4.1 Global trends and research contributions in nanozyme-based cancer therapy

This study systematically analyzed 2657 publications on the application of nanozymes in cancer, indexed in the Web of Science and Scopus databases from 2001 to 2025. The objective was to evaluate the spatiotemporal distribution of the literature, assess author contributions, identify leading journals, and explore research hotspots as well as emerging trends. The concept of nanozymes originated in 2007, when Professor Yan Xiyun’s team at the Chinese Academy of Sciences (CAS) first introduced it, marking the inception of the field [6]. During the initial decade, research primarily concentrated on concept validation and foundational exploration, progressing at a relatively slow pace. However, since 2017, as technology matured and clinical demand increased, nanozyme research entered an exponential growth phase, particularly in China, where publication numbers surged sharply, reflecting a marked acceleration in the field.

China and the CAS have played a pivotal role in the development of nanozyme research. As the birthplace of nanozyme science, China leads the field in publication output and has spearheaded significant technological advances in cancer-related applications. However, enhanced international collaboration remains necessary. The current analysis indicates that the proportion of internationally co-authored publications from China remains relatively low. Moreover, the average citation impact of Chinese publications is lower than that of countries such as Singapore and the United States. This discrepancy may partially reflect the relatively recent publication dates of many papers and potential self-citation effects, rather than research quality alone. Citation-based impact is also affected by collaboration patterns and the time elapsed since publication. Consequently, the relatively low citation rates may reflect both limited international collaboration and a greater focus on applied research rather than highly original theoretical studies. Overall, China’s global academic influence has not yet fully aligned with its quantitative output. Future efforts should prioritize enhancing research quality, fostering collaboration with leading international institutions, and accelerating the clinical translation of nanozyme technologies.

Among the representative authors, Professor Yang Piaoping (Harbin Engineering University) and Professor Fan Kelong (Institute of Biophysics, CAS) are particularly prominent. Yang, with the highest number of publications (41) and the greatest collaboration strength (134), has played a leading role in applied research and interdisciplinary collaboration, facilitating the translation of nanozyme technologies into practical cancer therapies. Fan, a key member of the pioneering team, has published 38 papers with a high citation impact (43,959 citations), focusing on mechanistic studies and the design of novel nanozymes. Their research demonstrates strong complementarity: Fan’s team establishes the theoretical foundation through basic research, while Yang’s team advances application development, collectively consolidating China’s leading position in nanozyme-based cancer therapy.

Research on nanozymes in cancer therapy has reached a stage of relative maturity. Findings are consistently published in leading JCR Q1 journals across materials science, chemistry, and biomedical engineering, including Advanced Materials and ACS Nano. Journal co-occurrence and co-citation analyses further emphasize the inherently interdisciplinary nature of the field: the materials science cluster provides the technological foundation, the biomedical cluster focuses on clinical translation, and the analytical chemistry cluster underscores diagnostic applications. The integration of these domains, along with the 'multi-center' journal collaboration network, has propelled nanozyme research from fundamental material innovation to frontier directions. These include synergistic therapies and tumor microenvironment modulation. High-impact journals not only disseminate research findings but also shape research agendas. They guide the development of a high-quality, interdisciplinary research ecosystem.

4.2 Analysis of bidirectional regulation of reactive oxygen species by nanozymes in tumor therapy

Our bibliometric analysis identifies the regulation of ROS as a central hotspot in nanozyme-based cancer therapy, highlighting its bidirectional modulation as a key therapeutic mechanism. Nanozymes perform dual roles in regulating reactive oxygen species (ROS) within the tumor microenvironment (TME). On one hand, nanozymes with peroxidase (POD)-like activity efficiently generate hydroxyl radicals (·OH), directly inducing tumor cell death or triggering ferroptosis. On the other hand, nanozymes that mimic catalase (CAT) activity scavenge excess ROS, alleviating hypoxia and reversing immune suppression, thereby ultimately enhancing the efficacy of immunotherapy [11]. These findings are consistent with the growing trend of integrating nanozyme technology into multimodal strategies that combine phototherapy and immunotherapy. Moving forward, research should prioritize spatiotemporal precision in ROS modulation, the investigation of novel cell death pathways, and the development of intelligent nanozymes for clinical applications.

4.3 Tumor cell death pathways regulated by nanozymes

Keyword evolution and burst detection analyses (Sect. 3.6.2) indicate that ferroptosis, pyroptosis, and immunogenic cell death (ICD) have emerged as prominent research frontiers since 2021, reflecting a transition from apoptosis-centered approaches toward catalytic strategies oriented around regulated cell death.

4.3.1 Apoptosis

Apoptosis continues to serve as a fundamental mechanism in nanozyme-based cancer therapy, primarily mediated by ROS amplification and redox imbalance within the tumor microenvironment. Representative nanozyme platforms, such as MnO₂@Lap/PAH/L-Arg@Au and NiFeMnCu-LDH systems, enhance apoptosis through synergistic ROS and nitric oxide (NO) production [12, 13]. These findings are consistent with our keyword co-occurrence analysis, which highlights oxidative stress and ROS regulation as central nodes within the research network.

4.3.2 Pyroptosis

Burst analysis identified pyroptosis as an emerging research frontier after 2022. Recent nanozyme platforms—including axially chlorinated single-atom iron/nitrogen-doped carbon nanodots and Fe-based single-atom nanozymes—have demonstrated the capacity to induce pyroptosis through ROS overproduction and inflammasome activation [14, 15]. In addition, copper-based and lanthanum-doped nanozymes further enhance inflammatory programmed cell death in tumor models [16, 17]. Importantly, nanozyme-induced pyroptosis is often associated with enhanced immune activation, consistent with clustering results that link catalytic therapy to immunomodulation.

4.3.3 Ferroptosis

Ferroptosis exhibited one of the strongest citation bursts in recent years, underscoring its central role in next-generation nanozyme research. Iron-based nanozymes and sulfur-vacancy redox-disrupting platforms can enhance Fenton-like reactions, deplete intracellular glutathione, and induce lipid peroxidation–dependent tumor cell death [18, 19]. These catalytic strategies enable precise redox regulation and improve therapeutic selectivity compared with conventional nanomaterials.

4.3.4 Immunogenic Cell Death (ICD)

Co-citation and clustering analyses revealed strong associations among ICD, dendritic cell activation, and multimodal therapy clusters. Nanozyme-mediated catalytic therapy can facilitate DAMP release and stimulate immune cell activation, particularly when integrated with immunotherapy-based platforms [20,21,22,23]. This dual catalytic–immunological mechanism represents a critical frontier in nanozyme-enabled precision oncology.

4.4 Nanozymes for in vivo cancer diagnosis

Nanozymes have emerged as promising tools not only for cancer therapy but also for in vivo cancer diagnosis, particularly in molecular imaging and theranostic applications. Owing to their enzyme-like catalytic activity and tunable surface properties, nanozymes can enhance imaging signals and improve tumor-specific detection across modalities such as fluorescence imaging, magnetic resonance imaging, and photoacoustic imaging [24, 25]. Representative studies have demonstrated that engineered nanozyme systems can achieve tumor-specific photoacoustic imaging, with reduced off-target signals and enhanced monitoring performance [26]. In addition, nanozyme-based platforms have demonstrated the potential to integrate noninvasive imaging with therapeutic guidance, underscoring their expanding role in cancer theranostics [27]. Recent examples further demonstrate this potential. For instance, Ru-CQDs-AS1411@PEG nanozymes enable precise photoacoustic tumor imaging and effective tumor ablation through the combined effects of photothermal activity and catalytic ROS generation [28]. Likewise, Fe3O4 core–shell nanoparticles enhance MRI-guided diagnosis and therapy by promoting ROS generation [29], while HA-coated Cu2+/IR820@PDA nanozymes exhibit efficient tumor accumulation and suppress tumor growth through ROS amplification and GSH depletion [30]. Collectively, these findings reinforce the expanding role of nanozymes in imaging-guided cancer diagnosis and theranostic interventions.

4.5 Advances in nanozyme-enabled multimodal therapies

Multimodal therapy has emerged as a prominent research frontier, as indicated by strong citation bursts in keywords such as photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), and sonodynamic therapy (SDT). Importantly, the bibliometric results indicate that nanozymes are increasingly recognized not merely as passive nanocarriers but as catalytic amplifiers that enhance therapeutic efficacy through ROS generation, GSH depletion, and modulation of TME.

Furthermore, recent advances in peptide-based cancer therapies, including LTX-315, have highlighted the critical role of stability optimization in enhancing drug efficacy. Through three rounds of stability-guided optimization, LTX-315 has demonstrated enhanced tumoricidal effects and attenuated immune responses, paving the way for more effective and stable peptide-based therapeutics in multimodal cancer therapy [31].

4.5.1 Photothermal and photodynamic therapies

Nanozyme-assisted PTT and PDT rely on catalytic enhancement of oxidative stress within tumor tissues. Representative nanozyme systems, such as MnO₂@Lap/PAH/L-Arg@Au and RePd nanozymes, synergize photothermal effects with ROS and nitric oxide (NO) production, while simultaneously improving immune activation [21, 32]. Similarly, platinum–palladium–gold nanozymes and Fe-doped carbon dots have demonstrated enhanced PDT efficacy through catalytic ROS amplification and the induction of pyroptosis [14, 33].In addition, tumor microenvironment–responsive nanozyme platforms have enabled multimodal imaging-guided PDT/PTT/CDT strategies, particularly in cervical cancer models [25]. These findings underscore that the catalytic activity of nanozymes differentiates them from conventional photothermal- or photosensitizer-based nanomaterials, enabling enhanced hypoxia alleviation and precise redox regulation.

4.5.2 Chemodynamic therapy

CDT is a promising cancer treatment, particularly for colorectal cancer, by enhancing ROS generation and inducing apoptosis without systemic toxicity [34]. Nanocomposites like C@M(Fe)T enable hydroxyl radical production through Fenton reactions, selectively targeting tumor cells and minimizing healthy tissue damage [35]. When combined with radiodynamic therapy and immune checkpoint blockade, CDT achieves tumor inhibition rates of 97.3% for primary and 98.5% for metastatic tumors [36]. Nanozymes, like Fe SANs, boost ROS production, induce ferroptosis, and improve CDT performance [37]. The combination of CDT with PTT and advanced nanocomposites such as Ti₃C₂-MXene/Fe-MOFs enhances treatment efficacy by further amplifying ROS production [38, 39]. These advancements underscore CDT’s transformative potential for colorectal cancer and broader oncological applications.

4.5.3 Sonodynamic therapy

SDT, which combines ultrasound with sonosensitizers, has shown broad antitumor efficacy. In pancreatic cancer, an HMME-loaded emulsion hydrogel enhanced dendritic cell maturation and cytotoxic T-cell infiltration [40]. In glioblastoma, 5-ALA–induced protoporphyrin IX exhibited therapeutic potential [41]. Nanozymes further expand SDT efficacy by enhancing ROS production and modulating TME. MoO₂/Fe@PEG nanozymes increased ROS 2.8-fold [42], and GSH-depleting nanozymes facilitated ROS accumulation [43]. Ru SANs both increased ROS and alleviated hypoxia, enhancing SDT-induced ferroptosis [44].

4.5.4 Synergistic strategies

Although PTT, CDT, PDT, and SDT each exhibit distinct antitumor potential when enhanced by nanozymes, a growing body of evidence suggests that their integration into synergistic modalities can produce more potent therapeutic outcomes. The primary advantage of such synergy lies in the additive mechanisms: nanozymes enhance ROS generation, alleviate tumor hypoxia, and deplete GSH, thereby compromising tumor defense systems and creating a favorable microenvironment for PTT, CDT, PDT, and SDT. When further integrated with chemotherapy, radiotherapy, or immunotherapy, these strategies not only improve therapeutic efficacy but also reduce the adverse effects associated with monotherapies. For instance, the CuS@GOx@ES nanoplatform enhances CDT and copper-induced cytotoxicity through PTT-mediated hyperthermia, resulting in superior antitumor effects [45]. Similarly, MnCaP nanocomposites exploit PTT to reduce Mn4+to Mn2+, thereby reinforcing CDT and improving MRI performance, ultimately achieving complete tumor suppression in mice after 14 days of treatment [46]. Another study reported a substantial reduction in U87 glioblastoma cell viability to 14.8%, further highlighting the therapeutic potential of PTT–CDT synergy [47]. In addition, the integration of chemodynamic therapy (CDT) with sonodynamic therapy (SDT), utilizing carbon dot-sensitized hollow Co9S8-x as a novel inorganic sonosensitizer, significantly enhanced ROS production and promoted cancer cell apoptosis [48]. More importantly, nanozymes-assisted immunotherapy has emerged as a transformative direction. For example, PTT combined with iodine-loaded acetylated starch nanoparticles downregulated IDO1 expression and induced ICD, thereby stimulating robust antitumor immunity and suppressing pulmonary metastasis in colorectal cancer models [49]. Likewise, PDT based on Ce6@THMSNs promoted dendritic cell maturation and activated CD8+ cytotoxic T lymphocytes, leading to strong systemic immune responses and prevention of distant metastasis [50]. Collectively, these studies underscore the remarkable potential of nanozymes to amplify the therapeutic efficacy of PTT, CDT, PDT, and SDT through synergistic interactions, while their integration with immunotherapy further enables systemic antitumor immunity, underscoring the transformative promise of nanozyme-based strategies in cancer treatment.

4.6 Single-atom nanozymes in cancer therapy

Keyword clustering and co-citation analyses identified single-atom catalysts as an emerging research focus, associated with high-frequency terms such as catalytic activity, ferroptosis, and immune regulation. This reflects the shift of nanozymes research toward precision catalysis and immuno-oncology applications. SANs, owing to their maximized atomic utilization, well-defined active sites, and outstanding enzyme-like activities, have shown remarkable promise in cancer therapy. Compared with conventional nanozymes, SANs exhibit higher selectivity and catalytic efficiency, enabling precise regulation of and GSH levels within the TME, thereby inducing oxidative stress and apoptosis [51]. Studies have demonstrated that Ru-, Pd-, and Fe-based SANs display notable antitumor effects in models of breast cancer, PTT, and osteosarcoma [52,53,54]. More recently, research on SANs has expanded beyond oxidative damage to include emerging cell death pathways such as ferroptosis, cuproptosis, and necroptosis, which are often closely linked to immune regulation [14, 37, 55]. Overall, SANs have emerged as a key direction in nanozymes research, with a clear shift in focus from the optimization of catalytic performance toward multimodal therapeutic integration and immune modulation, underscoring their broad clinical potential [56].

4.7 Challenges and future directions of nanozyme-based cancer therapy

Based on the bibliometric findings and research progress summarized in this study, nanozymes have progressed from conceptual validation to a growing range of translational applications in cancer therapy. Nevertheless, several critical challenges remain to be addressed before their full clinical potential can be realized. First, research quality and international influence still need improvement. Although China leads in publication output and technological development, international collaboration remains limited, and the average citation impact of individual papers is lower than that of countries such as Singapore and the United States. Second, the lack of standardization in nanozyme synthesis remains a major obstacle. Differences in preparation protocols across laboratories can lead to inconsistent physicochemical properties, reducing reproducibility and limiting comparisons across studies. Third, targeting efficiency and biosafety remain key concerns. The long-term biodistribution, metabolism, and potential toxicity of nanozymes in vivo are still not fully understood, and systematic clinical safety evaluation remains insufficient. Fourth, the complexity of TME can also restrict nanozyme catalytic activity. For example, low H2O2 levels and high GSH concentrations may suppress therapeutic efficacy.

Looking ahead, several strategies could facilitate the further development of nanozyme-based cancer therapies. Strengthening international collaboration and fostering interdisciplinary exchange may enhance research quality and global impact. Standardizing and scaling up preparation processes will be crucial to ensure the stability, reproducibility, and controllability of nanozyme products. Optimizing structural design and surface modification may improve tumor-targeting efficiency and enhance in vivo safety. Developing smart nanozymes with self-sustaining substrates or autocatalytic properties may help overcome TME-related limitations such as H2O2 deficiency and GSH accumulation. Future nanozyme platforms should also move beyond single catalytic functions by integrating multiple therapeutic modalities, including photothermal, photodynamic, chemodynamic, and sonodynamic therapies, as well as immunotherapeutic strategies. In addition, emerging computational approaches may provide theoretical support for optimizing the combination and scheduling of multimodal cancer therapies, thereby offering a complementary perspective for precision treatment design [57]. Importantly, clinical translation remains constrained by limited clinical trial evidence, as most studies are still at the preclinical stage. Further progress will require clearer regulatory pathways, standardized manufacturing protocols, reliable batch-to-batch consistency, and comprehensive safety evaluation frameworks. These frameworks should include assessments of biodistribution, metabolic clearance, long-term toxicity, immunogenicity, off-target effects, and dose–response relationships. In addition, potential immune-related adverse events should be carefully monitored during translational and clinical evaluation, especially when nanozyme-based platforms are combined with immunotherapeutic strategies [58]. More broadly, these trends align with the growing emphasis on precision and individualized therapeutic strategies in contemporary oncology [59, 60].

Although no nanozyme-based catalytic therapies have entered clinical trials to date, their potential translation to human applications would require strict adherence to established regulatory frameworks for nanomedicines. Key steps would include comprehensive characterization of the material (Chemistry, Manufacturing, and Controls, CMC), preclinical toxicology and pharmacokinetics studies, and phased clinical trials (Phase I–III) conducted in accordance with guidelines from regulatory authorities such as the FDA, EMA, or NMPA. Ensuring batch-to-batch consistency, reproducible catalytic activity, and long-term safety monitoring would be essential for eventual regulatory approval. These considerations offer a framework for translating preclinical nanozyme research toward future clinical applications.