which accelerate blood clearance and further complicate therapeutic efficacy. In response, surface-engineering efforts have shifted from conventional PEGylation to alternative coatings, such as zwitterionic or phosphorylcholine materials. These new coatings effectively reduce RES uptake and significantly prolong circulation time in non-human primates. However, these advancements in surface engineering are only part of the solution. Scalability issues also pose substantial limitations. Noble-metal precursors, which are commonly used in these nanoplatforms, exhibit significant batch-to-batch compositional variability. Moreover, their raw material costs are orders of magnitude higher than those of base metals. These factors restrict current Good Manufacturing Practice (GMP) synthesis to small, gram-scale lots, thereby impeding large-scale production and clinical adoption [11].
This review will systematically explore these aspects, offering a critical analysis that distinguishes it from previous summaries. By applying the proposed framework, we will not only catalog existing designs but also assess their maturation towards becoming truly intelligent theranostic systems. Finally, we will discuss the key challenges and outline future directions focused on rational material design, improved biocompatibility, and scalable manufacturing, which are essential for bridging the gap between laboratory innovation and clinical application in personalized oncology.

2. Properties and Applications of Metal-Doped Nanomaterials

By precisely regulating the type and content of doped metals as well as the structure of nanocarriers, metal-doped nanomaterials exhibit specific optical, electrical, magnetic, and chemical activities, thereby achieving the synergistic optimization of imaging and therapeutic functions. Nanomaterials doped with these elements demonstrate outstanding catalytic activity, magnetic responsiveness, and optical performance, making them particularly suitable for CDT [14], radiotherapy (RT) [15], and precise treatment guided by multimodal imaging [16].

2.1. Manganese-Doped Mesoporous Silica Nanoparticles (Mn-SMSNs)

Mesoporous silica nanoparticles (MSNs) possess excellent biocompatibility, a porous structure, and a large specific surface area, making them ideal candidates for delivering drugs and functional elements [17,18]. The introduction of manganese (Mn) not only endows Mn-SMSNs with magnetic responsiveness but also significantly enhances their chemodynamic activity, enabling the synergistic effect of CDT and tumor imaging (Figure 1) [19,20]. In the tumor microenvironment (TME), characterized by weakly acidic and elevated H2O2 levels, Mn2+ ions can catalyze H2O2 to generate highly cytotoxic hydroxyl radicals (·OH) through a Fenton-like reaction, effectively killing cancer cells [21,22]. Meanwhile, the released Mn2+ can also deplete intratumoral GSH, reverse its immunosuppressive microenvironment, and trigger antitumor immune responses by activating the cGAS-STING pathway, which subsequently activates CD8+ T cells and initiates an antitumor immune response [23,24,25,26]. Furthermore, as a positive contrast agent for magnetic resonance imaging (MRI) T1-weighted imaging, Mn2+ allows real-time monitoring of the accumulation of nanoparticles at tumor sites and the therapeutic effect of CDT, PPT and PDT [22,27,28,29]. For instance, Qin et al. [19] constructed Mn-SMSNs that were further co-loaded with doxorubicin (DOX) and the NIR dye IR-780. The resulting Mn-SMSN@DOX-IR-780 simultaneously functions as a T1-MRI contrast agent and a CDT nanocatalyst. In vitro studies on prostate-cancer cells showed that the particles evoked massive reactive oxygen species (ROS) production, significantly inhibited cell migration, and enabled real-time fluorescence/NIR imaging, exemplifying a true “see-and-treat” nano-theranostic.

2.2. Terbium-Doped Gadolinium Tungstate Nanoscintillators (GWOT NPs)

GWOT NPs represent a class of multifunctional nanoscintillators composed of a gadolinium tungstate (Gd2(WO4)3) matrix with terbium ions (Tb3+) uniformly doped within the crystal lattice. The material leverages the complementary properties of its constituent elements: tungsten provides strong X-ray attenuation due to its high atomic number, gadolinium offers MRI contrast capabilities, and terbium serves as the primary luminescence center through its characteristic green emission peaks [30,31], making it an ideal synergistic system for radiotherapy-X-ray-induced photodynamic therapy (X-PDT) guided by dual-modal CT/MRI [32,33,34,35]. Under X-ray irradiation, GWOT NPs act as nanoscintillators, converting X-ray energy into visible light (e.g., green emission around 542 nm from Tb3+ dopants) [36]. This emitted light then activates surrounding photosensitizers (e.g., MC540), leading to the generation of ROS such as singlet oxygen (1O2) and achieving X-PDT [37]. Concurrently, the high atomic number (high-Z) elements within the NPs (Gd and W) enhance local radiation dose deposition, directly damaging cancer cells through radiotherapy (Figure 2) [38]. This results in a synergistic tumor-killing effect, as the combined DNA damage from RT and membrane damage from PDT overwhelm cellular repair mechanisms.
A key advantage of this approach over traditional PDT is the excitation source. Unlike traditional photodynamic therapy, which relies on visible light with a tissue penetration depth of <1 cm, X-rays have extremely strong deep tissue penetration capability up to several centimeters, enabling effective treatment of deep solid tumors [37]. Moreover, doping with Tb3+ can reduce the effective radiation dose of X-rays, minimize damage to normal tissues, and significantly improve the safety and applicability of treatment. Studies demonstrate that a low dose (e.g., 4–5 Gy) in combination with GWOT NPs can achieve tumor inhibition effects comparable to much higher doses of radiotherapy alone (e.g., 6–12 Gy) [39,40].

2.3. Bimetallic Systems

Bimetallic nanosystems leverage the synergistic interplay between two distinct metal elements to integrate multiple physicochemical properties, thereby enabling multifunctional theranostic platforms that combine diagnostic imaging, therapeutic action, and controlled drug release [41,42]. Table 1 showcases different bimetallic systems in cancer therapy. Among them, gold/silver (Au/Ag) nanostructures are prominent due to their significant and tunable surface plasmon resonance (SPR) effect [43,44]. The SPR effect arises from the collective oscillation of conduction electrons in these noble metals when excited by light, leading to strong absorption and scattering in the visible to NIR spectrum [45]. This tunability of the SPR effect is crucial for their widespread application in various fields. For instance, in Surface-Enhanced Raman Spectroscopy (SERS), the SPR effect significantly enhances the Raman scattering signals, enabling ultra-sensitive bio-imaging [46]. In PTT for tumor ablation, the SPR effect allows for the efficient conversion of light into heat, which can be used to destroy cancer cells [47]. Additionally, the SPR effect is harnessed in the design of light-responsive systems for intelligent drug release, where light can trigger the release of therapeutic agents [48].
The SPR peak position is highly dependent on several factors, including the material composition, shape, and size of the nanoparticles. For gold (Au) nanomaterials, the SPR peak can be tuned to the NIR region by adjusting the aspect ratio and shape of the na-noparticles [49]. This is particularly advantageous because light in the NIR region exhibits superior tissue penetration depth and causes minimal damage to normal tissues [50]. For example, gold nanorods with a high aspect ratio can have their SPR peaks shifted to the NIR region, making them suitable for deep-tissue imaging and PTT [51]. Ag nanomaterials, on the other hand, exhibit excellent Raman enhancement effects [52], and their surfaces can be easily modified to achieve pH responsiveness [53]. By regulating the ratio and morphology of the two metals (e.g., core–shell structure, alloy structure), Au/Ag nanostructures can simultaneously realize SERS imaging and photothermal ablation therapy. In such a system, the Ag component provides a strong electromagnetic “hot spot” effect, enabling high-sensitivity SERS imaging of tumor sites for accurate lesion localization [54]. Concurrently, the Au component efficiently converts NIR laser energy into localized heat, achieving effective photothermal ablation of tumors [55]. Remarkably, the intensity of the SERS signal is highly sensitive to the local environment and cellular integrity, allowing for the dynamic monitoring of tumor cell apoptosis during the treatment process, thus enabling real-time feedback on therapeutic efficacy [56]. For instance, bimetallic Au/Ag nanostructures have been engineered as single-particle theranostic agents that unite real-time Raman imaging, mild-temperature photothermal therapy and stimuli-responsive gene regulation. Wang et al. [57] synthesized urchin-like Au@Ag core–shell nanoparticles whose inter-metallic gap hotspots yield a SERS enhancement factor, allowing femtomolar detection of circulating miR-21 in blood. Upon 808 nm irradiation, the same nanostructures rapidly raise local temperature, sufficient for 95% death of cells yet low enough to avoid surrounding-tissue coagulation [54]. The Ag shell can be etched by tumor-acidic H2O2, liberating a pre-loaded CRISPR/Cas9 plasmid that targets Sox2; this combined photothermal-gene silencing strategy eradicated CD44+/CD24− breast-cancer stem cells in vivo and reduced lung-metastatic foci by 9-fold relative to control [54].
Table 1. Comparative analysis of different bimetallic systems in cancer therapy.
Table 1. Comparative analysis of different bimetallic systems in cancer therapy.
Bimetallic SystemsMetal CombinationKey Mechanisms of ActionKey Performance IndicatorsClinical Feasibility AnalysisReferences
Dual-Targeting NanozymeNot Specified (Likely contains Fe/Mn/Ce)1. Dual-targeted precise delivery
2. NIR-enhanced Ferroptosis/Apoptosis
3. Synergistic cell death
4. GSH depletion		1. High targeting specificity (>3 × non-targeted systems)
2. Significant tumor growth inhibition in xenograft models
3. Induces mitochondrial dysfunction		Moderate to High. The active targeting strategy may reduce off-target effects. NIR light is clinically applicable, but tissue penetration depth can be a limiting factor.[58,59,60]
Dendrimer-Entrapped NanozymePt-Cu1. TME regulation (pH, O2, H2O2)
2. Cascade catalytic therapy (CDT)
3. Regulable activity		1. Multi-enzyme-like activities (POD, CAT, SOD)
2. Synergistic enhancement of CDT and PTT
3. Inhibition of tumor growth and metastasis		Moderate. The use of precious metals (Pt) may increase cost. The sophisticated design for TME regulation is promising but requires validation of large-scale manufacturing and long-term safety.[61,62]
Mitochondria-Targeted NanozymeFe-Cu1. Mitochondria-specific targeting
2. Synergistic induction of Ferroptosis and Cuproptosis
3. Ion-interference therapy (IIT)
4. ROS generation under NIR		1. Efficient tumor accumulation
2. Disruption of mitochondrial function
3. Validated anti-tumor efficacy in vivo		Promising, but early stage. Leveraging essential metal ions (Fe, Cu) could improve biocompatibility. The novel mechanism of cuproptosis induction is significant, but its long-term metabolic profile needs thorough investigation.[63]
Layered Double Hydroxide (LDH) NanoplatformMg/Fe/Zn/Al1. Immunotherapy via TME modulation (Ca2+ chelation)
2. Reduces tumor stiffness
3. Promotes immune cell infiltration
4. Inhibits metastasis		1. Targets advanced, large-volume tumors
2. Activates anti-tumor immune response		High. Metal ions are biocompatible. The material’s ability to modulate the immunosuppressive TME is highly relevant for treating advanced cancers. Likely favorable safety profile supports clinical translation.[64,65,66]
Heterometallic Iron ComplexesFe with Pt, Pd, Au, Ru, etc.1. ROS generation
2. Apoptosis induction
3. Cell cycle arrest
4. Theranostic capabilities (e.g., MRI)		1. Activity against Pt-resistant cancers
2. Multiple mechanisms of action		Variable. These are typically small molecules, not nanoparticles. Their development is at an earlier stage. Clinical feasibility will depend heavily on the specific metal pair and its pharmacokinetic and toxicity profile.[67,68]
Au/Ag NanoparticlesAu-Ag1. Multiple synergistic therapy (PTT, PDT)
2. Drug delivery
3. Gene expression modulation		1. Effective in PTT/PDT
2. Capable of targeted drug delivery		High. Gold and silver nanostructures are well-studied with tunable properties. Their application in thermally based therapies is clinically feasible, though concerns about long-term biodistribution of silver may need addressing.[56,57,69]

2.4. Metal–Organic Frameworks (MOFs)

MOFs are porous crystalline materials formed by coordination bonds between metal ions or metal clusters and organic ligands [70]. They possess ultra-high specific surface area, tunable pore size, and abundant active sites. The structural and functional versatility of MOFs allows for precise engineering through strategic selection of metal nodes and organic ligands [71,72,73]. By incorporating diverse metal ions (e.g., Ti, Zr, Ru, Mn, Fe) into their frameworks, MOFs can be endowed with catalytic activity, photoresponsiveness, and immunomodulatory functions, and they exhibit outstanding performance especially in the synergy between ultrasound-guided therapy and immunotherapy [74,75,76,77]. Figure 3 manifests how MOF-based nanotherapeutics function in cancer diagnosis and therapy. Table 2 showcases diverse types of MOFs.
TiZrRu-MOF nanosheets represent an emerging type of multifunctional MOF material with significant potential in cancer therapy. Their layered structure not only facilitates drug loading (e.g., immune checkpoint inhibitors, chemotherapeutic drugs), but also exhibits excellent Fenton-like catalytic activity under ultrasonic stimulation [78]. The synergistic effect of Ti4+, Zr4+, and Ru3+ significantly reduces the activation energy of the Fenton reaction [79]. Meanwhile, the mechanical effect of ultrasound can destroy the dense structure of tumor tissue, promote the deep penetration of MOF nanosheets, and improve drug delivery efficiency. More importantly, the cancer cell death process induced by TiZrRu-MOF nanosheets is immunogenic cell death (ICD). The excessive ROS generated triggers the exposure and release of damage-associated molecular patterns (DAMPs) from dying cancer cell, such as ATP and HMGB1 [80,81,82]. These DAMPs act as potent “eat-me” signals that promote the maturation and antigen-presenting capacity of dendritic cells (DCs), enhancing their ability to prime the adaptive immune system. Subsequently, the activated DCs stimulate CD8+ cytotoxic T cells, which can then infiltrate tumor beds to eliminate residual cancer cells and target metastatic lesions. This process establishes a powerful “chemo-like killing–immune activation” cycle, which has shown great potential in effectively inhibiting tumor recurrence and metastasis [81,83].
Table 2. Comparative analysis of different MOFs in cancer therapy.
Table 2. Comparative analysis of different MOFs in cancer therapy.
MOFsMetal Nodes and Organic LigandsKey Mechanisms of ActionKey Performance IndicatorsClinical Feasibility AnalysisReferences
Zeolitic imidazolate framework-8 (ZIF-8) MOFsZn2+ with 2-methylimidazole1. Drug carrier
2. PTT
3. CDT by Zn2+		1. Drug loading capacity up to 20–30 wt%.
2. Temperature increase at the tumor site up to 30–40 °C under NIR irradiation.
3. In vitro cell experiments show tumor cell inhibition rates of 70–90%.		Moderate: Good biocompatibility, but Zn2+ may dissolve under certain conditions, requiring assessment of potential toxicity to normal tissues. Large-scale production and purification processes need optimization, and costs are relatively high.[84,85,86]
UiO-66 MOFsZr4+ with terephthalic acid1. Radiotherapy sensitization
2. Fluorescence imaging
3. Combination Therapy		1. Radiotherapy sensitization ratio of 1.5–2.0.
2. Fluorescence quantum yield of approximately 1–5%.
3. In animal experiments, tumor growth inhibition rate increased by 30–50% compared to radiotherapy alone.		Moderate. Zr4+ has good biostability, but degradation products of organic ligands may be toxic. The size and dispersibility of MOFs affect their distribution and metabolism in the body, requiring further optimization.[87,88,89]
MIL-100(Fe) MOFsFe3+ with 1,4-benzenedicarboxylic acid1. CDT by Fe3+
2. MRI Contrast		1. Increased ·OH generation rate in the acidic tumor microenvironment.
2. Transverse relaxation rate (r2) of approximately 10–20 mM−1 s−1.
3. In vivo experiments clearly show tumor sites, providing accurate positioning for treatment.		Moderate. Fe3+ is an essential element with relatively good biocompatibility. However, MRI effects are significantly influenced by MOFs size and concentration, and iron overload may occur during treatment.[90,91,92]
PCN-224 MOFsZr4+ with terephthalic acid and porphyrin1. PDT by porphyrin under light irradiation
2. Fluorescence and photoacoustic imaging		1. Singlet oxygen quantum yield of approximately 0.5–0.7.
2. Fluorescence lifetime of approximately 10–20 ns.
3. High signal-to-noise ratio in photoacoustic imaging, accurately displaying tumor boundaries and size.		Moderate. Porphyrin ligands have certain photostability, but their metabolic processes in the body are complex. Photosensitivity of PCN-224 may cause photodamage to normal tissues, requiring precise control of light irradiation parameters.[75,93,94]
HKUST-1 MOFsCu2+ with 1,3,5-benzenetricarboxylic acid1. CDT by Cu2+
2. Immunotherapy		1. Significant increase in ·OH and ·O2− generation in tumor tissues.
2. In vitro experiments promote polarization of TAMs from M2 to M1 type, enhancing antitumor immune responses.		Low to Moderate. Cu2+ has certain toxicity and may cause damage to organs such as the liver and kidneys. The stability and biodegradability of HKUST-1 need further research to ensure safety in the body.[95,96,97]

3. Synergistic Therapeutic Mechanisms and Applications

3.1. Chemodynamic Therapy

CDT utilizes metal ions (Fe2+, Cu+, Mn2+) to catalyze H2O2 hydroxyl radical production for tumor cell destruction. Given the limited H2O2 concentration of these cations in the TME, self-sustaining H2O2 supply can be achieved through glucose oxidase (GOx)-mediated glucose oxidation or addition of peroxide precursors like CaO2 [98,99,100]. This need for an enhanced H2O2 supply dovetails with the principles of starvation therapy (ST), which has garnered considerable attention by targeting the primary energy source, glucose, utilized by cancer cells for proliferation. GOx, a catalyst facilitating glucose consumption, has emerged as a critical therapeutic agent for ST. Specifically, the GOx-mediated consumption of glucose not only starves the tumor cells but also simultaneously generates a substantial amount of H2O2 in situ, which can then be utilized by the metal ions for highly efficient CDT [101].
A pioneering PGC-DOX nanoplatform has been developed, which employs GOx-mediated glucose depletion for starvation therapy while simultaneously generating H2O2 enhanced CDT effects [102]. Since GSH serves as a primary antioxidant scavenger of ·OH, strategies leveraging metal ion redox cycling, such as the Cu2+/Cu+ cycle, can amplify CDT efficacy. For instance, the Cu-T@MH nanoplatform releases Cu-T MOFs within the TME, simultaneously consuming GSH and producing ·OH to significantly inhibit tumor growth [103].
Furthermore, multicomponent synergies (e.g., Fe3O4-CuS) can expand pH adaptability and improve catalytic efficiency, making it effective even in the weakly acidic TME [104]. To overcome limitations of single-modality treatments, CDT is frequently combined with other therapeutic approaches. For instance, the integration of chemotherapy or photothermal therapy with CDT creates a combinatorial regimen that attacks cancer cells through multiple mechanisms, thereby significantly enhancing therapeutic outcomes [105,106].

3.2. Photothermal Therapy and Photodynamic Therapy

PTT employs photothermal materials, including gold, silver, carbon-based composites, rare-earth-doped nanomaterials and two-dimensional transition metal dichalcogenides, to convert light energy into thermal ablation, accomplishing rapid tumor ablation within minutes. The Ag-PDA hybrid system achieved 35.7% photothermal conversion efficiency under 808 nm laser irradiation (1 W/cm2), enabling complete tumor ablation [107]. Carbon-based composites can be designed to absorb specific wavelengths of light, generating ROS to kill cancer cells [108]. Two-dimensional materials such as molybdenum disulfide (MoS2) have garnered significant attention due to their exceptional optical and photothermal conversion properties. MoS2 nanosheets exhibit remarkable light absorption capabilities, especially in the NIR region, enabling efficient conversion of light energy into heat for photothermal therapy [109]. Additionally, MoS2 can be surface-functionalized to load drugs and achieve targeted delivery, thereby enhancing therapeutic efficacy.
PDT utilizes photosensitizers like porphyrins and indocyanine green (ICG) to generate ROS upon light activation. However, tumor hypoxia and intrinsic antioxidant GSH frequently blunt its efficacy [110]. To overcome this, Cai et al. [111] constructed CuTz-1-O2@F127 MOF therapeutic platform, presenting enhanced PDT by simultaneously overcoming intracellular hypoxia and reducing GSH levels in the tumor.
Combining PTT with PDT effectively addresses tumor hypoxia while reducing individual treatment doses. For instance, UiO-Ra-DOX-CuS simultaneously generates oxygen (1O2) and thermal energy under single-wavelength irradiation, achieving synergistic therapeutic effects. Upconversion materials convert near-infrared light into visible light to activate PDT, resolving tissue penetration depth limitations [89].
Magnetic Hyperthermia (MHT) is a technology that uses magnetic nanoparticles, such as superparamagnetic iron oxide nanoparticles (SPIONs), to produce heat under an alternating magnetic field (AMF) to treat diseases. Its core principle is that magnetic nanoparticles absorb magnetic field energy in the AMF and convert it into heat energy through mechanisms like Néel and Brownian relaxation, thus heating tumor tissue locally, resulting in the death of tumor cells [112,113]. Compared with PTT and PDT, MHT has better tissue penetration ability, because the AMF can penetrate deeper tissues [114]. For instance, a study reported that PEGylated 7-nm Mn0.5Zn0.5Fe2O4 SPIONs (PEG-MnZn-SPION-7) exhibited remarkably high T2 relaxivity (r2) and effectively elevate the temperature when subjected to an AMF [115].

3.3. Synergistic Therapeutic Strategies

The combination of multiple treatment modalities significantly improves efficacy while minimizing side effects. ST (e.g., glucose depletion via Glucose Oxidase catalysis) combined with CDT disrupts tumor energy supply and enhances oxidative stress. Researchers have developed the plasma trizyme-metallocene oxide (plasEnMOF) platform integrating glucose oxidase, catalytic oxidation (CAT), and horseradish peroxidase (HRP), enabling tri-modal therapy (starvation, hyperthermia therapy, CDT) under enhanced near-infrared II photothermal effects [85]. Combining chemotherapeutic agents with metal nanoplatforms enables pH or GSH-responsive drug release, reducing systemic toxicity. For example, PDA-encapsulated CPT@MIL-53(Fe) releases elatidine under acidic conditions while Fe3+ participates in the Fenton reaction for CT/CDT synergy [107]. Immunotherapy (e.g., PD-L1 antibody) activates systemic anti-tumor immunity and inhibits metastasis. Sonodynamic therapy (SDT) utilizes ultrasound-induced photosensitizers (e.g., MnCO3) to generate ROS, making it suitable for deep tumor treatment [116]. Figure 4 demonstrates synergistic therapy mechanism of GOx-metal catalyst-based NPs (G-M) from different therapeutic agents.
Future development will focus on the synergistic advancement of multiple key directions. The primary task is to develop novel biodegradable nanomaterials, such as fully organic systems or bioabsorbable metals, to enhance biosafety. Building on this, it is necessary to further optimize surface engineering strategies, aiming to significantly improve the targeting efficiency and immune compatibility of materials. Concurrently, exploring more efficient synergistic therapeutic mechanisms, such as combined immunotherapy or intelligent drug release systems controlled by logic gates, will also be a key research focus. Ultimately, by vigorously promoting clinical translation research and establishing standardized preparation and evaluation systems, it is expected to accelerate the implementation of these technologies. With the deep integration of nanotechnology, biomaterials, and medicine, metal-doped nanoplatforms are expected to achieve clinical breakthroughs within the next decade, providing powerful tools for precision oncology.
In summary, collaborative therapeutic strategies utilizing metal nanomaterials are driving the evolution of cancer treatment toward higher efficacy, precision, and intelligent approaches. Through interdisciplinary integration, these advanced nanotechnology platforms are poised to be successfully translated into clinical applications in the near future, providing a powerful new weapon in the fight against cancer.

4. Conclusions and Outlooks

Metal-doped nanoplatforms represent a transformative paradigm in cancer theranostics by seamlessly integrating diagnostic imaging and targeted therapy within a single, multifunctional system. These advanced nanomaterials leverage the unique physicochemical properties of transition metals and rare earth elements to enable precise tumor visualization, enhanced therapeutic efficacy, and real-time treatment monitoring. From manganese-doped mesoporous silica nanoparticles that facilitate CDT and MRI-guided intervention, to terbium-doped nanoscintillators enabling deep-tissue X-ray-induced photodynamic therapy, these platforms demonstrate unprecedented versatility. Bimetallic systems such as Au/Ag nanostructures further expand functionality through combined SERS imaging, photothermal ablation, and stimuli-responsive drug delivery, while MOFs like TiZrRu-MOFs amplify ROS generation under ultrasound and promote robust antitumor immunity via immunogenic cell death.
Despite their immense potential, clinical translation faces critical challenges, including inconsistent batch production, high costs associated with noble metals, and complex biodistribution profiles. First, batch-to-batch variability remains a significant hurdle. Conventional bulk synthesis methods lack precise control over critical parameters such as temperature, mixing efficiency, and reaction time, leading to inconsistencies in nanoparticle size, morphology, and surface properties. This variability directly impacts the reproducibility of in vivo pharmacokinetics, biodistribution, and therapeutic efficacy, posing a major challenge for regulatory approval [117,118,119]. Second, high production costs, particularly those associated with noble metal precursors (e.g., Au, Pt, Pd), are prohibitive. Traditional methods often suffer from low reagent utilization, and the failure of a single batch results in substantial financial loss [120]. Furthermore, the complexity and expense of meeting GMP standards add another layer of cost. Finally, the complexity of GMP-level scalability and regulatory compliance presents a formidable obstacle. The “scale-up” from lab-bench to industrial-volume production is non-trivial, as changing reactor sizes and dynamics can alter product characteristics, complicating process validation and increasing regulatory risks.
To address these challenges, microfluidic technology represents a transformative synthesis platform based on continuous, precise fluidic control at the microscale. Operating within channels of tens to hundreds of micrometers, it facilitates superior control over reaction kinetics by enabling rapid mixing and efficient heat/mass transfer. This control is achieved by generating specific fluidic states—from laminar to vortex or turbulent flow—by adjusting the Reynolds number (Re) through channel design and flow rates. Such precise manipulation of the reaction environment, from nucleation to growth, is critical for achieving reproducible synthesis of nanomaterials with tailored sizes, morphologies, and complex structures like high-entropy alloys or multilayer core–shell quantum dots [118,121,122].
The core advantage of microfluidics lies in its ability to directly enhance production yield and batch consistency by intensifying fundamental processes. Within the confined microchannels, rapid mass and heat transfer ensures instantaneous and homogeneous mixing of precursors. This controlled environment separates the nucleation and growth stages more effectively than bulk methods, leading to nanoparticles with narrow size distributions and defined morphologies. This inherent control directly mitigates the issue of batch variability. Moreover, the continuous-flow nature of microfluidics reduces reagent consumption and waste, thereby addressing cost concerns associated with expensive precursors [117,123]. Perhaps most critically for translation, microfluidic systems facilitate a more reliable “scale-out” or numbering-up strategy for production scaling. By paralleling identical microreactor units, production volume can be increased without altering the well-defined reaction conditions established at the lab scale, significantly simplifying the path to GMP compliance and regulatory approval by ensuring process consistency across scales. Importantly, microfluidic technology directly addresses the high costs and scalability issues associated with noble-metal precursors. The precise control over reaction conditions minimizes waste and maximizes the utilization of expensive reagents, thereby reducing production costs. Additionally, the ability to scale production through parallelization of microreactors allows for the synthesis of gram-scale lots without compromising the quality and consistency of the nanoparticles. This scalability is crucial for meeting the demands of clinical applications while maintaining cost-effectiveness.
The application of microfluidic synthesis has already demonstrated significant success in producing a wide array of metal-doped nanomaterials with advanced functionalities. Notable examples include the continuous production of monodisperse silver and gold nanoparticles for plasmonic applications, the synthesis of complex core–shell structures (e.g., Fe3O4/graphene) for combined therapy and imaging, and the fabrication of MOFs with tailored pore structures for drug delivery. The technology’s precision is particularly valuable for creating bimetallic or high-entropy alloy nanoparticles and for engineering sophisticated heterostructures that integrate multiple therapeutic and diagnostic modalities. Looking forward, the integration of microfluidics with real-time monitoring, artificial intelligence for feedback control, and advanced manufacturing techniques like 3D printing will further unlock its potential [124]. This convergence promises to enable intelligent, patient-tailored nanomedicine manufacturing, ultimately accelerating the clinical translation of metal-doped nanoplatforms.
While significant progress has been made in the development of metal-doped nanoplatforms, several long-term translational barriers remain. Achieving scalable GMP production is a critical step for clinical translation, and microfluidic technology offers a promising solution by enabling precise control over reaction conditions and facilitating reliable scale-out strategies. Future efforts should focus on optimizing microfluidic systems for large-scale production while maintaining the high quality and consistency required for clinical use. Additionally, the high costs associated with noble metal precursors remain a significant barrier. Research into alternative, cost-effective materials and the development of efficient synthesis methods that maximize reagent utilization will be essential. Exploring the use of more abundant and less expensive metals could help reduce costs without compromising performance. Ensuring the safety and biocompatibility of metal-doped nanomaterials is paramount, and comprehensive in vitro and in vivo studies are needed to evaluate potential toxicity and long-term effects. Developing robust safety profiles will be crucial for gaining regulatory approval and public trust. Navigating the complex regulatory landscape is a formidable challenge, and collaborative efforts between researchers, industry, and regulatory bodies are necessary to establish clear guidelines and pathways for the approval of nanomaterial-based therapies. Engaging with regulatory agencies early in the development process can help streamline the approval process and reduce regulatory risks. Finally, the successful translation of metal-doped nanoplatforms will require multidisciplinary collaboration involving materials scientists, clinicians, engineers, and regulatory experts. Integrating diverse expertise will facilitate the development of innovative solutions and accelerate the transition from bench to bedside.
In summary, while metal-doped nanoplatforms hold great promise for cancer theranostics, addressing the challenges of scalable production, cost-effectiveness, safety, and regulatory compliance will be essential for their clinical adoption. Continued innovation and collaboration across disciplines will be key to overcoming these barriers and realizing the full potential of these transformative materials in clinical practice.

Author Contributions

Conceptualization, software, validation, resources, writing—original draft preparation, X.J.; writing—review and editing, visualization, supervision, project administration, funding acquisition, Q.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (No. 82304389) and R&D Program of Beijing Municipal Education Commission (No. KM202310025023).

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. (A) Schematic illustration for the synthesis of Mn-MSN@Met-M NPs. (B) Mn-MSN@Met-M NPs increase the local Mn2+ ion and metformin concentration; further promote the activation of STING. Adapted from ref. [20], https://doi.org/10.1016/j.isci.2024.110150 (19 July 2024), under the terms of the CC BY NC 4.0 license, http://creativecommons.org/licenses/by-nc/4.0/. (19 July 2024).
Figure 1. (A) Schematic illustration for the synthesis of Mn-MSN@Met-M NPs. (B) Mn-MSN@Met-M NPs increase the local Mn2+ ion and metformin concentration; further promote the activation of STING. Adapted from ref. [20], https://doi.org/10.1016/j.isci.2024.110150 (19 July 2024), under the terms of the CC BY NC 4.0 license, http://creativecommons.org/licenses/by-nc/4.0/. (19 July 2024).
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Figure 2. Mechanisms of high-Z NP radiosensitization. Reproduced from ref. [38], https://doi.org/10.3390/molecules29112438 (29 April 2024), under the terms of the CC BY 4.0 license, https://creativecommons.org/licenses/by/4.0/. (29 April 2024).
Figure 2. Mechanisms of high-Z NP radiosensitization. Reproduced from ref. [38], https://doi.org/10.3390/molecules29112438 (29 April 2024), under the terms of the CC BY 4.0 license, https://creativecommons.org/licenses/by/4.0/. (29 April 2024).
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Figure 3. Main scope of this perspective regarding the use of MOF-based nanotherapeutics for light-mediated cancer diagnosis and therapy. Reproduced from ref. [77], https://doi.org/10.1186/s12951-022-01631-2 (24 September 2022), under the terms of the CC BY 4.0 license, https://creativecommons.org/licenses/by/4.0/. (24 September 2022).
Figure 3. Main scope of this perspective regarding the use of MOF-based nanotherapeutics for light-mediated cancer diagnosis and therapy. Reproduced from ref. [77], https://doi.org/10.1186/s12951-022-01631-2 (24 September 2022), under the terms of the CC BY 4.0 license, https://creativecommons.org/licenses/by/4.0/. (24 September 2022).
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Figure 4. Synergistic therapy mechanism of G-M from different therapeutic agents. G-M NPs enter the tumor and release the therapeutic agents. GOx promotes glucose oxidation to achieve ST, which reduces pH and produces excessive H2O2. Meanwhile, the effect of PTT is enhanced with a decrease in ATP and heat shock protein (HSP) expression. Due to the catalysis of CAT-like and Fenton metals, H2O2 acts as a substrate for the next catalytic reaction, contributing to the generation of ·OH and O2. O2 production can enhance PDT and SDT. Moreover, the generation of ·OH forms the basis of CDT and immunotherapy and provides the possibility for ferroptosis. Moreover, PTT and PDT are induced by NIR I/II. SDT is generated by ultrasound (US). Electrodynamic therapy and CT can be combined with the G-M catalytic systems to achieve a more diverse synergistic therapy. Reproduced from ref. [101], https://doi.org/10.1186/s12951-023-02158-w (31 October 2023), under the terms of the CC BY 4.0 license, https://creativecommons.org/licenses/by/4.0/. (31 October 2023).
Figure 4. Synergistic therapy mechanism of G-M from different therapeutic agents. G-M NPs enter the tumor and release the therapeutic agents. GOx promotes glucose oxidation to achieve ST, which reduces pH and produces excessive H2O2. Meanwhile, the effect of PTT is enhanced with a decrease in ATP and heat shock protein (HSP) expression. Due to the catalysis of CAT-like and Fenton metals, H2O2 acts as a substrate for the next catalytic reaction, contributing to the generation of ·OH and O2. O2 production can enhance PDT and SDT. Moreover, the generation of ·OH forms the basis of CDT and immunotherapy and provides the possibility for ferroptosis. Moreover, PTT and PDT are induced by NIR I/II. SDT is generated by ultrasound (US). Electrodynamic therapy and CT can be combined with the G-M catalytic systems to achieve a more diverse synergistic therapy. Reproduced from ref. [101], https://doi.org/10.1186/s12951-023-02158-w (31 October 2023), under the terms of the CC BY 4.0 license, https://creativecommons.org/licenses/by/4.0/. (31 October 2023).
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Jin, X.; Sun, Q. Application of Metal-Doped Nanomaterials in Cancer Diagnosis and Treatment. J. Nanotheranostics 2025, 6, 35. https://doi.org/10.3390/jnt6040035

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Jin X, Sun Q. Application of Metal-Doped Nanomaterials in Cancer Diagnosis and Treatment. Journal of Nanotheranostics. 2025; 6(4):35. https://doi.org/10.3390/jnt6040035

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Jin, Xinhao, and Qi Sun. 2025. "Application of Metal-Doped Nanomaterials in Cancer Diagnosis and Treatment" Journal of Nanotheranostics 6, no. 4: 35. https://doi.org/10.3390/jnt6040035

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Jin, X., & Sun, Q. (2025). Application of Metal-Doped Nanomaterials in Cancer Diagnosis and Treatment. Journal of Nanotheranostics, 6(4), 35. https://doi.org/10.3390/jnt6040035

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