Towards precision medicine: design considerations for nanozymes in tumor treatment

Currently, there are three main modes of action of nanozymes used to treat tumors: direct action on tumors, indirect treatment of tumors by augmenting other therapeutic means, and enhancement of drug efficacy by combining drugs to treat tumors.

Since different tumors have different physiological environments and properties, the treatment of tumors with nanozymes cannot be generalized; here, we summarize the design and study of nanozymes in different types of tumors and look for correlations between the design of different types of nanozymes and different tumors (Table 2).

Table 2 Summary of nanozymes for the treatment of different cancersGliomas

Glioma, a prevalent primary brain tumor, is typically treated through a combination of surgical tumor resection, radiotherapy, and adjuvant chemotherapy. However, the highly invasive nature of glioblastoma multiforme (GBM) makes it nearly impossible to achieve complete surgical resection. Additionally, the effectiveness of traditional chemotherapeutic agents is significantly limited by their inability to penetrate the blood‒brain barrier and reach tumors [76, 77]. Moreover, the remarkable adaptability of glioblastoma multiforme (GBM) cells leads to the development of resistance to both chemotherapy and radiotherapy, further complicating treatment efforts [78].

Since conventional drugs penetrate the blood‒brain barrier very inefficiently, synthetic nanoparticles that can penetrate the blood‒brain barrier have become a new hope in the field of glioma therapy [79]. Most of the current mainstream research has focused on achieving therapeutic goals by wrapping traditional chemotherapeutic drugs for gliomas with nanoplatforms that can penetrate the blood‒brain barrier, while there are few studies on nanozymes applied to gliomas.

In a recent study, Shi et al. developed ultramicrocarbon dots supporting iron single-atom nanozymes (Fe-CDs) characterized by six enzymatic activities. These Fe-CDs can accurately intervene in the ROS-mediated autophagy signaling pathway, offering a novel strategy to overcome drug resistance in solid glioblastoma multiforme (GBM) tumors [17]. Fe-CDs are designed to accumulate within lysosomes, where they exhibit inherent oxidase/peroxidase (OXD/POD)-like activities that disrupt lysosomal degradation, thereby activating autophagic flux. Additionally, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)-like enzymes generate reactive oxygen species (ROS), which further enhance both autophagy and lysosomal apoptosis. To ensure precise delivery across the blood‒brain barrier (BBB), the Fe-CDs were functionalized with angiopep-2, resulting in Fe-CDs@Ang, which enhances the efficiency of drug delivery (Fig. 2A). Shi et al. discovered that the autophagy pathway is more effective at targeting drug-resistant glioma cells than the apoptosis pathway, suggesting that influencing the glioma autophagy pathway could provide a significant approach for nanozyme-based glioma therapy.

Fig. 2figure 2

Nanozymes used for treating gliomas. A Fe-CDs@Ang enhances the efficiency of penetrating the blood–brain barrier (BBB) through angiopep-2. Reproduced with permission [17]. Copyright 2022, Elsevier. B, C A Transwell apparatus was used to conduct BBB penetration experiments, and an 808 nm laser at a power of 1.0 W/cm2 was applied to appropriate samples. After 6 h of culture, 13.40% of PCN and 13.63% of PN had penetrated the BBB monolayer. Compared to cells that were not exposed to laser irradiation, the penetration rate for the PCN + near-infrared (NIR) group increased by 2.18 times. This finding suggests that PCN and PN can cross the BBB, and that near-infrared irradiation can significantly enhance this permeability. Reproduced with permission [82].Copyright 2023, ACS NANO. D The G@IT-R nanomachines interact differently with cancer cells and normal cells, enabling the implementation of distinct photothermal therapy (PTT) strategies. Reproduced with permission [54].Copyright 2023, Wiley

In addition to directly targeting gliomas, enhancing current glioma treatments represents a crucial research focus. Recently, photothermal therapy (PTT) has emerged as an effective method for treating gliomas. This approach leverages the conversion of light energy into heat upon exposure to specific wavelengths, selectively damaging or destroying tumor cells while minimizing harm to surrounding healthy tissue [80]. However, challenges such as the nonspecific accumulation of photothermal agents in tissues and the induction of an inflammatory response can adversely affect adjacent brain tissues. These factors may compromise the overall therapeutic efficacy of photothermal therapy (PTT) in the treatment of gliomas, necessitating careful consideration and management to optimize treatment outcomes and minimize collateral damage [81].

Zhang et al. developed a hybrid nanomaterial named Gd2O3@Ir/TMB-RVG29 (G@IT-R) specifically for photothermal therapy (PTT) treatment of gliomas [54]. This nanomaterial is designed to enable tumor-specific PTT while simultaneously mitigating inflammation, thereby safeguarding normal brain tissues. The Ir nanozymes within this system serve a dual purpose: they act as a logical control mechanism that initiates a chromogenic reaction for targeted PTT in tumor cells, and, crucially, in the surrounding normal brain tissue, they function to neutralize the reactive oxygen species (ROS) generated by the treatment. This dual functionality not only enhances the specificity of treatment for tumor cells but also offers protective benefits to adjacent healthy brain tissue, revealing a significant advancement in minimizing collateral damage during glioma treatment. Zhang et al. improved the drug delivery efficiency of nanomaterials by crossing the blood‒brain barrier (BBB) with the rabies virus glycopeptide 29 peptide (RVG29) and targeting gliomas.

In addition, Shi and Huang et al. designed a nanoenzymatic hemostatic matrix system (Surgiflo@PCN) [55], which acts as a photothermal agent while inducing immunogenic cell death after surgical resection of gliomas, which not only assists in enhancing therapeutic treatments but also exerts a killing effect on glioma cells (Fig. 2B, C). While the first role of Surgiflo@PCN is to kill glioma cells via ROS and adjuvant PTT, reversing the immunosuppressive tumor microenvironment and augmenting the antitumor immune response are other critical steps in therapeutic strategies for glioma. It is worth mentioning that the delivery strategy of these nanozymes involves postoperative multifunctional hydrogel implantation, which has good clinical translational value because of its ability to break the blood‒brain barrier. It is important to note that the in vivo validation of the nanozyme combined with photothermal therapy (PTT) for treating glioma used an intracranial mouse model, and since mouse skulls are much thinner than human skulls, potential discrepancies in skull thickness could impact the effectiveness of treatment during clinical translation. PTT is still infrequently used in the clinical treatment of glioma. Therefore, actual clinical features must be carefully considered when designing nanozymes for such therapies.

According to the above-summarized nanozyme treatment modalities, if nanozymes for gliomas are to be administered in vivo, breaking through the blood‒brain barrier is the key issue to be considered, but direct postoperative intracranial administration is also not a poor solution, and it should not be limited to a single design. In addition, it seems that glioma treatment can be more effective by changing the immune microenvironment of glioma than by inducing apoptosis alone. Glioma, as an intracranial tumor, deserves special consideration for therapeutic strategies and approaches more than other tumors, and there is still much to be explored in the design of nanozymes for gliomas, hopefully focusing on the points summarized above.

Breast cancer

Breast cancer is one of the most common malignant tumors, with a 5-year survival rate of only 20% due to drug resistance], high heterogeneity and lack of receptors for hormonal therapy [86, 87]. Generally, low-grade breast cancers are mainly resected, and hormone receptor-positive and HER-2-overexpressing breast cancers can also be treated medically with hormones and targeted agents [88]; however, treatment remains tricky for untargeted and triple-negative breast cancers [89]. Nanozymes can compensate for the shortcomings of breast cancer treatment by catalyzing the production of various factors that can alter the tumor microenvironment and directly or indirectly enhance the death of breast cancer cells [90].

Triple-negative breast cancer has a toxic acidic environment, a high concentration of hydrogen peroxide, hypoxia and other characteristics common to the tumor microenvironment [91]. Owing to the limitations in the catalytic efficiency of typical nanozymes for chemodynamic therapy (CDT), Huang et al. crafted a porous Fe2O3/Au hybrid nanozyme aimed at the Fe2O3/Au hybrid nanozyme operating within the tumor microenvironment, primarily generating hydroxyl radicals due to its exceptional peroxidase-like activity. This activity not only disrupts tumor cells by depleting their energy through glucose consumption but also, crucially, the incorporation of gold nanoparticles significantly boosts the photothermal conversion efficiency of the nanoparticles. Consequently, the Fe2O3/Au hybrid can attack tumors through a multifaceted approach that includes starvation therapy, cascade catalytic reactions, ferroptosis induction, and photothermal treatment modalities. This innovative approach combines the unique properties of both Fe2O3 and Au, enhancing the catalytic activity required for effective CDT and thereby offering a new pathway for the treatment of this challenging cancer type in combination with the synergistic treatment of triple-negative breast cancer [92].

As an emerging noninvasive treatment, photothermal therapy is gradually gaining attention for the treatment of breast cancer [93], but it is limited by the complex pathological barriers of tumors and the uneven dispersion of photosensitizers, which greatly affects the final therapeutic effect. Therefore, the development of nanozymes that can enhance the efficiency of PTT for breast cancer treatment is also a major consideration of current research. Wang et al. reported a novel nanomedicine delivery strategy in which breast cancer cell membranes were extracted and coated with CuS nanoparticles loaded with β-lapachone to inhibit phagocytosis by macrophages via “do not-eat-me” signaling in combination with effective photothermal and chemokinetic precision therapies for the treatment of breast cancer [83]. These nanozymes enable photothermal and chemodynamic precision therapy for breast cancer, creating a new paradigm for safe and limited tumor treatment (Fig. 3A).

Fig. 3figure 3

Nanozymes used for treating other tumors. A The preparation of CD47@CCM-Lap-CuS NPs and the mechanism of CD47@CCM-Lap-CuS NPs mediated precise photothermal and chemodynamic therapy for breast cancer. Reproduced with permission [83]. Copyright 2023, ACS Appl. Mater. Interfaces. B The synthesis process of D/L-Arginine@Ru nanozymes and a schematic diagram of how D/L-Arginine@Ru inhibits lung cancer cell activity through a “cocktail therapy” approach. Reproduced with permission [18]. Copyright 2023, Wiley. C M@TPE-s COF-Au@cisplatin nanoparticles internalize and inactivate the membranes of HepG2 cells, effectively combining photothermal and chemotherapeutic effects. This enables targeted treatment of hepatocellular carcinoma and significantly inhibits tumor growth. Reproduced with permission [84]. Copyright 2023, iScience. D The synthesis of BSA-Cu SAN and its function in disrupting pathogen-tumor symbiosis for antitumor therapy, illustrated schematically. Reproduced with permission [85]. Copyright 2023, Springer Nature. E Schematic illustration of microneedle integrated with PSi loaded with bifunctional nanozymes (including copper-doped graphene quantum dots (CuGQD) and palladium nanoparticles (PdNPs)) to induce ferroptosis of subcutaneous melanoma through nanocatalytic strategy. Reproduced with permission [71]. Copyright 2023, Wiley

In addition to PTT, photodynamic therapy (PDT), which relies on localized oxygen molecules to produce highly cytotoxic single-linear states of oxygen, is one of the therapies worth considering for the treatment of breast cancer [94]. Moreover, nanozymes can improve the therapeutic efficacy of PDT due to hypoxia in solid tumors [95]. OxgeMCC-r single-atom nanozymes with high Ce6 photosensitizer loading capacity can selectively accumulate at breast cancer sites to generate oxygen to improve tumor hypoxia, and their good in vivo tracking imaging capability is a promising anticancer therapeutic agent, as reported by Zhao et al. [57].

Sonic dynamic therapy (SDT) is also an effective way to treat tumors because it can penetrate 7–10 cm deep into tissues, so it is efficient at killing deep tumors and is a good means of treating breast cancer [96, 97]. However, it is similar to PDT and is limited by the lack of an oxygen environment in the tumor, which leads to a greatly reduced therapeutic effect [98]. Therefore, the preparation of sonic sensitizers with multienzyme properties for SDT is also one of the design approaches worth considering. Liu et al. designed a cascade nanozyme-based platform (HABT-C@HA) to modulate hypoxia and immunosuppression in the tumor microenvironment and to enhance the efficiency of SDT, providing a strategy for efficient SDT treatment of breast cancer [19].

In addition to the nanozyme designs summarized above, many new nanozymes are being used for the treatment of breast cancer. Because there are many adjuvant therapies for breast cancer, nanozymes can take full advantage of their efficient catalytic ability to improve the tumor environment and increase the efficiency of other modalities. However, little attention has been given to nanozymes for grading breast cancer with a poor prognosis, such as triple-negative breast cancer, and in the future, more consideration needs to be given to the characteristics of breast cancer itself to design more targeted nanozyme therapeutic agents for breast cancer treatment.

Lung cancer

Lung cancer is one of the most dangerous malignant tumors because it is not easy to diagnose in the early stage and spreads easily in the late stage [99]. Despite significant advances in lung cancer detection and treatment, lung cancer remains the world's deadliest cancer due to the failure to detect lung cancer early and the lack of effective treatments for patients with advanced disease [100]. At present, for early-stage tumors, under the two basic premises of ensuring patient physical function and early-stage disease, surgery is the main treatment; for middle- and late-stage tumors, radiotherapy and chemotherapy are combined with each other [101].

PDT, an advanced minimally invasive ablation technique for localized tumors, has also been used to treat lung cancer because of its minimal invasiveness and easy scalability [102]. Lin et al. designed a catalase-like nanozyme (AuNCs-NH2) to improve the hypoxic environment of lung cancer cells and enhance the therapeutic effect of PDT through the catalytic-like activity of AuNCs-NH2 [16]. Similarly, Liang et al. designed PEG-based mesoporous Mnb single-atom nanozymes (PmMn/SAE) exhibiting catalase-like (CAT), oxidase-like (OXD), and peroxidase-like (POD) activities to ameliorate hypoxia in lung cancer cells, thus synergistically enhancing PTT treatment [65]. However, the above two nanozymes were not designed for lung cancer, and their functions were only verified in lung cancer cells; therefore, more in-depth research is needed to determine their clinical application in lung cancer.

Adjuvant therapy, such as PTT and PDT, is a good adjuvant way to improve early lung cancer and actively cooperate with surgery. For middle- and late-stage lung cancer, from the perspective of lung cancer itself, we should pay more attention to its characteristics, such as immunosuppression and easy metastasis. One of the most prominent problems is immune resistance [103]. In some patients, after the use of immunotherapeutic drugs, tumor cells are still able to evade the attack of the immune system, leading to treatment failure [104]. TAMs are the main cause of immunosuppression in the tumor microenvironment; therefore, inducing macrophage M1 polarization is an effective strategy for remodeling the tumor microenvironment to suppress lung cancer cells [105]. Professor Liu Jie's team proposed a composite ruthenium nanoenzyme (D/L-arginine@Ru), which can mimic the activities of oxidase and nitric oxide synthase (NOS) at the same time, catalyzing the generation of ROS from low concentrations of H2O2 and catalyzing the production of high concentrations of NO, which induces M1 polarization of macrophages. This not only induced apoptosis and ferroptosis in lung cancer cells but also efficiently inhibited their growth and metastasis [18] (Fig. 3B). Liu et al. provided a new strategy for the treatment of lung cancer through the ability of endogenous catalytic therapy to improve the tumor microenvironment and activate autoimmunotherapy.

The use of nanozymes in the treatment of lung cancer has not been well characterized, especially for the early diagnosis of lung cancer, for which much research is still lacking. To further improve the diagnostic and therapeutic effects of nanozymes, nanozymes can be combined with multidisciplinary techniques such as pharmacology and pharmacology. Different dosage forms of nanozymes (solution, inhaler or gel, etc.) can be designed according to the site of disease (mouth, lung, airway, etc.).

Liver cancer

Liver cancer is a common malignant tumor [106]. Summarizing the characteristics of liver cancer, we summarize them as the “five most”: the most difficult to detect, the most difficult to diagnose, the most difficult to treat, the fastest development, and the worst prognosis [107,108,109,110,111]. Hepatocellular carcinoma has the second highest mortality rate of all malignant tumors after lung cancer [112]. Its early symptoms are not obvious, while there is almost no effective treatment available to control it in the late stage [113]. Therefore, early detection, early diagnosis and early treatment are the only means to improve the prognosis of liver cancer patients. We summarize the research on nanozymes in the field of hepatocellular carcinoma, which is generally categorized into early prevention and improvement of adjuvant therapeutic strategies for hepatocellular carcinoma.

The combination of targeted nanoprobe-based photothermal therapy, which has the advantages of precision and efficiency, provides an effective method for the diagnosis and treatment of liver cancer and enables the simultaneous diagnosis and treatment of early-stage liver cancer using a single highly efficient material. Zhang and Wang et al. reported a biomimetic multifunctional COF nanoenzyme (M@TPE-s COF-Au@cisplatin) [84]. The nanoenzyme was endocytosed on the membrane of inactivated HepG2 cells, and under laser irradiation, the COF nanoenzyme underwent high-temperature cleavage, resulting in the release of COF nanozymes and a high concentration of drugs, which efficiently exerted combined photothermal and drug therapeutic effects and were able to target hepatocellular carcinoma and significantly inhibit tumor growth. Covalidated in three animal models, TPE-s COF-Au nanozymes can be specifically fused with autologous hepatocellular carcinoma cells for dual imaging and combination therapy (Fig. 3C).

Liver fibrosis is considered a major risk factor for hepatocellular carcinoma. Associate Professor Nan Li’s team proposed a therapeutic strategy of “remodeling the hepatic fibrosis microenvironment” and developed nilotinib (NIL)-loaded hyaluronic acid (HA)-coated Ag@Pt nanodelta nanohydrolase (APNH NT) to inhibit hepatic stellate cell activation and remodel the hepatic fibrosis microenvironment [114]. Compared with conventional drugs, this nanodelivery system can simultaneously scavenge reactive oxygen species, improve the oxygen-depleted microenvironment, and degrade extracellular collagen at the liver site, thus hindering the progression of liver fibrosis and preventing the progression of hepatocellular carcinoma from an early stage.

Currently, there are few studies on nanozymes in the early diagnosis and treatment of liver cancer, and researchers need to focus on how to improve the efficiency of early diagnosis, which is more clinically relevant for the treatment of liver cancer.

Colorectal cancer

Colorectal cancer is the third most common cancer and the fourth leading cause of cancer deaths worldwide and is a major public health problem [115]. Despite improvements in surgical and oncologic treatments, it continues to have high morbidity and mortality rates. Surgical resection is the cornerstone of colorectal cancer treatment and is traditionally the only curative treatment; however, it often causes considerable inconvenience and pain to patients after surgery [116]. Neoadjuvant radiotherapy is used for locally progressive rectal cancer to increase the complete resection rate and reduce the risk of recurrence, and this method is also suitable for patients who need strong organ preservation [117]. Improving therapeutic strategies for colorectal cancer through nanozymes is an important goal of current research. We summarize the research on nanozymes in the field of colon cancer, providing a variety of new ideas on nanozymes for therapeutic management of colon cancer from early disease progression to development.

Chronic inflammation is a well-recognized carcinogen in colitis-associated colorectal cancer, and concomitant anti-inflammatory and antitumor therapies are required clinically [118, 119]. Zha and Huang et al. reported the use of polyethylene glycol (PEG)-coated ultrasmall rhodium nanodots (Rh-PEG NDs) as metalloenzymes. It possesses reactive oxygen and nitrogen species (RONS) scavenging properties as well as photothermal activity for anti-inflammatory and antioxidant purposes [120]. Rh-PEG NDs have good anti-inflammatory effects while being able to completely ablate CT-26 colon tumors by virtue of their high photothermal conversion efficiency, providing a paradigm for the potential management of colon disease using metal nanozymes and preventing the progression of colon cancer at an early stage.

SDT is an emerging modality for colorectal cancer treatment because of its high tissue penetration and noninvasive advantages [121]. However, the outcome of SDT is usually hampered by inefficient generation of reactive oxygen species (ROS) and activation of protective autophagy. To address the limitations faced by sonodynamic therapy (SDT) in treating colorectal cancer, such as the inefficient generation of reactive oxygen species (ROS) and the activation of protective autophagy, Zhang et al. innovatively created a cascade nanoreactor. This design cleverly incorporates the acoustic sensitizer Ce6 and the autophagy inhibitor chloroquine into hollow polydopamine nanocarriers. These carriers are uniquely modified with membranes from homologous tumor cells and predoped with platinum nanoribonuclease, culminating in the creation of CCP@HP@M. This strategic integration is aimed at enhancing the generation of ROS and inhibiting autophagy, thereby improving the antitumor efficacy of SDT for colorectal cancer [122]. When subjected to ultrasound irradiation, CCP@HP@M demonstrated the ability to effectively alleviate hypoxia and reduce the resistance of colon cancer to sonodynamic therapy (SDT). This synergistic approach not only enhances the production of reactive oxygen species (ROS) but also prevents the initiation of ROS-induced protective autophagy. By addressing these two major hurdles, the effectiveness of SDT is fundamentally assured, making this strategy a promising option for tumor treatment. This innovative method has the potential to significantly improve therapeutic outcomes in colon cancer by optimizing the conditions for ROS generation and minimizing cellular defense mechanisms against therapy-induced stress.

The microbiota is considered a major oncogenic factor in CRC and influences treatment outcomes, and there is growing evidence that intratumoral bacteria enhance the survival of circulating tumor cells and promote metastasis [123]. Qin et al. designed a copper single-atom nanoenzyme (BSA-Cu SAN) that kills the intratumoral pathogen Clostridium nucleatum to disrupt symbiosis and synergistically kill colorectal cancer (CRC) cells [85]. Nanozymes are based on the structure of proteins, are natural enzymes with metal elements as active centers, and act as catalytic therapeutics by generating reactive oxygen species (ROS) and consuming GSH. This study provides a promising pathogen-centric approach to cancer therapy by disrupting a pathogen-tumor symbiosis that is not commonly used as a therapeutic target, providing new ideas for the treatment of CRC (Fig. 3D).

The treatment of colorectal cancer is evolving toward a more individualized approach, emphasizing the assessment of individual risk and fostering patient-centered shared decision-making. This shift is complemented by advances in nanozyme therapeutic methods, facilitating organ preservation strategies via local excision or combined radiotherapy and immunotherapy. Moreover, the advent of precision tumor therapy, grounded in comprehensive whole-tumor genome sequencing and monitoring of therapeutic efficacy by circulating tumor DNA, represents significant strides in tailoring treatment to the specific genetic and molecular profile of the tumor. This evolution toward personalized medicine aims to optimize treatment efficacy, minimize unnecessary exposure to systemic therapies, and improve overall patient outcomes in colorectal cancer care.

Cutaneous melanoma

Cutaneous melanoma (CM) is a fatal malignant cancer of the skin [124]. CM differs from other malignant tumors in that it occurs predominantly in the epidermal and dermal layers of the skin rather than in deeper tissues, and an important reason for the high mortality rate of CM is the lack of reliable and effective treatments.

Exploring the response of malignant cells to intracellular metabolic stress is critical for understanding pathological processes and developing anticancer therapies. Recently, Wu et al. prepared a dual-nanozyme-loaded porous silicon nanocatalytic composite system (CuGQD/PdNPs@PSi) using porous silicon obtained by electrochemical etching as a novel nanoenzyme carrier [70]. The enzyme possesses peroxidase-like (POD) and glutathione oxidase (GSHOx) activities, and the enzyme-like activity of the nanozyme complex can be further enhanced by the photothermal effect induced by near-infrared light. The integration of CuGQD/PdNPs@PSi into MNs can enable the nanozyme complex to penetrate the epidermal barrier and form reversible microchannels to enter CM lesion sites, which can achieve efficient nanocatalytic induction of ferroptosis and thus efficient treatment of melanoma (Fig. 3E). MNs encapsulating CuGQD/PdNPs@PSi could not only provide a potential nanocatalytically induced ferroptosis strategy for melanoma treatment but also meet the medical need for eradicating superficial tumors.

Currently, there are few studies on the application of nanozymes in treating melanoma, and drug delivery for superficial tumors such as melanoma is a key point to consider. Wu et al. provided a good idea to make nanozymes penetrate the skin barrier by using MNs as the medium, and the method of drug delivery works in superficial tumors. Combining nanozymes with penetrating ointment for treating dermatologic diseases may be a new idea for nanozyme design.

Osteosarcoma

Osteosarcoma is a common primary malignant bone tumor that occurs mostly in children and adolescents [125]. The current standard of care is an integrated neoadjuvant chemotherapy-surgery-adjuvant chemotherapy model consisting of doxorubicin, cisplatin, and high-dose methotrexate (MAP) [126]. Although perioperative chemotherapy has dramatically improved 5-year survival and limb preservation in patients with osteosarcoma [127], no further breakthroughs in survival benefit from chemotherapy have been achieved in the last 40 years, and the current state of treatment is in dire need of improvement.

Liang et al. designed a two-dimensional titanium carbide (Ti3C2Tx) carrier composed of RhRu alloy nanoclusters (RhRu/Ti3C2Tx), which possessed good catalase (CAT) and peroxidase (POD)-like activities [72]. Liang et al. verified the synergistic CDT/PDT/PTT effect of RhRu/Ti3C2Tx on osteosarcoma by in vitro and in vivo experiments, which is expected to provide a new research direction for the treatment of osteosarcoma and other tumors.

The rapid proliferation of residual tumor cells and poor quality of new bone reconstruction are considered the main challenges in the postoperative treatment of osteosarcoma [

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