Nanozyme for precision treatment of hepatocellular carcinoma

Shu Feng; Ying Xuan; Hong Jin; Meng Cui; Xinyue Meng; Jun Liao; Jianwei Feng

doi:10.1016/j.mtbio.2026.102840

. 2026 Jan 24;37:102840. doi: 10.1016/j.mtbio.2026.102840

Nanozyme for precision treatment of hepatocellular carcinoma

Shu Feng ^a,¹, Ying Xuan ^a,¹, Hong Jin ^a,¹, Meng Cui ^a,^⁎, Xinyue Meng ^a,^⁎, Jun Liao ^b, Jianwei Feng ^a,^⁎⁎

PMCID: PMC12874347 PMID: 41660123

Abstract

Hepatocellular carcinoma (HCC) remains a formidable challenge due to profound heterogeneity, recurrence, and pervasive therapeutic resistance, creating a significant unmet clinical need. Engineered nanozymes, nanomaterials with intrinsic catalytic activities, have emerged as a transformative paradigm. Unlike passive nanocarriers, nanozymes function as active therapeutic agents. Their prowess is predicated on catalytically manipulating the tumor microenvironment (TME), enabling localized ROS generation, inducing regulated cell death, and remodeling the immunosuppressive TME. This review systematically delineates the principles and potential of nanozyme strategies for HCC, focusing on catalytic therapy, nanozyme-enhanced immunotherapy, photothermal therapy, and integrated combination platforms, highlighting their capacity for synergistic antitumor effects. The review also critically discusses formidable challenges spanning metabolic heterogeneity, TME-driven immunosuppression, and biocompatibility hurdles that impede clinical translation. This work provides critical insights for the rational design of next-generation nanozymes and accelerating their integration into future multidisciplinary HCC treatment frameworks.

Keywords: Hepatocellular carcinoma, Nanozymes, Nanomedicine, Biomaterials, Drug delivery

Graphical abstract

1. Introduction

Hepatocellular carcinoma (HCC), which accounts for approximately 90 % of all primary liver cancers, represents a formidable global health challenge, consistently ranking among the leading causes of cancer-related morbidity and mortality worldwide [[1], [2], [3]]. Over the past few decades, the clinical management of HCC has evolved to include a range of therapeutic modalities, such as surgical resection, liver transplantation, local ablation, radiotherapy, chemotherapy, targeted therapy, and immunotherapy [[4], [5], [6], [7]]. Despite these advances, the overall prognosis for patients, particularly those with intermediate-to-advanced stage disease, remains dismal. The efficacy of conventional treatments is severely constrained by the aggressive nature, high heterogeneity, and profound propensity for drug resistance characteristic of HCC [[8], [9], [10]]. For instance, multi-kinase inhibitors like sorafenib, while once a standard of care, offer only modest survival benefits and are associated with low objective response rates and significant adverse effects [[11], [12], [13]]. More recently, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary therapeutic pillar; however, a substantial proportion of patients fail to respond, a phenomenon largely attributed to the complex and profoundly immunosuppressive TME of HCC [[14], [15], [16]]. Consequently, there is an urgent and unmet clinical need to develop innovative, highly effective, and minimally toxic therapeutic strategies against this devastating malignancy.

The convergence of nanotechnology and biomedicine has opened new frontiers for cancer therapy [17]. While conventional nanomedicines, such as liposomes and polymeric nanoparticles, have primarily been developed as passive drug delivery systems to improve the pharmacokinetics of encapsulated payloads, a distinct and more advanced paradigm has emerged with the advent of nanozymes [[18], [19], [20], [21]]. These are nanomaterials engineered with intrinsic, enzyme-like catalytic activities [[22], [23], [24], [25]]. Crucially, unlike traditional nanocarriers that merely transport therapeutic agents, nanozymes act as the therapeutic entity itself [[26], [27], [28]]. Their therapeutic effect stems not from a loaded drug but from their inherent ability to catalyze specific biochemical reactions directly within the TME [[29], [30], [31]]. This catalytic prowess enables them to convert endogenous, often benign, substrates into highly cytotoxic ROS, a process termed chemodynamic therapy (CDT) [[32], [33], [34]]. This mechanism of TME-triggered, on-site therapeutic generation offers the potential for enhanced tumor selectivity and reduced systemic side effects [[35], [36], [37]]. Furthermore, when compared to their biological counterparts, natural enzymes, nanozymes exhibit superior stability under harsh conditions, cost-effectiveness, facile large-scale production, and tunable catalytic activities, thereby overcoming the inherent limitations of natural enzymes such as fragility and high purification costs [[38], [39], [40]].

In this review, we provide a comprehensive and mechanistically oriented overview of nanozyme-based therapeutic strategies for HCC. We first outline the pathological features of HCC such as oxidative stress dysregulation, metabolic reprogramming, hypoxia, and immune suppression that create unique biochemical vulnerabilities exploitable by catalytic nanomaterials. We then classify and evaluate major categories of nanozymes, highlighting their catalytic principles, structural characteristics, and therapeutic applicability to different facets of the HCC microenvironment. Furthermore, we summarize cutting-edge advances in nanozyme-enhanced phototherapy, catalytic therapy, immunomodulation, and multimodal combination platforms, emphasizing how these approaches synergistically overcome the limitations of conventional treatments. Finally, we discuss the challenges that currently impede clinical translation, including biosafety, pharmacokinetics, tumor specificity, and large-scale manufacturing, and propose future directions for rational nanozyme design tailored to the clinical needs of HCC. Collectively, this review aims to bridge the gap between emerging catalytic nanotechnology and the pressing therapeutic demands of HCC, offering perspective for the development of next-generation precision oncology strategies (Fig. 1).

Fig. 1 — Schematic diagram of HCC treatment based on different nanozymes through catalytic therapy, immunotherapy, photothermal therapy (PTT) and combined therapy.

2. Molecular pathogenesis of HCC

The development and progression of HCC is a complex, multi-stage pathological process driven by a confluence of factors [41] (Fig. 2). Its pathogenesis is not triggered by a single oncogenic event but arises from the cumulative interplay of multi-dimensional molecular alterations [42]. Against a backdrop of persistent hepatocellular injury and chronic inflammation, these alterations include genomic instability, epigenetic reprogramming, dysregulation of cellular signaling pathways, remodeling of the TME, metabolic adaptation, and immune evasion [43]. Collectively, these events endow tumor cells with the capacity for malignant proliferation and invasion.

2.1. Pathophysiology of hepatocarcinogenesis

Hepatocellular carcinoma (HCC) typically develops in the setting of chronic liver injury and persistent inflammation, which together establish a tumor microenvironment characterized by sustained oxidative stress, metabolic dysregulation, hypoxia, and immune tolerance [44]. Independent of the underlying etiology, including viral hepatitis or metabolic-associated fatty liver disease, continuous hepatocyte damage leads to excessive reactive oxygen species production, mitochondrial dysfunction, and activation of stress-adaptive signaling pathways [45]. These processes give rise to a redox-imbalanced microenvironment with elevated hydrogen peroxide levels and enhanced antioxidant buffering capacity, features that are directly relevant to the catalytic behavior of nanozymes [46]. Chronic inflammation also profoundly reshapes the hepatic immune landscape. Long-term exposure to inflammatory mediators and damage-associated molecular patterns promotes immune tolerance through the enrichment of immunosuppressive cell populations and the attenuation of effective antitumor immune surveillance [47]. In parallel, hypoxia caused by abnormal vascular architecture and rapid tumor expansion further exacerbates therapeutic resistance and immune dysfunction [[48], [49], [50]]. In addition, the liver's central role in systemic metal metabolism results in dysregulated iron and copper homeostasis during hepatocarcinogenesis, creating biochemical conditions that can be exploited by metal-based nanozyme systems [[51], [52], [53]]. Collectively, these pathophysiological features intensify with disease progression and provide the biological basis for nanozyme-responsive therapeutic strategies in HCC.

2.2. Genetic and epigenetic alterations driving HCC progression

At the molecular level, HCC is associated with recurrent genetic and epigenetic alterations that contribute to genomic instability, uncontrolled proliferation, and phenotypic heterogeneity [[54], [55], [56]]. Frequent driver events include telomerase reactivation, impairment of cell cycle and DNA damage control, and aberrant activation of developmental signaling pathways such as Wnt/β-catenin [57]. Epigenetic dysregulation, encompassing altered DNA methylation patterns, imbalanced histone modifications, and dysregulated non-coding RNA expression, further reshapes transcriptional programs and reinforces malignant behavior [[58], [59], [60]]. Although these molecular alterations are essential for understanding HCC biology, they currently serve primarily as contextual determinants of tumor behavior rather than direct intervention targets for most nanozyme-based therapies [61]. Unlike targeted inhibitors or gene-specific interventions, nanozyme strategies predominantly leverage the downstream consequences of these alterations, including oxidative vulnerability, metabolic stress, immune evasion, and microenvironmental heterogeneity. Accordingly, in this review, genetic and epigenetic changes are discussed to provide mechanistic context for tumor microenvironment features that influence nanozyme activation, selectivity, and therapeutic efficacy, rather than as stage-specific or mutation-specific treatment determinants. Additionally, the dysregulation of histone modifications, such as the increase in the repressive H3K27me3 mark due to EZH2 overexpression, and the aberrant expression of non-coding RNAs, further modulate gene expression networks to propel tumor initiation and progression. Table 1.

Table 1.

Major stromal and immune cell subtypes in the HCC TME.

Cell Type	Key Markers	Principal Pro-tumorigenic Functions	Representative Secreted Factors
Hepatic stellate cells (HSCs)	α-SMA, Desmin	Fibrosis, ECM remodeling, angiogenesis, support of tumor proliferation	TGF-β, HGF, PDGF, VEGF, MMPs
Tumor-associated macrophages (TAMs)	CD68, CD163/CD206 (M2)	Immunosuppression, angiogenesis, invasion, metastasis	IL-10, TGF-β, VEGF, CCL22
Regulatory T cells (Tregs)	CD4, CD25, FOXP3	Suppression of cytotoxic T-cell function	IL-10, TGF-β
Myeloid-derived suppressor cells (MDSCs)	CD11b, Gr-1	Broad suppression of T-cell and NK-cell activity	Arginase-1, iNOS, ROS, TGF-β
Cancer-associated fibroblasts (CAFs)	FAP, α-SMA	ECM deposition, secretion of growth factors, immune modulation	CXCL12, TGF-β, HGF

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2.3. Dysregulation and network reconstruction of core signaling pathways

The genetic and epigenetic alterations accumulated during hepatocarcinogenesis ultimately converge on a limited number of core signaling programs that collectively promote proliferation, survival, and stress adaptation [[62], [63], [64]]. Rather than acting in isolation, pathways such as Wnt/β-catenin, PI3K/AKT/mTOR, MAPK, and Hippo signaling form a highly interconnected regulatory network that endows HCC cells with robust growth advantages and resistance to apoptosis [[65], [66], [67]]. Importantly, sustained activation of these signaling networks is tightly coupled to metabolic rewiring, redox adaptation, and microenvironmental stress tolerance [68], Aberrant signaling enhances glycolytic flux, antioxidant capacity, and survival under hypoxic or inflammatory conditions, thereby increasing the dependence of tumor cells on non-oncogene stress–response mechanisms [69]. From a therapeutic perspective, this convergence creates functional vulnerabilities that can be exploited without directly targeting individual driver mutations [70,71]. Nanozyme-based strategies are therefore positioned to act downstream of oncogenic signaling, leveraging the resultant oxidative imbalance, metabolic stress, and microenvironmental dependencies rather than engaging specific signaling nodes [[72], [73], [74]].

2.4. Tumor microenvironment remodeling and metabolic reprogramming

The malignant behavior of tumor cells is not solely a consequence of their intrinsic alterations but is also intricately linked to their dynamic interplay with the TME [[75], [76], [77]]. Activated hepatic stellate cells contribute to liver fibrosis and matrix stiffening by secreting large amounts of ECM proteins. They also establish paracrine signaling loops with tumor cells by secreting factors like hepatocyte growth factor and transforming growth factor-beta (TGF-β), thereby promoting tumor cell invasion and angiogenesis [[78], [79], [80]]. Within the TME, an enrichment of immunosuppressive cells, particularly M2-polarized TAMs, suppresses the anti-tumor function of cytotoxic T cells by secreting IL-10 and TGF-β and expressing programmed death-ligand 1 (PD-L1) [81,82]. Tumor cells further evade immune surveillance by activating immune checkpoint pathways, most notably the PD-1/PD-L1 axis, which inhibits T-cell function and fosters an immunotolerant state [[83], [84], [85]]. The clinical success of ICIs, such as anti-PD-1/PD-L1 therapies, has represented a major breakthrough in HCC treatment, demonstrating significant efficacy in a subset of patients. To fuel their rapid proliferation and meet the immense demand for energy and biosynthetic precursors, HCC cells undergo profound metabolic reprogramming. The classic “Warburg effect,” characterized by a preference for aerobic glycolysis, is a hallmark of HCC [[86], [87], [88]]. This metabolic shift, driven by oncogenic pathways such as HIF-1α and PI3K/AKT, involves the upregulation of glucose transporters and key glycolytic enzymes [[89], [90], [91]]. This allows cancer cells to efficiently generate ATP even in hypoxic conditions and provides the necessary carbon backbones for nucleotide and lipid synthesis. Furthermore, a “glutamine addiction” has been widely observed in HCC, where glutamine serves as a critical anaplerotic substrate for the TCA cycle and a precursor for antioxidant synthesis, supporting cancer cell survival in a high-oxidative-stress environment [[92], [93], [94]].

3. Clinical therapeutic strategies and challenges in HCC

The clinical management of HCC represents one of the most formidable challenges in modern oncology [[95], [96], [97]]. Its complexity arises not only from the aggressive nature of the tumor itself but also from the fact that the vast majority of cases develop within the context of chronic liver disease, such as cirrhosis. This necessitates a delicate balancing act in therapeutic decision-making, where the dual objectives of oncological control and preservation of liver function must be simultaneously addressed [[98], [99], [100]]. Consequently, a successful treatment strategy requires the close collaboration of a multidisciplinary team to holistically assess tumor stage, hepatic functional reserve, and the patient's overall performance status to formulate an individualized therapeutic plan. In recent years, the treatment paradigm for HCC has undergone a profound transformation, driven by innovations in surgical techniques, the diversification of locoregional therapies, and breakthrough advances in systemic treatments, particularly immunotherapy. This chapter will systematically review the current progress in the clinical management of HCC [101]. Guided by the internationally recognized Barcelona Clinic Liver Cancer (BCLC) staging system [[102], [103], [104], [105]], we will conduct an in-depth exploration of the standard-of-care therapies, recent advancements, and inherent limitations at each stage, thereby providing a solid theoretical foundation for understanding the rationale and clinical need for novel therapeutic strategies like nanozymes.

Therapeutic decisions in HCC are critically dependent on accurate disease staging. The BCLC staging system is globally accepted as the gold standard for guiding clinical practice and research design, endorsed by major academic bodies such as the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver [106]. Its prominence stems from its comprehensive integration of the three core prognostic determinants: tumor burden, liver function, and patient Performance Status (PS) [107]. The system stratifies patients into five stages 0 (very early), A (early), B (intermediate), C (advanced), and D (terminal) and provides a clear therapeutic algorithm for each [[108], [109], [110]]. The 2022 update to the BCLC staging system marked a significant conceptual shift [111], moving from a previously rigid treatment algorithm to a more flexible and dynamic concept of “treatment stage migration.” This update acknowledges the complexities of clinical practice and emphasizes the importance of more individualized decision-making within an MDT framework, based on patient response, tumor biology, and available technologies [[112], [113], [114]]. For instance, the application of transarterial chemoembolization (TACE) is no longer strictly confined to BCLC B patients, and its role in unresectable/incurable stage A patients or as a downstaging modality is now recognized, reflecting an enhancement in therapeutic flexibility [[115], [116], [117], [118]] (Fig. 3).

Fig. 3 — Schematic representation of the Barcelona Clinic Liver Cancer classification and its hallmarks at different stages.

However, a core limitation of the BCLC system is the profound clinical and prognostic heterogeneity that exists within its stages, particularly in the intermediate (B) and advanced (C) populations [119]. The tumor burden among BCLC B patients can vary dramatically, from a few small nodules to large, diffuse tumors. This leads to a vast disparity in outcomes following TACE, with reported median survival times ranging from 11 to 45 months [120]. This profound heterogeneity creates a “treatment gap” where the monolithic recommendation of TACE is not the optimal choice for many patients [121]. Recognizing this, clinical practice and research have begun to explore more refined therapeutic stratification. For example, landmark systemic therapy trials such as IMbrave150 included select BCLC B patients unsuitable for TACE and demonstrated a survival benefit for atezolizumab plus bevacizumab over sorafenib [122]. Concurrently, for patients with large or poorly located lesions unsuitable for ablation, advanced locoregional techniques like Stereotactic body radiotherapy (SBRT) have also shown excellent efficacy. Therefore, the flexibility advocated by the 2022 BCLC update is a direct response to this “treatment gap,” driving a shift from a “one-size-fits-all” guideline to a dynamic, MDT-led decision-making model based on individual patient characteristics [123]. This not only exposes the limitations of existing staging systems but also provides a strong rationale for developing biomarkers that can predict treatment response and for designing strategies tailored to specific patient subgroups [124].

3.1. Curative-intent therapies for early-stage HCC

For patients with early-stage HCC (BCLC 0 and A), the therapeutic goal is tumor eradication and long-term survival [125]. Curative-intent treatments currently include surgical resection, liver transplantation, and percutaneous local ablation [126]. Although these approaches can achieve excellent local tumor control in appropriately selected patients, their long-term effectiveness is frequently compromised by high recurrence rates. Table 2 summarizes the clinical treatment strategies, methods, drugs, advantages, and limitations of HCC.

Table 2.

Clinical therapeutic strategies for HCC – approaches, agents, advantages, and limitations.

Treatment Type	Main Approaches/Agents	Advantages	Limitations/Challenges
Curative-Intent Therapies (BCLC 0–A)	• Hepatic resection • Liver transplantation • Local ablation	• Potentially curative • High local control rates • LT removes both tumor and diseased liver	• High recurrence rate • Donor organ shortage, strict eligibility for LT • Ablation efficacy limited by tumor size and location
Locoregional Therapies (BCLC B)	• TACE: cTACE, DEB-TACE • Transarterial radioembolization • SBRT	• Suitable for unresectable multifocal tumors • Can serve as bridging or downstaging strategy • SBRT achieves local control up to 90 %	• Highly heterogeneous outcomes with TACE • No consistent survival benefit of DEB-TACE over cTACE • TARE/SBRT limited by hepatic reserve and technical expertise • Risk of radiation-induced liver disease (RILD)
Systemic Therapies (BCLC C)	• Targeted TKIs: sorafenib, lenvatinib • Immunotherapy: atezolizumab + bevacizumab • STRIDE regimen	• TKIs delay progression, improve PFS • ICI + anti-angiogenic combo markedly prolongs OS • Durable responses in subsets of patients	• Primary and acquired resistance common • Immune-related adverse events (irAEs) • Majority of responders eventually relapse • Overall survival benefits still limited
Cross-Cutting Clinical Challenges	• High recurrence • Therapeutic resistance • Impaired liver function limits therapy intensity	–	• Current therapies fail to fully address recurrence and immunosuppressive TME • Strong rationale for novel strategies to remodel TME, reduce hepatotoxicity, and achieve multi-mechanistic synergy

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Surgical resection remains the preferred option for patients with preserved liver function and limited tumor burden. Advances in perioperative management and surgical techniques have markedly improved safety, resulting in acceptable postoperative mortality and favorable survival outcomes in selected cohorts [127]. Nevertheless, postoperative recurrence remains a major limitation, with a substantial proportion of patients experiencing tumor relapse within several years. Early recurrence is generally attributed to occult micrometastatic disease present at the time of surgery, whereas late recurrence often reflects de novo tumor formation arising from the chronically diseased liver, highlighting the concept of field cancerization [[128], [129], [130]]. Liver transplantation is regarded as the most definitive curative strategy for early-stage HCC, as it simultaneously removes the tumor and the underlying cirrhotic liver. Patients meeting established selection criteria achieve survival outcomes comparable to those of non-malignant transplant indications. Despite ongoing efforts to expand eligibility through refined selection and downstaging strategies, the applicability of transplantation remains severely constrained by donor organ shortages and stringent inclusion criteria, limiting its availability to a small subset of patients [131]. Percutaneous ablation represents a standard curative alternative for patients who are not candidates for surgery. Techniques such as radiofrequency and microwave ablation offer effective local control for small tumors and are widely used in clinical practice. However, their efficacy is strongly dependent on tumor size and location, and incomplete ablation or local recurrence remains a concern, particularly for larger lesions or tumors adjacent to critical structures [[132], [133], [134], [135]]. Collectively, these curative-intent modalities reveal a central paradox in early-stage HCC management: high rates of local tumor control do not translate into definitive cure for a large proportion of patients. Tumor recurrence persists as the dominant cause of treatment failure, driven by both residual microscopic disease and the carcinogenic liver microenvironment [[136], [137], [138], [139]]. This unmet clinical need underscores the limitations of purely local therapies and provides a compelling rationale for the development of effective adjuvant strategies. Therapeutic approaches capable of targeting minimal residual disease and modulating the pro-tumorigenic liver microenvironment represent a critical frontier, forming the clinical foundation for exploring emerging modalities such as nanozyme-based therapies [[140], [141], [142]].

3.2. Locoregional therapies for intermediate-stage HCC

For patients with intermediate-stage hepatocellular carcinoma who are not candidates for curative-intent treatment, the therapeutic objective shifts toward controlling intrahepatic tumor progression and prolonging survival through liver-directed locoregional therapies [143]. TACE remains the standard of care for this stage and is widely applied in clinical practice. By combining arterial delivery of cytotoxic agents with embolization-induced ischemia, TACE can achieve effective tumor control in selected patients [144]. However, treatment response is highly heterogeneous, and durable disease control is uncommon, with repeated sessions often required [145]. Transarterial radioembolization (TARE), also referred to as selective internal radiation therapy, represents an important alternative for patients unsuitable for TACE, particularly those with large tumor burden, portal vein involvement, or borderline liver function [[146], [147], [148]]. In addition, SBRT has emerged as a non-invasive locoregional modality capable of achieving high local control rates for tumors that are technically inaccessible to ablation or surgery [149]. Despite these advances, the long-term benefits of locoregional therapies remain limited by tumor recurrence, incomplete disease control, and progressive liver dysfunction [150].

3.3. Systemic therapy for advanced-stage HCC

For patients with advanced-stage HCC characterized by vascular invasion or extrahepatic spread, systemic therapy constitutes the mainstay of treatment [151]. Over the past decade, the therapeutic landscape has undergone a paradigm shift from molecular targeted therapy to immunotherapy-based regimens [152]. lthough tyrosine kinase inhibitors were historically the first agents to demonstrate survival benefit, immune checkpoint inhibitors, particularly in combination with anti-angiogenic therapy, have redefined first-line treatment and significantly improved outcomes for a subset of patients [[153], [154], [155]]. Nevertheless, the clinical success of systemic therapy is tempered by several persistent challenges [156]. A substantial proportion of patients exhibit primary resistance to both targeted therapy and immunotherapy, and most initial responders eventually develop acquired resistance. Emerging evidence indicates that therapeutic resistance is closely linked to tumor heterogeneity and to an immunosuppressive tumor microenvironment shaped by chronic inflammation, hypoxia, metabolic stress, and immune checkpoint signaling [157,158]. Increasing attention has therefore been directed toward combination strategies that integrate locoregional and systemic treatments. Locoregional modalities such as SBRT may not only achieve effective tumor debulking but also induce immunogenic cell death and antigen release, potentially enhancing systemic immune responses when combined with immunotherapy. Despite early encouraging results, these approaches have not eliminated the fundamental problems of recurrence and immune escape. Across all disease stages, tumor recurrence and therapeutic resistance remain the dominant causes of treatment failure and mortality in HCC. Importantly, these phenomena share a common biological foundation rooted in a dysfunctional liver microenvironment characterized by chronic inflammation, immune tolerance, and metabolic dysregulation. This convergence suggests that transformative therapeutic strategies must extend beyond direct tumor cell killing to actively remodel the pro-tumorigenic microenvironment. In this context, nanozyme-based approaches are explored in this review as emerging platforms with the potential to address both recurrence and resistance by targeting shared microenvironmental vulnerabilities. Finally, the persistent constraint of impaired liver function is a ubiquitous limiting factor in HCC treatment. Most patients have underlying cirrhosis of varying severity, which not only restricts the scope of surgical resection but also increases the risk of toxicity from locoregional therapies like TACE and SBRT and can affect a patient's tolerance to certain systemic drugs. Therefore, developing highly effective therapies with low hepatotoxicity remains a critical goal in HCC drug development (Fig. 4).

Fig. 4 — Schematic diagram of the methods and limitations of traditional clinical treatment strategies for liver cancer.

In summary, while the clinical management of HCC has made significant strides, it still faces major unmet clinical needs, including high recurrence rates, pervasive therapeutic resistance, and the limitations imposed by poor liver function. These challenges collectively point the way for future research: the development of innovative therapies that can overcome heterogeneity, effectively prevent recurrence, remodel the immunosuppressive microenvironment, and have minimal impact on liver.

4. Nanozyme-based therapies for HCC

To strengthen the mechanistic integration between HCC pathology and nanozyme design, we highlight here how specific TME characteristics directly guide nanozyme-based therapeutic strategies, thereby supporting the concept of precision treatment. The HCC microenvironment is marked by excessive hydrogen peroxide accumulation, acidic pH, hypoxia, elevated GSH levels, immune tolerance, and metal metabolic dysregulation. These biochemical abnormalities are not only hallmarks of disease progression but also provide exploitable catalytic triggers for nanozyme activation. In regions enriched with H₂O₂, iron- or copper-based nanozymes catalyze its conversion into highly toxic ·OH through peroxidase-like or Fenton/Fenton-like processes, initiating oxidative damage and ferroptosis. Meanwhile, the abnormally high intracellular GSH concentration in HCC can be leveraged by nanozymes capable of consuming or oxidizing GSH, suppressing the GPX4-dependent lipid peroxide repair pathway and thus collapsing the redox buffering capacity of tumor cells [159]. Hypoxia, a major barrier to photodynamic therapy, can be overcome by catalase-like nanozymes that decompose endogenous H₂O₂ to generate oxygen, restoring intratumoral oxygenation, enhancing ROS-based phototherapy responses, and attenuating HIF-1α-driven resistance [[160], [161], [162], [163], [164]]. In parallel, nanozyme-mediated ferroptosis and cuproptosis trigger ICD characterized by DAMPs exposure and effector T cell recruitment, providing a mechanistic basis for converting “cold” HCC into an immune-responsive “hot” state and improving responsiveness to immune checkpoint blockade. Furthermore, iron and copper dysregulation, a common metabolic feature in HCC, is directly harnessed by metal-based nanozymes to amplify lipid peroxidation or mitochondrial stress, driving regulated cell death in a tumor-selective manner [[165], [166], [167]]. Collectively, these mechanistic correspondences establish a precise mapping from pathological microenvironment features to catalytic nanozyme functions, thereby reinforcing the central theme that nanozymes achieve highly targeted and microenvironment-responsive therapy in HCC.

The unique physicochemical properties of nanozymes and their ability to catalytically modulate the TME have positioned them as powerful next-generation tools for HCC therapy [[168], [169], [170]]. Their therapeutic mechanisms are not reliant on conventional cytotoxic pathways but rather on the strategic manipulation of the tumor's intrinsic biological and chemical landscape [[171], [172], [173]]. This paradigm circumvents many of the resistance mechanisms that plague conventional therapies and offers a pathway toward highly specific, minimally toxic treatments [174,175]. Table 3 summarizes the representative nanozyme elements for HCC treatment: characteristics, advantages, and potential limitations. Nanozymes exert therapeutic effects largely through enzyme-mimetic catalytic behavior, and understanding their catalytic mechanism is fundamental to rational design for precision therapy. The catalytic activity of metal-, oxide-, and carbon-based nanozymes originates from active centers that mediate electron transfer during substrate conversion; for example, Fe²⁺/Fe³⁺ redox cycling drives Fenton-like ·OH generation, while single-atom Fe–N₄ or Cu–N₄ coordination structures facilitate peroxidase-like electron transfer directly on the catalytic surface. The activity of nanozymes is highly structure-dependent, where parameters such as particle size, crystal facet exposure, vacancy/defect density, and heteroatom doping directly influence catalytic turnover rate, substrate affinity, and ROS yield. Smaller nanozymes typically offer higher surface-to-volume ratios and more exposed catalytic sites, while oxygen vacancies in CeO₂ or defect-rich Mo-based frameworks promote accelerated H₂O₂ adsorption and decomposition. Meanwhile, coordination chemistry fine-tuning alters d-band electronic structure, thereby regulating catalytic kinetics and ROS species selectivity. Substrate specificity is similarly governed by interfacial binding energy and electron-coupling efficiency, explaining why Fe-based materials preferentially catalyze Fenton reactions, whereas Pt-, Mn- or Co-based systems better perform CAT/SOD-like oxygen regulation in hypoxic tumors. By coupling mechanistic understanding with structural tunability, nanozymes can be engineered to target redox imbalance, lipid peroxidation susceptibility, or immunometabolism vulnerabilities unique to HCC, forming the theoretical basis for microenvironment-responsive and precision-oriented therapeutic strategies. This chapter delineates the primary therapeutic strategies employing nanozymes against HCC, categorized into four major approaches: catalytic therapy, nanozyme-enhanced immunotherapy, PTT, and advanced combination therapy platforms. Each section will first introduce the core principles of the strategy and its specific relevance to the pathophysiology of HCC, setting a solid theoretical stage for the detailed discussion of representative studies that follows.

Table 3.

Representative nanozyme elements for HCC therapy: Features, advantages, and potential limitations.

Nanozyme Element	Key Features	Advantages	Potential Limitations
Fe (Iron-based nanozymes)	• High Fenton reaction activity • Induce ferroptosis • Can be combined with photothermal/magnetic therapy	• Abundant, low-cost, relatively biocompatible • Directly trigger ROS burst and lipid peroxidation • Well-studied with mature mechanisms	• Strongly dependent on H₂O₂ concentration • Easily neutralized by GSH • Risk of iron-overload toxicity
Cu (Copper-based nanozymes)	• Fenton-like activity over a wider pH range • Induce cuproptosis • Excellent photothermal/photodynamic properties	• Highly reactive in acidic environments • Synergize with ferroptosis for dual cell-death pathways • Promote ICD	• Complex systemic copper homeostasis • Risk of hepatotoxicity and metabolic burden
Mn (Manganese-based nanozymes)	• CAT/SOD-mimetic activities • Oxygen generation to relieve hypoxia • Applicable as MRI contrast agents	• Enhance PDT/RT efficacy • Theranostic potential (diagnosis + therapy) • Moderate redox activity improves biosafety	• Relatively low ROS yield • Poor stability, prone to inactivation
Mo (Molybdenum-based nanozymes)	• High photothermal conversion efficiency • Broad redox catalytic capacity • NIR-II absorption properties	• Excellent PTT platform • Potent enhancer of CDT and combination therapies • Superior biosafety compared to some transition metals	• Complex synthesis procedures • Long-term metabolism and safety not fully elucidated
Au (Gold-based nanozymes)	• Outstanding photothermal properties • Capable of drug/photosensitizer loading • Highly modifiable surface chemistry	• High-efficiency PTT and imaging guidance • Excellent stability and functionalization capacity • Compatible with immunotherapy and gene therapy	• High cost • Uncertain long-term biodegradability
Pt (Platinum-based nanozymes)	• Strong POD/CAT-like enzymatic activity • Catalyze H₂O₂ decomposition • Potent enhancer of PDT	• High ROS generation • Synergistic with phototherapy and radiotherapy • Some derivatives already used in clinical oncology	• Expensive noble metal • Risk of systemic toxicity
Ce (Cerium-based nanozymes)	• Reversible Ce³⁺/Ce⁴⁺ cycling • SOD/CAT-mimetic activity • Bidirectional ROS regulation	• Dual function: ROS scavenging or production • Applicable in both anti-cancer and hepatoprotective settings • Versatile therapeutic potential	• Strongly influenced by microenvironment • Mechanistic role in immune regulation remains unclear

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4.1. Catalytic therapy

Catalytic therapy represents the most fundamental application of nanozymes, directly leveraging their intrinsic enzyme-mimicking activities to induce tumor cell death [[176], [177], [178]]. This strategy is primarily centered on CDT, a process that converts endogenous, low-toxic substrates within the TME into highly toxic ROS. The HCC microenvironment is uniquely suited for CDT, characterized by several key features stemming from the aberrant metabolism of cancer cells known as the Warburg effect: hypoxia, mild acidity (pH ∼6.5), and, most importantly, an overproduction of hydrogen peroxide (H₂O₂). Nanozymes with peroxidase-like (POD-like) activity can be activated within the acidic TME to efficiently catalyze the decomposition of this endogenous H₂O₂ into the highly cytotoxic hydroxyl radical (•OH) via Fenton or Fenton-like reactions [[179], [180], [181], [182], [183]]. POD activity and Fenton/Fenton-like reactions are two frequently referenced but fundamentally distinct catalytic routes for ·OH generation in nanozyme-mediated cancer therapy. POD-like catalysis typically occurs on the surface of nanozymes with enzyme-mimetic catalytic sites, where H₂O₂ is directly decomposed into ·OH through a two-electron oxidoreductive cycle, analogous to natural horseradish peroxidase. In contrast, Fenton and Fenton-like reactions rely on redox cycling of transition metal ions (e.g., Fe²⁺/Fe³⁺, Cu⁺/Cu²⁺), requiring continuous electron exchange to generate ·OH via a hydroxyl radical-producing cleavage of H₂O₂. Mechanistically, POD catalysis focuses on surface-mediated electron transfer, whereas Fenton-based catalysis emphasizes metal-center redox cycling. Recent evidence highlights that nanozymes with stronger POD activity tend to exhibit higher ·OH yield and improved catalytic therapeutic outcome, underscoring the necessity of differentiating these mechanisms in nanozyme design for HCC therapy. The resulting burst of ⋅OH induces overwhelming oxidative stress, leading to lipid peroxidation of cellular membranes, protein carbonylation, and DNA strand breaks. This damage cascade ultimately drives cancer cell death, not only through apoptosis but also, significantly, through ferroptosis a non-apoptotic, iron-dependent form of regulated cell death to which many HCC subtypes are particularly sensitive [184]. To further amplify therapeutic efficacy, more advanced catalytic strategies involve nanozymes with catalase-like (CAT-like) or superoxide dismutase-like (SOD-like) activities to modulate the TME's redox state [[185], [186], [187]]. For instance, by consuming the endogenous antioxidant glutathione (GSH), nanozymes can dismantle the tumor's primary self-protective mechanism against oxidative damage, particularly by inhibiting glutathione peroxidase 4 (GPX4), rendering the cancer cells exquisitely sensitive to ROS-induced ferroptosis [188]. To further underscore the precision-oriented advantages of nanozymes, it is crucial to highlight that nanozymes are not merely passive catalytic species but highly engineerable and tunable material platforms with structural programmability. Their catalytic performance and biological behavior can be rationally modulated through the regulation of particle size, crystal composition, heteroatom doping, surface coordination environment, vacancy or defect density, and ligand chemistry, which together determine substrate affinity, electron transfer kinetics, and microenvironment responsiveness. Such structural tunability not only enables the controlled enhancement of POD, CAT, or Fenton-like catalytic pathways, but also allows the construction of nanozymes with switchable redox states, hypoxia responsiveness, GSH-triggered activation, or enzyme cascade amplification tailored to specific features of the HCC TME. Beyond catalysis, nanozymes provide a versatile theranostic scaffold: their surfaces can be modified with targeting ligands, immune modulators, or stealth coatings, and their internal cavities or interfaces can encapsulate chemotherapeutics, photosensitizers, siRNA, or metal ions to integrate CDT, PDT/PTT, immunotherapy, or drug delivery into a single platform. This inherent designability and multifunctional assembly capacity grant nanozymes exceptional compatibility with precision medicine principles, enabling treatment strategies that are not only tumor-selective but also adaptable, combinable, and programmable according to disease phenotype and therapeutic needs (see Fig. 5).

Fig. 5 — Highlights the conceptual evolution of nanozymes from enzyme mimetics to precision therapeutic platforms, with increasing emphasis on tumor microenvironment responsiveness, immune modulation, and translational considerations in hepatocellular carcinoma.

To address challenges in HCC therapy, such as drug resistance from single pathway cell death and the insufficient efficacy of catalytic therapies due to the TME, Wei et al. [189]. developed an ultrasound amplified, multi enzyme mimicking, ultrasmall nanozyme (BSO) (Fig. 6). The TME is typically characterized by acidity, hypoxia, and high GSH levels. The nanozyme, based on ultrasmall Bi₂Sn₂O₇ nanoparticles with a particle size of approximately 6.24 nm, was surface coated with PVP to ensure excellent dispersion and physiological stability. Characterization via XRD and XPS confirmed its crystalline phase and elemental valence states. Its electronic band structure, with a band gap of 3.06 eV, a valence band at approximately 0.86 eV, and a conduction band at approximately −2.2 eV, indicated its potential for efficient ROS generation under ultrasound irradiation. Functional assays revealed that BSO possesses multiple enzymes like activities, including POD, CAT, and GPx. Its POD like activity was significantly enhanced in weakly acidic conditions, with Michaelis Menten kinetics yielding a Km of 345.55 mM and a Vmax of 0.1476 μM s⁻¹. Furthermore, its CAT like activity decomposed H₂O₂ to generate oxygen, alleviating tumor hypoxia, while its GPx like activity depleted intracellular GSH, thereby dismantling the cell's antioxidant defenses. Crucially, under ultrasound irradiation (1.0 MHz, 1.25 W cm⁻², 50 % duty cycle, 3 min), electron spin resonance spectroscopy detected the simultaneous generation of •OH, superoxide anions (•O₂⁻), and singlet oxygen (¹O₂). This confirmed that the system achieves highly efficient ROS accumulation through a synergistic mechanism of ultrasound energy amplification and multi enzyme catalysis, laying the foundation for the comprehensive activation of cell death pathways. Based on this design, the authors targeted PANoptosis as the therapeutic endpoint. PANoptosis is an inflammatory form of programmed cell death that integrates apoptosis, pyroptosis, and necroptosis, and it aims to overcome tumor escape and resistance through multi pathway redundancy. In vitro, Hepa1-6 cells treated with BSO combined with ultrasound exhibited a substantial increase in intracellular ROS levels and a significant drop in GSH. This established a classic cascade of damage involving ROS, mitochondria, and lysosomes. Under these conditions, cell viability was reduced to a minimum of 18.7 %, a significantly greater effect than any single or dual factor treatment. Transcriptomic analysis identified 418 differentially expressed genes enriched in inflammation and cell death pathways such as TNF, NOD like receptor, IL-17, and NF-κB signaling. Flow cytometry confirmed a surge in the apoptotic cell population to 61.8 %. Mechanistic validation by Western blotting confirmed the activation of all three PANoptosis branches: apoptosis, pyroptosis (increased NLRP3, cleaved Caspase 1, and N-GSDMD with elevated LDH/IL-1β release), and necroptosis. In a subcutaneous HCC mouse model, both intravenous and intratumoral administration of BSO with ultrasound demonstrated outstanding tumor suppression, achieving tumor growth inhibition rates of 79.3 % and 84.9 %, respectively. Histological analysis revealed decreased Ki67, increased TUNEL positive cells, and synchronous upregulation of key PANoptosis related proteins. Furthermore, in a lung metastasis model, the BSO and ultrasound treatment significantly reduced metastatic nodules, indicating its potential to inhibit metastasis. Safety evaluations confirmed its biocompatibility, showing a low hemolysis rate of 0.36 % and clearance within 72 h, demonstrating favorable metabolic characteristics. Overall, this work pioneers a strategy that integrates ultrasound amplified multi enzyme catalysis with the induction of PANoptosis, presenting a highly effective and translatable paradigm for HCC catalytic therapy. The potential of such enzyodynamic strategies is further highlighted in clinically relevant orthotopic HCC models, where similar approaches have achieved tumor inhibition rates of 83.4 % and extended median survival to 52 days, compared to less than 30 days for controls. This body of work provides a strong theoretical and practical basis for overcoming TME induced therapeutic limitations by amplifying enzyodynamic effects and engaging multiple cell death signals for a comprehensive anti-tumor response.

Fig. 6 — (a) Schematic illustration of the multienzyme-mimetic catalytic reactions of Bi₂Sn₂O₇. (b) Schematic scheme of the PANoptosis inducer based on ultrasmall BSO nanozymes, which is applied for ultrasound-enhanced enzyodynamic tumor therapy and lung metastasis suppression. (c) Schematic representation of the molecular mechanism underlying PANoptosis triggered by ultrasmall BSO nanozymes. Copyright from Ref. [189] Wiley-VCH 2024.

Effectively overcoming the significant metabolic heterogeneity of HCC has recently emerged as a critical challenge limiting the efficacy of nanozyme-based therapies. Due to the pronounced spatiotemporal differences in glucose supply within tumors, glucose-replete regions can readily sustain glycolysis and resist oxidative stress, whereas glucose-deficient regions distant from blood vessels experience nutrient deprivation. Consequently, conventional catalytic therapies based on a single mechanism often fail to address the distinct therapeutic requirements of these different zones. To address this, Zhou et al. [190]. have developed a metabolically adaptive, organic-inorganic hybrid biomimetic nanozyme, designated M@GOx/Fe-HMON (Fig. 7). This system is engineered by co-loading glucose oxidase (GOx) and an Fe²⁺/Fe³⁺ redox couple into a nanoplatform camouflaged with homologous cancer cell membranes, enabling precise modulation of HCC regions with disparate metabolic states. The core design principle of this nanozyme is to leverage the differential availability of glucose to trigger two distinct forms of programmed cell death. In glucose-replete regions, GOx catalyzes glucose to produce gluconic acid and H₂O₂, which is then converted into highly reactive •OH by the Fe²⁺/Fe³⁺ couple via a Fenton reaction. This process induces potent ferroptosis through lipid peroxidation and GSH depletion. In parallel, the GSH-responsive degradation of the organosilica framework further exacerbates intracellular redox imbalance. Conversely, in glucose-deficient regions, the system accelerates the consumption of residual glucose. This leads to the depletion of NADPH and ATP, which in turn inhibits the reduction of cystine to cysteine, causing an over-accumulation of intracellular disulfides. This disulfide stress inflicts irreversible damage to cytoskeletal proteins such as actin, inducing the recently reported cell death pathway of disulfidptosis. This metabolism-dependent “dual-switch” effect significantly broadens the therapeutic adaptability of the nanozyme within heterogeneous TMEs. Quantitative experiments have validated the efficacy of this strategy. In vitro, M@GOx/Fe-HMON induced a 63.6 % death rate in H22 cells under high-glucose conditions and maintained significant cytotoxicity of approximately 50 % under low-glucose conditions, both of which were substantially higher than controls. Molecular analysis confirmed the activation of ferroptosis through elevated malondialdehyde (MDA) levels, a decreased GSH/GSSG ratio, and a significant loss of mitochondrial membrane potential. In parallel, the occurrence of disulfidptosis under low-glucose conditions was verified by the notable accumulation of cystine, the formation of disulfide-crosslinked bands in cytoskeletal proteins such as FLNA/B and MYH9, and the observation of F-actin collapse via fluorescence staining. In vivo, the nanozyme demonstrated superior anti-tumor effects in both subcutaneous and orthotopic HCC models, with significant inhibition of tumor growth and a marked reduction in Ki67 staining. Notably, long-term survival analysis showed that over 50 % of the treated mice were still alive at day 60, whereas nearly all mice in the control group had perished. Additionally, the iron-based framework endows the system with superparamagnetic properties, exhibiting a high transverse relaxivity rate (r₂) of 20.39 mM⁻¹ s⁻¹, enabling its use as a sensitive T₂-weighted MRI contrast agent for theranostic integration.

Fig. 7 — Schematic Diagram of the Synthesis and Biomedical Applications of M@GOx/Fe-HMON. (A) Schematic representation of the preparation procedure for M@GOx/Fe-HMON. (B) Schematic overview of the therapeutic and monitoring workflow utilizing M@GOx/Fe-HMON. Copyright from Ref. [190] Elsevier 2025.

In summary, this research is the first to integrate the emerging cell death modalities of ferroptosis and disulfidptosis into a single nanoplatform. By enabling differential cell killing through metabolic sensing, this approach overcomes the limitations of conventional nanozymes that activate only a single pathway. Its potent, adaptive anti-tumor effects, combined with its imaging capabilities, establish a new paradigm for the precision catalytic treatment of metabolically heterogeneous HCC. While both metal-based and metal-free nanozymes have been explored for catalytic therapy in hepatocellular carcinoma, their mechanistic strengths and limitations differ substantially and merit explicit comparison. Metal-based nanozymes, particularly those containing Fe, Cu, or Pt, generally exhibit higher catalytic robustness and redox turnover efficiency, enabling effective hydroxyl radical generation and ferroptosis induction under HCC-relevant conditions. However, their performance is often constrained by microenvironmental dependencies, such as limited H₂O₂ availability or rapid neutralization by elevated glutathione, and by safety concerns related to metal ion leakage and off-target oxidative damage. In contrast, metal-free nanozymes, including carbon-based and organic frameworks, offer improved biosafety and redox stability, as they avoid direct metal-mediated Fenton chemistry and typically generate milder oxidative stress. Nevertheless, these systems frequently suffer from lower catalytic potency and reduced capacity to overcome the strong antioxidant buffering characteristic of HCC, which limits their efficacy in deeply hypoxic or GSH-rich tumor regions. Notably, several metal-free platforms demonstrate promising in vitro ROS modulation but fail to sustain sufficient oxidative pressure in vivo, highlighting a key reason why some catalytic nanozyme strategies have remained at the proof-of-concept stage. These comparisons suggest that catalytic success in HCC requires not only activity demonstration but also careful matching of catalytic phenotype to tumor redox constraints and safety thresholds.

4.2. Nanozyme-enhanced immunotherapy

The profound immunosuppressive nature of the HCC microenvironment is a major barrier to effective anti-tumor immunity and a primary cause of resistance to immune checkpoint blockade (ICB) therapy. Nanozymes are emerging as potent immunomodulators capable of reversing this immunologically “cold” tumor phenotype into an immune-responsive “hot” state. Their therapeutic action in this domain is multifaceted. Firstly, the ROS generated through nanozyme-mediated catalytic therapy can induce ICD in cancer cells. ICD is a distinct form of regulated cell death that triggers the release of damage-associated molecular patterns (DAMPs) that powerful “danger signals” such as the surface exposure of calreticulin (CRT) and the extracellular release of ATP and high-mobility group box 1 (HMGB1) [[191], [192], [193]]. These DAMPs function as an in-situ vaccine, potently recruiting and activating dendritic cells to enhance antigen presentation and prime a robust, tumor-specific cytotoxic T lymphocyte (CTL) response. Secondly, nanozymes with CAT-like activity can alleviate tumor hypoxia by catalyzing H2 O2 into oxygen. This reoxygenation not only inhibits the proliferation and function of immunosuppressive cells like M2-polarized TAMs and MDSCs but also enhances the infiltration, survival, and effector function of CTLs [[194], [195], [196]]. By comprehensively remodeling the TME from an immunosuppressive to an immune-supportive state, nanozymes can synergize powerfully with existing immunotherapies, particularly ICB, to unlock potent anti-tumor immunity in previously non-responsive HCC patients. Beyond direct tumor cytotoxicity, nanozyme-induced ROS plays a multifaceted role in shaping antitumor immune responses by intersecting with antigen presentation, T-cell functional states, and immune memory formation. Moderate and spatially confined ROS generation promotes immunogenic cell death of tumor cells, characterized by calreticulin exposure, ATP release, and HMGB1 secretion, thereby enhancing tumor antigen availability and facilitating uptake and cross-presentation by dendritic cells. This process supports efficient priming of tumor-specific CD8⁺ T cells and initiation of adaptive immunity. At the same time, ROS levels critically influence T-cell fate decisions: transient ROS signaling can enhance T-cell activation and effector function, whereas excessive or sustained oxidative stress may impair mitochondrial integrity, promote expression of exhaustion markers, and limit T-cell persistence, particularly within the hypoxic and immunosuppressive HCC microenvironment. Importantly, emerging evidence suggests that appropriately tuned redox modulation can favor the differentiation of memory T-cell populations by avoiding chronic overstimulation and preserving metabolic fitness. Consequently, nanozyme platforms that enable precise control over ROS intensity, duration, and localization are better positioned to induce durable antitumor immunity rather than short-lived effector responses. This mechanistic coupling between nanozyme-mediated redox regulation and adaptive immune programming highlights the necessity of precision-oriented design to balance cytotoxic efficacy with long-term immune protection.

To address two core challenges in HCC immunotherapy, namely immune escape via the PD-1/PD-L1 axis and the limited durability of single checkpoint blockade due to complex regulatory networks in the immunosuppressive microenvironment, Sun et al. [197]. developed a nanozyme-enhanced immunotherapeutic strategy. Their platform, designated siRNA-CaP@PD1-NVs, integrates ICB, gene silencing, and microenvironment modulation. The system features a calcium phosphate (CaP) nanozyme core that is loaded with dual-target siRNAs against PD-L1 and Pbrm1. The pH-responsive CaP core dissolves in the acidic TME to release Ca²⁺, which exerts an enzyme-like activity to enhance immune cell activation. This core is biomimetically coated with membranes derived from PD-1-overexpressing cells, which serves two functions: it blocks the PD-1/PD-L1 pathway via protein mimicry and enhances tumor accumulation through homologous targeting. This multi-layered design enables a triple-acting mechanism of ICB, gene silencing, and nanozyme-mediated immunomodulation. In vitro, the platform successfully downregulated PD-L1 and Pbrm1 expression in HCC cells and increased the maturation of dendritic cells, with the CD80⁺/CD86⁺ population rising to 45.9 % from under 20 % in controls. In an orthotopic HCC mouse model, the treatment significantly increased CD8⁺ T cell infiltration, boosted IFN-γ secretion 8.3-fold, and reduced the proportion of immunosuppressive Treg cells to 6.3 %. This robust immune activation resulted in a tumor volume inhibition rate exceeding 80 % and extended the median survival to 77 days, with some mice achieving complete tumor eradication and demonstrating a durable immune memory response in a re-challenge experiment. Histological analysis confirmed these findings, showing reduced Ki67 staining, increased TUNEL-positive cells, and widespread CD8⁺ T cell infiltration, indicating the TME was successfully remodeled into an inflammatory state. The system also exhibited excellent biocompatibility with no significant toxicity observed. In summary, this work establishes a new paradigm of “nanozyme-enhanced immunotherapy” by integrating a responsive nanozyme with checkpoint blockade and gene silencing, offering a solid basis for overcoming resistance and recurrence in HCC immunotherapy (Fig. 8).

Fig. 8 — (A) Schematic representation of the fabrication process for siRNA-CaP@PD1-NVs.; (B) Schematic illustration of multifunctional biomimetic nanocarriers applied in dual-targeted immuno-gene therapy. A virus-mimetic multifunctional nanocarrier is constructed using siRNA therapeutic agents, an immune adjuvant, and an immune checkpoint inhibitor. Endowed with superior long-circulation performance and lysosome escape ability, this nanocarrier enables efficient co-delivery of payloads. Copyright from Ref. [197] Wiley-VCH 2024.

Yao et al. [179]. addressed the “immunologically cold” nature of solid tumors like HCC, where therapeutic responses are often limited. They identified the GPX4 driven lipid repair pathway as a key mechanism by which tumor cells evade immune surveillance. Recognizing that ferroptosis, an emerging form of programmed cell death, is inherently immunogenic, they developed a carbon quantum dot nanozyme (ChA-CQDs) derived from a natural food source, coffee. Synthesized via a hydrothermal method from chlorogenic acid, these nanozymes are 2–5 nm in size and exhibit excellent biocompatibility. Unlike traditional metal-based nanozymes, ChA-CQDs display potent glutathione oxidase-like activity, catalyzing the oxidation of GSH to GSSG within the TME. This action inhibits GPX4, dismantles the tumor's antioxidant defenses, and selectively induces ferroptosis in HCC cells. Mechanistically, ChA-CQDs were shown to induce GSH depletion and ROS accumulation in HepG2 cells, leading to the downregulation of key ferroptosis regulators such as GPX4 and SLC7A11. In an H22 liver cancer mouse model, ChA-CQDs suppressed tumor growth by nearly 70 %, outperforming the standard drug Sorafenib. Critically, immunological analysis revealed that the treatment converted “cold” tumors into “hot” ones by promoting significant infiltration of CD4⁺ and CD8⁺ T cells, NK cells, and M1 macrophages. This demonstrates that the induced ferroptosis triggers ICD, which subsequently activates both innate and adaptive immune responses. The system also showed a favorable safety profile with no significant organ toxicity. In conclusion, this study provides compelling evidence that a natural product-derived nanozyme can function as an immunotherapy sensitizer by activating an immune response via ferroptosis, offering a novel strategy for combined HCC treatment.

Targeting two major bottlenecks in HCC immunotherapy, which are tumor immune evasion through antioxidant and metal homeostasis systems and the limited efficacy of checkpoint inhibitors, Yang et al. [198]. proposed an immune enhancing strategy based on a single atom nanozyme. They designed and synthesized a biomimetic dual ion site single atom nanozyme (Cu–Fe SANs) that leverages the synergistic action of precisely engineered Fe–N₄ and Cu–N₄ active centers to simultaneously trigger both ferroptosis and cuproptosis. The Fe–N₄ sites catalyze a Fenton like reaction to generate hydroxyl radicals and promote lipid peroxidation, inducing ferroptosis. Concurrently, the Cu–N₄ sites disrupt mitochondrial acylated proteins and iron sulfur cluster stability, initiating cuproptosis. This “iron copper dual death” mechanism not only enhances direct tumor cell killing but also induces ICD through the release of DAMPs, thereby remodeling the tumor immune microenvironment. In HepG2 cells, the Cu–Fe SANs induced a significant ROS burst depleted GSH by approximately 65 %, and downregulated GPX4 expression by over 60 %, confirming ferroptosis. Simultaneously, ATP levels dropped by 55 % and mitochondrial membrane potential was lost, consistent with the molecular signatures of cuproptosis. In a H22 subcutaneous mouse model, the treatment achieved a 78 % tumor volume inhibition rate. Immunological analysis showed a 3.5-fold increase in CD8⁺ T cell infiltration, a 4-fold rise in IFN-γ levels, and a reduction in the Treg cell proportion to 7.2 %. The dual ion nanozyme also promoted the release of ICD markers such as HMGB1 and ATP, establishing a positive feedback loop between metal dependent cell death and immune activation. Consequently, the median survival of treated mice was extended to 72 days, and a robust immune memory effect was observed. This study demonstrates a powerful strategy for sensitizing HCC to immunotherapy by using dual ion nanozymes to synergistically induce ferroptosis and cuproptosis, thereby amplifying immune activation signals (Fig. 9).

Fig. 9 — Schematic illustration of synthesis of the dis-SAzyme-Dox@M and the synergistic therapeutic mechanism to HCC. Copyright from Ref. [198] Wiley-VCH 2025.

Recent studies have highlighted the unique potential of nanozymes in enhancing immunotherapy for HCC. The work by Yao et al. [179]. utilized a natural product-derived carbon quantum dot nanozyme to induce ferroptosis, a form of ICD. This approach not only directly suppressed tumor growth but also significantly promoted the infiltration of CD8⁺ T cells and NK cells, thereby converting “immunologically cold” tumors into “hot” ones. Concurrently, Sun et al. constructed a biomimetic nanozyme platform integrating ICB and gene silencing, which successfully enhanced dendritic cell maturation and CD8⁺ T cell effector functions, effectively alleviating the immunosuppressive microenvironment. Building on this, Yang et al. proposed a dual-ion-site single-atom nanozyme strategy to synergistically induce both ferroptosis and cuproptosis. This dual-death mechanism amplified the immune response through the release of DAMPs and enhanced antigen presentation, leading to a robust immune memory and long-term anti-tumor effects. A common thread among these studies is the tight integration of the nanozymes' catalytic properties with immune activation. By leveraging distinct pathways such as ferroptosis, cuproptosis, gene silencing, or checkpoint blockade, these approaches have successfully addressed the bottlenecks of resistance and low response rates in HCC immunotherapy. While these studies provide a strong proof of concept for “nanozyme-enhanced immunotherapy,” several critical questions remain. First, the immunogenicity of ferroptosis or cuproptosis may be governed by a “dose window.” Moderate levels of cell death can release DAMPs to activate the immune system, but an excessive ROS burst or metal ion disturbance could potentially damage infiltrating effector cells or even induce immune exhaustion. This balance must be carefully controlled for clinical translation. Second, existing research is predominantly validated in murine models, whereas the human HCC immune microenvironment is far more complex. Factors such as MDSCs, CAFs, and metabolic reprogramming could diminish the immunological effects of nanozymes. Third, long-term safety and systemic toxicity, particularly the potential accumulation of metal ions from single-atom nanozymes, require further investigation. Future directions may lie in combination strategies that pair nanozymes with ICIs, personalized neoantigen vaccines, or metabolic interventions to achieve dual precision control over both catalytic and immune therapies. Simultaneously, advanced engineering could endow nanozymes with more controllable release and targeting capabilities to better balance therapeutic efficacy and safety.

Nanozyme-enhanced immunotherapy strategies also display marked divergence in mechanism and translational promise, particularly when comparing metal-based and metal-free systems. Metal-based nanozymes that induce ferroptosis or cuproptosis often generate strong immunogenic cell death signals, including lipid peroxidation–derived danger-associated molecular patterns, which can effectively promote dendritic cell maturation and cytotoxic T-cell infiltration. However, excessive or poorly confined ROS generation may compromise immune cell viability or exacerbate local inflammation, posing challenges for sustained immune activation. Metal-free nanozymes, by contrast, typically modulate immune responses more indirectly, for example by mild ROS signaling, metabolic interference, or antigen presentation enhancement, resulting in a more favorable safety profile but often weaker immune priming. Importantly, several nanozyme platforms that initially demonstrated immune activation in simplified tumor models did not progress beyond early preclinical stages, largely due to insufficient efficacy in immunosuppressive and hypoxic microenvironments such as HCC. These observations underscore that successful immunomodulatory nanozymes must balance sufficient oxidative or metabolic stress to trigger immunogenicity while preserving immune cell functionality, a balance that remains difficult to achieve with single-mechanism designs.

4.3. Nanozyme-based photothermal therapy

PTT is a minimally invasive therapeutic modality that utilizes photothermal agents to convert near-infrared (NIR) light, particularly within the NIR-II biological window (1000–1700 nm) which affords deep tissue penetration, into localized hyperthermia (>42 °C) to ablate tumor tissues [189,[199], [200], [201], [202]]. A significant advantage of many nanozyme platforms is their inherent possession of strong NIR absorbance, allowing them to function as dual-purpose agents for both catalytic therapy and PTT. This integration creates a powerful synergistic effect. The localized heat generated during PTT does not only cause direct thermal damage to cancer cells by denaturing proteins and disrupting membrane integrity, but it also significantly accelerates the catalytic reaction rates of the nanozyme, following the principles of the Arrhenius equation [203]. This heat-enhanced catalytic activity leads to a burst-like generation of ROS, resulting in a much more potent anti-tumor effect than could be achieved by either CDT or PTT alone. Conversely, the ROS generated by CDT can enhance PTT efficacy by inhibiting the expression of heat shock proteins (HSPs), thereby lowering the thermal tolerance of cancer cells. Moreover, the mild hyperthermia can increase the permeability of tumor blood vessels and cell membranes, which facilitates the intratumoral accumulation of the nanozymes and enhances the susceptibility of cancer cells to oxidative stress [[203], [204], [205], [206]]. This subsection will focus on the design and application of such multifunctional nanozymes that harness the synergistic interplay between photothermal and catalytic effects for advanced HCC treatment.

In the treatment of HCC, the efficacy of therapies targeting traditional apoptotic pathways is often limited by the acquired anti-apoptotic properties of tumor cells. This has shifted focus toward novel non-apoptotic cell death modalities, such as ferroptosis and cuproptosis. However, the therapeutic potential of these pathways is constrained by the limited intracellular concentrations of copper and iron, the complexity of the TME, and an unclear understanding of their cross-regulatory mechanisms. To address this challenge, Zhang et al. [207]. have designed a composite nanoplatform that combines photothermal properties with enzyme-mimicking activities. Their system, designated O2-PFH@CHPI, was constructed by doping hollow Prussian blue nanoparticles with copper ions (CHP) and subsequently loading them with the photosensitizer indocyanine green (ICG) and oxygen-rich perfluorohexane (PFH). This platform not only achieves efficient photothermal conversion under NIR light but also triggers the release of copper and iron ions in the acidic TME, which synergistically catalyze Fenton/Fenton-like reactions and deplete GSH, thereby disrupting the redox homeostasis of tumor cells. Mechanistic validation revealed that the O2-PFH@CHPI nanozyme possesses both POD-like and GPx-like activities, enabling it to efficiently catalyze the generation of •OH from H₂O₂ and consume GSH. Under NIR irradiation (808 nm, 1.0 W/cm²), the nanoparticles raised the solution temperature to 55.3 °C within 5 min, demonstrating a high photothermal conversion efficiency of 56.3 %. The photothermal effect not only directly induced tumor cell death but also significantly accelerated ROS production and GSH depletion, thus amplifying the nanozyme's catalytic activity. Furthermore, the incorporation of PFH enabled photothermally triggered oxygen release, which effectively alleviated tumor hypoxia and enhanced the photodynamic therapy (PDT) efficacy of ICG by promoting the sustained generation of ¹O₂. In vitro experiments confirmed the platform's potent cytotoxic effects on Huh7 liver cancer cells. Following light irradiation at an optimal concentration of 100 μg/mL, cell viability was reduced to just 11.3 %. Flow cytometry analysis indicated that 64.3 % of the treated cells exhibited high levels of ROS, while intracellular GSH levels dropped to 37.7 % of the control. At the molecular level, immunofluorescence and protein analysis confirmed the downregulation of GPX4, a massive accumulation of lipid peroxides, and significant aggregation of dihydrolipoamide S-acetyltransferase, indicating the simultaneous activation of both ferroptosis and cuproptosis. Further validation through inhibitor assays showed that both the ferroptosis inhibitor Lip-1 and the cuproptosis inhibitor UK-5099 partially restored cell viability. The combination of both inhibitors restored viability by up to 73.2 %, confirming the synergistic contribution of both cell death pathways to the anti-tumor effect. This work not only elucidates the coupling between photothermal effects and nanozyme catalysis but also establishes a new paradigm for using photothermal nanozymes to achieve multimodal, synergistic induction of ferroptosis and cuproptosis for HCC therapy (Fig. 10).

Fig. 10 — Schematic diagram of the O₂-PFH@CHPI nanozymes for cuproptosis/ferroptosis co-activated tumor therapy. Copyright from Ref. [207] Wiley-VCH 2024.

In the field of liver cancer research, dynamic therapies, particularly PTT and microwave thermodynamic therapy, have garnered significant attention due to their non-invasive nature and excellent spatiotemporal controllability. However, conventional therapy faces three major obstacles in practical application: first, the hypoxic TME limits the efficiency of ROS generation; second, the therapeutic process can induce the overexpression of VEGF, leading to risks of tumor recurrence and metastasis; and third, the combination of heat and weak oxidation alone is often insufficient to achieve complete tumor eradication. To address these issues, Chen et al. [208]. have designed a nanozyme-engineered metal-organic framework (MOF) platform, designated Apatinib@ZIF67@PDA (AZP NCs). This nanosystem is designed to degrade in the acidic TME, releasing cobalt ions (Co²⁺) and the anti-angiogenic drug Apatinib (AP). Through a nanozyme-catalyzed cascade and drug synergy, this platform aims to achieve the dual effects of ROS enhancement and angiogenesis inhibition in addition to PTT. Mechanistic validation demonstrated that the AZP NCs possess significant enzyme-mimicking activities. In acidic conditions, Co²⁺ acts as a peroxidase-like catalyst to generate highly oxidative •OH from H₂O₂. The resulting Co³⁺ then catalyzes the decomposition of H₂O₂ under microwave (MW) irradiation to produce oxygen, effectively alleviating tumor hypoxia. In solution, the oxygen concentration of the AZP NCs + MW group increased by 5.39 mg/L within 5 min, which was 6.57 times that of the control. Furthermore, ROS levels in the presence of H₂O₂ were 69.2 times higher in the AZP NCs + MW group compared to the H₂O₂ + MW group. The platform also exhibited an excellent microwave thermosensitizing effect, achieving a temperature increase of 24.8 °C. These results confirm that the nanozyme not only enables efficient PTT but also significantly enhances tumor-killing efficacy through a coupled mechanism of “oxygen generation → ROS amplification → hypoxia relief.” The AZP NCs demonstrated potent anti-tumor effects in both cellular and animal experiments. In vitro, treatment with AZP NCs + MW reduced the viability of HepG2 and H22 cells to just 24.1 %. Concurrently, intracellular VEGF expression was significantly downregulated, confirming the release and anti-angiogenic function of AP. In a patient-derived xenograft (PDX) model, the AZP NCs + MW group achieved a 100 % tumor inhibition rate, with complete tumor regression over a 30-day period and no recurrence. The platform also showed excellent biocompatibility. Overall, this work presents a comprehensive therapeutic strategy that synergizes nanozyme catalysis, photothermal effects, and anti-angiogenesis, thereby overcoming the limitations of conventional PTT/MDT and demonstrating significant clinical translational potential in a PDX model (Fig. 11).

Fig. 11 — (A) Synthetic schematic of AZP NCs nanozymes. (B) Schematic of in-situ cascade catalytic therapy strategy driven by AZP NCs nanozymes. With excellent microwave thermodynamic sensitization and tumor antiangiogenesis synergy, these nanozymes enhance MW thermodynamic therapy and induce cell apoptosis in PDX model. Copyright from Ref. [208] Elsevier 2022.

4.4. Combination therapy platforms

Addressing the complexity, heterogeneity, and adaptive resistance of HCC often requires a multi-pronged therapeutic strategy that can simultaneously target different oncogenic pathways [[209], [210], [211]]. Nanozymes serve as exceptionally versatile platforms for constructing such integrated combination therapies. Their large surface area and tunable surface chemistry allow for the co-loading of various therapeutic agents, such as conventional chemotherapeutic drugs, targeted inhibitors, photosensitizers for PDT, or even siRNA/shRNA for gene therapy. This “all-in-one” nanoplatform can execute multiple therapeutic modalities in a coordinated and spatiotemporally controlled manner. This section is intentionally centered on HCC and highlights combination nanozyme platforms that target HCC-specific pathological features, such as oxidative stress dysregulation, hypoxia-driven resistance, and immunosuppressive microenvironments. While a limited number of studies originally validated in non-HCC tumor models are referenced, they are included solely to illustrate mechanistic or design principles that are directly translatable to HCC therapy. For instance, a nanozyme can be designed to deliver a chemotherapy drug while simultaneously performing TME-activated CDT and NIR-triggered PTT [212]. The ROS generated by CDT can disrupt ATP-dependent drug efflux pumps, thus reversing multidrug resistance, while PTT-induced hyperthermia can act as a trigger for on-demand drug release. Furthermore, nanozymes composed of high-Z elements can act as radiosensitizers, enhancing the local deposition of X-ray energy during radiotherapy (RT) to generate more cytotoxic ROS [213]. By rationally integrating the unique catalytic functions of nanozymes with established therapeutic modalities like chemotherapy, radiotherapy, and immunotherapy, these sophisticated nanoplatforms can achieve a profound synergistic anti-tumor cascade, creating a “1 + 1>2″ or even “1 + 1+1 > 3″ effect. This represents a leading-edge direction in the development of next-generation HCC therapeutics.

The clinical efficacy of single-modality therapies for HCC is often constrained by the complex TME. Sorafenib (SF), a conventional molecularly targeted drug, is limited by drug resistance and low bioavailability, while the effectiveness of PDT is hampered by tumor hypoxia. To address this, Lu et al. [214]. developed a biomimetic mineralized nanozyme platform, designated BSA@Pt/Ce6/SF@M (PCFM). This system integrates molecular targeting with PDT and simultaneously modulates autophagy. The platform uses albumin to stabilize platinum nanozymes and the photosensitizer Ce6, while co-encapsulating SF and camouflaging the entire structure with a cancer cell membrane coating. This design not only facilitates drug delivery and immune evasion but also leverages the nanozyme's catalytic activity to generate oxygen, thereby alleviating hypoxia and enabling a trimodal therapeutic strategy of “PDT–autophagy–targeted therapy.” The platform exhibits a threefold synergistic effect. First, the platinum nanozyme displays peroxidase-like activity in the acidic TME, efficiently decomposing endogenous H₂O₂ into oxygen to relieve hypoxia and enhance the PDT efficacy of Ce6. Second, SF acts as an autophagy inducer, which, in concert with PDT-generated ROS, shifts protective autophagy toward autophagy-dependent cell death. Third, upon laser irradiation, Ce6 generates abundant ROS, which directly induces apoptosis and further amplifies autophagic flux. In vitro, the PCFM + light treatment reduced HepG2 cell viability to below 40 %, significantly outperforming SF or PDT alone. In an H22 tumor-bearing mouse model, the combination therapy achieved optimal tumor suppression. More impressively, in a PDX model, the platform achieved nearly 100 % tumor inhibition with no recurrence, confirming the effective induction of autophagy-dependent cell death. This study presents an integrated therapeutic platform that combines PDT, targeted therapy, and autophagy modulation, offering a novel approach for the multi-modal precision treatment of HCC (Fig. 12).

Fig. 12 — (A) Synthesis of cancer-cell-membrane-coated nanoparticles BSA@Pt/Ce6/SF@M. (B) Synergistic therapy of BSA@Pt/Ce6/SF@M nanoenzyme. The nanoparticles accumulate precisely at tumor sites via cancer cell membrane. Ce6 irradiation activates PDT to generate ROS; meanwhile, BSA@Pt produces oxygen to alleviate tumor hypoxia and enhance PDT. SF induces cellular autophagy, and PDT-generated ROS further triggers excessive autophagy, culminating in anti-tumor effect via autophagic death. Copyright from Ref. [214]. Elsevier 2024.

Conventional adjuvant therapies for HCC, such as TACE and radiotherapy, often cause collateral liver damage while suppressing residual tumors, thereby compromising patient survival. To resolve this conflict between anti-tumor efficacy and hepatoprotection, Zhang et al. [215]. developed a novel combination therapy platform: an MC@PHDA hydrogel. This system co-embeds photothermal MoS₂ nanozymes and chlorophyll-rich Chlorella into a hyaluronic acid-dopamine network. The design integrates PDT, PTT, and immune activation, while utilizing the SOD/CAT-like activity of MoS₂ to scavenge excess ROS and mitigate liver injury, thus achieving an integrated “tumor ablation–liver repair” therapeutic model. Mechanistically, the hydrogel demonstrates multiple synergistic effects. Chlorella generates ROS under 660 nm light for PDT, while the MoS₂ nanozyme exhibits excellent photothermal conversion under 808 nm laser irradiation, raising the local temperature to ∼46.6 °C for PTT-induced apoptosis. Critically, sequential dual-wavelength irradiation (660 nm → 808 nm) significantly amplified the synergistic effect, achieving a cell death rate of 63.5 %, far superior to single or reverse-order irradiation. This combined treatment also triggered robust ICD, evidenced by increased ATP secretion, CRT exposure, and HMGB1 release, which in turn promoted dendritic cell maturation and pro-inflammatory cytokine secretion. In a subcutaneous Hepa1–6 tumor model, this sequential laser treatment resulted in the most significant tumor suppression, with one mouse achieving complete tumor regression. The therapy also reduced serum ALT and AST levels, indicating its hepatoprotective function. In summary, this study presents a novel combination platform that balances potent anti-tumor effects with liver protection, offering a new strategy for the comprehensive management of HCC (Fig. 13).

Fig. 13 — A) Schematic of MC@PHDA hydrogels fabrication. (B) Antitumor mechanisms: sequential PDT/PTT via MC@PHDA, with sustained Chlorella and MoS₂ release at tumors for cancer eradication and ICD induction post-laser. Hydrogel-mediated antigen capture boosts DCs maturation to activate T cells and curb tumor growth. (C) Intraperitoneal injection of MC@PHDA enables sustained MoS₂ delivery and liver protection. (D) MoS₂ and Chlorella in the hydrogel exert strong photothermal/photodynamic effects. Copyright from Ref. [215] Wiley-VCH 2025.

In solid tumors such as non-small cell lung cancer, the efficacy of conventional therapies is severely hampered by the tumor's adaptive mechanisms, including high glucose metabolism, excessive GSH accumulation, and an acidic microenvironment. To overcome these barriers, Li et al. [171]. proposed a strategy of “energy homeostasis disruption + multimodal synergistic therapy” by designing a Cu₂O@Au nanozyme. This platform uniquely possesses triple enzyme-like activities to simultaneously cut off the tumor's energy supply by consuming glucose, self-supply H₂O₂ for CDT, and dismantle the antioxidant shield by depleting GSH. Combined with its photothermal properties, this system integrates starvation therapy (ST), CDT, PTT, and ferroptosis into a single, synergistic combination therapy. The Cu₂O@Au nanozyme efficiently catalyzes glucose oxidation to produce H₂O₂ and lower the local pH, which in turn enhances the Fenton-like reaction kinetics for CDT. NIR laser irradiation (808 nm) rapidly increases the temperature to 50 °C, further accelerating •OH generation and demonstrating the synergistic enhancement of CDT by PTT. Concurrently, the nanozyme continuously consumes GSH and downregulates GPX4, leading to the accumulation of lipid peroxides and inducing ferroptosis, which is further amplified by its ability to upregulate p53 and negatively regulate the p53–SLC7A11–GPX4 axis. In a NCI-H1299 tumor-bearing nude mouse model, the Cu₂O@Au + NIR treatment almost completely arrested tumor growth. Histological analysis confirmed suppressed proliferation, enhanced cell death, and significant downregulation of GPX4 in tumor tissues, providing in vivo evidence of ferroptosis. This “all-in-one” nanozyme platform successfully disrupts tumor energy homeostasis and achieves superior anti-tumor efficacy through a multi-pronged synergistic approach, offering a new direction for combining metabolic intervention with catalytic therapy.

In summary, various nanozyme-mediated therapeutic modalities for HCC each possess distinct advantages and limitations. Catalytic dynamic therapy offers high selectivity by leveraging excess H₂O₂ in the TME but is often limited by insufficient endogenous H₂O₂ and the tumor's robust antioxidant system. PTT provides precise spatiotemporal control and can be integrated with theranostics, but its efficacy is constrained by limited tissue penetration depth and the risk of collateral thermal damage. Immunotherapy (IT) holds the unique advantage of inducing systemic, durable, and memory-based anti-tumor effects but is frequently hampered by the immunosuppressive TME in HCC, resulting in limited clinical response rates for single-agent checkpoint inhibitors. In contrast, combination therapy (CT), which integrates modalities such as CDT, PTT, and IT, offers a compelling path forward. Such integrated platforms can mechanistically complement one another, effectively overcoming multiple barriers like hypoxia, antioxidant defense, and immune escape to achieve significant synergistic effects. Although challenges related to their complexity and clinical translation remain, combination platforms are widely regarded as the most promising future direction for nanozyme-mediated HCC therapy. Table 4 summarizes representative nanozyme strategies discussed in this review by grouping studies with shared mechanisms and design logic, rather than listing individual reports.

Table 4.

Representative nanozyme-based therapeutic strategies for HCC.

Therapeutic modality	Nanozyme type/composition	Dominant mechanism	Generalized design rationale	Tumor model	Key advantage	Major limitation
Catalytic therapy	Fe-based nanozymes (including Prussian blue derivatives, Fe oxides)	Fenton/POD-like ROS generation; ferroptosis induction	Exploit elevated H₂O₂ levels and iron dysregulation in HCC to induce localized oxidative stress and lipid peroxidation	Subcutaneous & orthotopic HCC (mouse)	No external stimulus; effective against apoptosis-resistant tumors	Limited endogenous H₂O₂; ROS neutralization by high GSH; insufficient as monotherapy
Catalytic therapy	Cu-based or dual-metal nanozymes (Fe–Cu, Cu-doped systems)	Fenton-like catalysis; cuproptosis–ferroptosis synergy	Leverage copper imbalance and mitochondrial vulnerability to broaden non-apoptotic death pathways	Orthotopic HCC (mouse)	Enhanced cytotoxicity via dual-death mechanisms	Metal homeostasis complexity; potential off-target toxicity
Nanozyme-enhanced immunotherapy	Single-atom nanozymes (Fe, Cu, dual-ion sites)	ROS-induced ICD; antigen release and DC maturation	Convert immune-tolerant HCC into immunogenic state through controlled redox stress	Subcutaneous & orthotopic HCC (mouse)	Promotes CD8⁺ T-cell infiltration and immune memory	Risk of immune suppression with excessive ROS; murine-only validation
Nanozyme-enhanced immunotherapy	Biomimetic/hybrid nanozyme platforms	ICD + checkpoint blockade or gene silencing	Integrate catalytic stress with immune modulation to overcome low ICI response rates	Orthotopic HCC (mouse)	Synergistic immune activation	Increased structural and regulatory complexity
Photothermal-assisted therapy	NIR-absorbing nanozymes (Pt-, Fe-, Cu-doped, PB-based)	PTT-enhanced catalysis; heat-accelerated ROS generation	Use mild hyperthermia to accelerate catalytic kinetics and reduce HSP-mediated resistance	Orthotopic HCC (mouse)	Spatiotemporal control; strong synergy	Limited light penetration; recurrence risk if used alone
Integrated/combination therapy	Multifunctional nanozyme platforms	ROS + PTT + immune modulation	Modular integration to overcome multiple TME barriers simultaneously	Orthotopic HCC (mouse)	Highest antitumor efficacy; broad mechanism coverage	Design complexity; scalability and safety challenges

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5. Challenges and future perspectives in clinical translation

Although nanozymes have demonstrated revolutionary therapeutic potential in preclinical studies, translating them from laboratory “proof-of-concept” to clinically available “off-the-shelf” products requires overcoming a series of formidable hurdles [216]. This transition from “bench to bedside” is often termed the “valley of death,” where many promising nanomedicines fail. For a malignancy as complex as HCC, with its unique pathological background and microenvironment, the translational path for nanozymes is fraught with even more specific and severe challenges [217]. While nanozymes offer compelling therapeutic advantages, their long-term biosafety remains a critical consideration for clinical translation, particularly with respect to metal ion release, oxidative stress propagation, and immunotoxicity. Metal-based nanozymes may undergo partial degradation or ion leaching in physiological environments, leading to excess accumulation of Fe²⁺, Cu⁺, or Co²⁺ ions in non-tumoral tissues, which can disrupt metal homeostasis and induce unintended cytotoxicity through aberrant Fenton-like reactions. In parallel, the strong ROS-generating capacity of nanozymes, while beneficial for tumor ablation, raises concerns regarding collateral oxidative damage to surrounding hepatocytes, endothelial cells, or immune cells if spatial or temporal control is insufficient. Excessive ROS exposure may impair mitochondrial function, trigger inflammatory signaling, or promote fibrosis in normal liver tissue. Furthermore, nanozyme-induced immune modulation requires careful balance, as sustained oxidative stress or metal exposure may adversely affect antigen-presenting cells, lymphocyte viability, or cytokine homeostasis, potentially leading to immunotoxicity or immune exhaustion. Recent toxicological studies emphasize the importance of engineering strategies such as controlled ion coordination, biodegradable frameworks, redox-buffering coatings, and microenvironment-triggered activation to minimize off-target toxicity and ensure safe clearance. A comprehensive understanding of these toxicological mechanisms, combined with long-term biodistribution and metabolism studies, is essential to advance nanozyme-based therapies toward clinically viable and precision-oriented applications in HCC.

In parallel with identifying successful design paradigms, it is equally instructive to extract lessons from nanozyme strategies that have remained confined to proof-of-concept demonstrations despite promising preclinical results. A recurring limitation is the overemphasis on maximal catalytic activity without sufficient consideration of biological context. Many early nanozyme systems achieved impressive reactive oxygen species generation in simplified in vitro settings, yet failed to translate in vivo due to rapid neutralization by elevated glutathione levels, insufficient hydrogen peroxide availability, or diffusion-limited penetration within heterogeneous HCC tissue. This highlights that catalytic potency alone is not predictive of therapeutic efficacy unless it is matched to the biochemical constraints of the tumor microenvironment. Another frequently observed bottleneck is inadequate spatiotemporal control of catalysis. Nanozymes that remain constitutively active during circulation or in non-tumoral liver tissue often induce off-target oxidative stress, hepatotoxicity, or inflammatory responses, which severely limit their therapeutic window in the chronically diseased liver. Such outcomes underscore that failure to incorporate microenvironment-gated activation or self-limiting catalytic behavior can undermine otherwise effective catalytic designs. Similarly, some multifunctional platforms failed to progress because therapeutic modalities were combined in an additive rather than mechanistically integrated manner, resulting in increased complexity without proportional therapeutic gain. In these cases, photothermal, catalytic, or immunomodulatory components operated in parallel rather than reinforcing a shared biological bottleneck, diminishing translational relevance. From an immunological perspective, several nanozyme-based immunotherapeutic strategies stalled because oxidative stress levels sufficient to induce tumor cell death simultaneously impaired immune cell viability or promoted immune exhaustion, particularly in immunosuppressive and hypoxic environments such as HCC. These findings reveal a critical trade-off between immunogenicity and immunotoxicity that cannot be resolved by increasing catalytic output alone, but instead requires fine-tuned modulation of redox intensity, duration, and localization. Finally, translational limitations have also arisen from practical considerations, including poor reproducibility of defect-rich or multi-metal architectures, batch-to-batch variability in catalytic performance, and uncertain long-term biodistribution or clearance profiles, all of which complicate regulatory evaluation. Collectively, these lessons emphasize that unsuccessful or limited nanozyme strategies do not fail due to lack of catalytic capability, but rather due to insufficient alignment between material behavior and biological complexity. Recognizing these failure modes reinforces the need for precision-oriented nanozyme engineering, in which catalytic selectivity, microenvironment responsiveness, immune compatibility, and translational feasibility are treated as co-equal design constraints rather than sequential optimization targets. This chapter dissect the four core challenges currently facing the clinical translation of nanozymes for HCC therapy and propose future directions. Table 5 summarizes the characteristics, advantages, and potential limitations of the aforementioned different nanozyme therapies for the treatment of liver cancer.

Table 5.

Nanozyme-based therapeutic modalities for HCC: Advantages, limitations, and clinical potential.

Therapeutic Modality	Advantages	Limitations/Challenges	Clinical Potential
Catalytic Therapy (CDT)	• Exploits excess H₂O₂ in the TME to selectively generate ROS • Requires no external energy input, minimally invasive • Nanozyme engineering can enhance Fenton/Fenton-like reactivity	• Limited endogenous H₂O₂ concentration and slow kinetics • Antioxidant defenses attenuate efficacy • Difficult to achieve complete tumor eradication as monotherapy	Promising as an adjuvant/sensitizer strategy; combination with ferroptosis induction, phototherapy, or metabolic intervention can improve feasibility
PTT	• Externally controlled laser enables precise spatial and temporal selectivity • Heat-induced disruption of membranes and proteins • Can be integrated with photoacoustic imaging for theranostics	• Limited laser penetration depth (∼1 cm) • High temperatures risk collateral injury to surrounding tissues • Monotherapy associated with recurrence risk	Clinically explored with gold nanorods and ICG-based agents; high potential for local ablation of superficial tumors and postoperative residual disease
Immunotherapy (IT)	• Activates systemic and durable anti-tumor immunity • Immunological memory reduces risk of recurrence and metastasis • Synergistic with ferroptosis/cuproptosis-mediated ICD	• HCC often exhibits an “immune-cold” phenotype with strong immunosuppressive TME • Response rate to single-agent checkpoint blockade <20 % • Risk of immune-related adverse events (irAEs)	Approved PD-1/PD-L1 inhibitors in HCC; nanozyme-induced ICD offers potential to enhance response rates and efficacy
Combination Therapy (CT)	• Integrates CDT, PTT, and/or IT to overcome multi-level barriers • Enables synergistic tumor killing via complementary mechanisms • Offers opportunities for imaging-guided, multifunctional platforms	• Complexity of design and manufacturing • Safety, pharmacokinetics, and regulatory hurdles remain • Translational barriers for large-scale clinical application	Widely regarded as the most promising future strategy; multifunctional nanozyme platforms could reshape HCC therapy by combining local and systemic benefits

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5.1. Biocompatibility and long-term safety

Safety is the primary cornerstone for the clinical translation of any novel therapy. For nanozymes intended to act on the liver, their safety assessment must be conducted within the specific pathological context of chronic liver diseases that frequently accompany HCC [218]. The formation of a “protein corona” upon the entry of nanozymes into the bloodstream can not only mask their active catalytic sites, leading to deactivation, but more critically, it targets them for clearance. The liver is the principal organ of the mononuclear phagocyte system, where Kupffer cells constitute the first line of defense for clearing circulating foreign materials. This presents a paradox: nanozymes targeting liver cancer are inherently susceptible to extensive clearance by immune cells within the same organ. This clearance mechanism, on one hand, prevents the drug from effectively reaching tumor cells. On the other hand, the phagocytosis of a large number of nanoparticles in an already chronically inflamed liver may exacerbate local immune responses or even induce hepatotoxicity. For instance, an iron-based nanozyme designed to generate ROS, if extensively endocytosed by healthy hepatocytes or Kupffer cells, could exert uncontrolled peroxidase-like activity and inflict severe oxidative damage on normal hepatic tissue [219]. Many highly effective nanozymes are composed of non-biodegradable noble metals or metal oxides. The long-term accumulation of these materials in the liver poses a significant safety concern. In most HCC patients, the liver's function as the primary metabolic and detoxification organ is already compromised. Long-term retention of nanoparticles may: 1) physically obstruct hepatic sinusoids, impairing liver microcirculation; 2) slowly release toxic metal ions that interfere with normal enzymatic functions and metabolism, for example, while manganese ions released from manganese-based nanozymes can be used for MRI, their excess is neurotoxic and hepatotoxic; and 3) act as persistent foreign bodies, potentially inducing hepatic fibrosis and worsening pre-existing cirrhosis. Therefore, the future design of nanozymes must pivot from a focus on “high efficacy” to “high efficacy and safety.” Priority should be given to developing intelligent nanozymes that are specifically degradable within the TME or can be safely cleared after completing their therapeutic mission, such as those based on biodegradable metal-organic frameworks or bioresorbable materials like black phosphorus and silicon nanomaterials.

5.2. In vivo behavior and therapeutic uncertainty

The vast majority of HCCs develop within a fibrotic, cirrhotic liver. The dense collagenous matrix, combined with high interstitial fluid pressure, creates a nearly insurmountable physical barrier [220]. This renders passive targeting strategies that rely on the enhanced permeability and retention effect highly inefficient in HCC. Larger nanozymes (>50 nm) are virtually unable to penetrate this barrier, accumulating only around tumor blood vessels without reaching the tumor core. Even with active targeting strategies, such as modification with antibodies against Glypican-3 which is highly expressed on HCC cells, the nanozyme must first overcome this physical barrier to reach the target cells. This explains why many nanozymes that show excellent efficacy in subcutaneous tumor models exhibit markedly diminished performance in orthotopic liver cancer models, which more closely mimic the clinical scenario. The therapeutic efficacy of nanozymes is critically dependent on the concentration of specific substrates within the TME, which is a significant variable in human HCC. The effectiveness of CDT depends on a “sufficient” concentration of H₂O₂ in the TME. Although cancer cells generally produce high levels of H₂O₂, its concentration varies dramatically across different HCC subtypes, between patients, and even within different regions of the same tumor [221]. If the local H₂O₂ level falls below the catalytic activation threshold of the nanozyme, the therapy will be completely ineffective. We currently lack non-invasive methods to monitor and quantify the true H₂O₂ concentration inside human tumors in real-time, making the prediction of CDT efficacy exceedingly difficult. Many therapeutic strategies aim to amplify oxidative stress or induce ferroptosis by depleting GSH. However, cancer cells can adaptively counteract this depletion by upregulating GSH synthesis pathways, leading to dynamic resistance [215].

5.3. Large-scale manufacturing and regulatory science

Nanozymes exquisitely synthesized in the laboratory, with perfect morphology and high catalytic activity, are akin to “works of art.” However, transforming them into “pharmaceutical products” compliant with Good Manufacturing Practices is a monumental challenge [222]. The core difficulty lies in achieving large-scale production while ensuring high batch-to-batch consistency in parameters such as particle size distribution, surface charge, crystal structure, and critically, the number and state of catalytic active sites. For example, the catalytic activity of a single-atom iron nanozyme is highly dependent on the coordination environment and oxidation state of the iron atoms parameters that are exceedingly difficult to control precisely during mass production. Any minor deviation could lead to significant changes in its catalytic kinetic parameters, thereby affecting clinical efficacy and safety [190]. The regulatory pathway for nanozymes is exceptionally complex because they are inherently “combination products.” Their nanoparticle carrier possesses “medical device” characteristics, while their catalytic metal center or organic molecule has “drug” properties. If further conjugated with a targeting antibody, it becomes a “device-drug-biologic” triple combination. Nanozymes also face regulatory challenges that are distinct from those encountered by conventional therapeutics, largely due to their hybrid nature at the intersection of drugs, devices, and biologics. Unlike small-molecule drugs, nanozymes do not exert effects through defined molecular targets, but instead through catalytic activity that depends on material composition, surface structure, and microenvironmental conditions. At the same time, they differ from medical devices in that their therapeutic function is dynamic and persists after administration, and from biologics in that their activity does not originate from genetically encoded enzymes. This classification ambiguity complicates regulatory evaluation, as it remains unclear which approval pathway should govern nanozyme-based therapies. Additional challenges include defining appropriate quality control metrics for catalytic activity, ensuring batch-to-batch consistency of active sites, assessing long-term in vivo catalytic behavior, and evaluating potential cumulative toxicity associated with persistent or slowly degradable materials. Addressing these issues will require regulatory frameworks that integrate principles from drug, device, and nanomedicine evaluation, as well as early dialogue between developers and regulatory agencies. This presents unprecedented challenges for regulatory agencies: 1) How should dosage be defined? By the total mass of nanoparticles (mg/kg) or by catalytic activity units (U/kg)? 2) How should pharmacokinetic studies be conducted? Is it necessary to track the in vivo fate of both the carrier and the active center simultaneously? 3) How is the mechanism of action to be established? Is it the Fenton reaction, immunomodulation, or a combination of mechanisms? This complexity requires developers to provide a far more comprehensive and rigorous preclinical data package than for traditional drugs and necessitates early and in-depth communication with regulatory agencies, significantly increasing the cost and timeline of development.

5.4. The gap between preclinical models and human pathology

The vast majority of successful nanozyme research is built upon studies in immunocompromised mice bearing subcutaneous or, to a lesser extent, orthotopic xenograft tumors [223]. These models fundamentally differ from the true pathological ecosystem of clinical HCC. The immune microenvironment of human HCC is exceedingly complex, enriched with various immunosuppressive cells and exhausted T cells. Many nanozyme-based strategies for enhancing immunotherapy, such as remodeling the TME by alleviating hypoxia, are highly dependent on a complete and interactive immune system. In immunocompromised mice, these critical interactions are absent. Even in immunocompetent mouse models, the types, markers, and functions of immune cells differ significantly from those in humans. Therefore, the spectacular phenomenon of a “cold” tumor turning “hot” observed in mouse models may not be reproducible in human patients [224]. Clinically, HCC arises from a pathological foundation of chronic hepatitis and cirrhosis that develops over decades. This “soil” not only determines the physical barriers of the tumor but also shapes its unique metabolic and immune phenotypes. In contrast, current animal models typically involve the rapid induction or implantation of tumors in the livers of healthy young mice, completely ignoring this critical pathological context. This prevents these models from assessing pharmacokinetic changes of nanozymes in the context of impaired liver function or predicting their complex interactions with the liver's resident immune cells. Future research must pivot towards models that more faithfully mimic the complexity of human HCC, such as genetically engineered mouse models, PDX models, and orthotopic cancer models induced in a cirrhotic liver background, to enhance the predictive value of preclinical research for human outcomes.

5.5. Generalizable design principles for nanozyme-based precision therapy in HCC

Rather than reiterating individual challenges, this subsection distills transferable design principles that emerge from cross-comparison of nanozyme systems and therapeutic modalities in HCC. A first principle is mechanism-matched nanozyme selection, in which the intended therapeutic bottleneck determines the optimal catalytic phenotype rather than assuming “stronger ROS is better.” For example, Fe-dominant catalytic systems are generally most suitable when the goal is to amplify lipid peroxidation and ferroptosis, whereas Pt- or Mn-associated catalase-like architectures are often better positioned to mitigate hypoxia and thereby potentiate photodynamic or immune responses; Cu-centered systems can expand the death-pathway repertoire by engaging cuproptosis-like mitochondrial stress in parallel with redox disruption, but at the cost of more complex metal homeostasis constraints. This logic implies that “precision” in nanozyme therapy begins with defining the dominant vulnerability of a given HCC context (redox imbalance versus hypoxia versus immune exclusion) and then choosing an active-center chemistry that is kinetically and biologically aligned with that vulnerability, rather than defaulting to a generic CDT narrative.

A second principle is active-center engineering for catalytic selectivity and substrate-context fidelity. Therapeutic efficacy is ultimately dictated not only by nominal activity labels (POD-like, CAT-like, SOD-like, Fenton-like) but by how the active site controls adsorption, electron transfer, and product selectivity in the actual tumor milieu. Nanozymes intended for •OH-mediated killing should be engineered to favor tumor-restricted ROS production through controllable surface redox cycles that improve H₂O₂ activation while minimizing uncontrolled side reactions in normal tissue. Conversely, oxygen-generating nanozymes should be designed for efficient H₂O₂ disproportionation without simultaneously triggering indiscriminate oxidative bursts that compromise immune or stromal cells. Importantly, HCC exhibits high intratumoral heterogeneity in pH, oxygenation, and antioxidant buffering; therefore, structure–activity design must explicitly consider substrate availability windows (H₂O₂ level, GSH/GSSG status) and avoid overreliance on idealized in vitro conditions. Practically, this means reporting and optimizing not only qualitative ROS assays but quantitative kinetic descriptors, alongside microenvironment-dependent performance (acidic versus neutral, high versus low GSH), and correlating these parameters with biological endpoints such as lipid peroxidation, GPX4 suppression, or ICD markers. The field is moving toward “precision catalysis” where catalytic pathways are selected and tuned to match the biochemical constraints of the HCC TME rather than maximizing a single readout.

A third principle is microenvironment-gated activation and spatiotemporal confinement, which is particularly essential in HCC because therapy occurs within a chronically diseased liver and in proximity to vulnerable hepatocytes and resident immune populations. As emphasized in this review, liver-targeted nanozymes face a central paradox: they are sequestered by the liver's mononuclear phagocyte system (Kupffer cells), and extensive uptake in non-tumor liver compartments can cause off-target oxidative injury or inflammation in an already compromised organ. Therefore, precision design should favor nanozymes that remain catalytically muted during circulation and in normal parenchyma, and are activated predominantly by tumor-associated triggers. In practice, this can be achieved through “protect–activate” architectures such as protective shells that suppress catalysis until tumor-specific degradation, pro-catalyst states that require intratumoral reduction/oxidation to become active, or cascade schemes where one tumor-local reaction generates the substrate for a second catalytic step. External-energy–coupled strategies can further provide temporal control, accelerating catalysis only when and where irradiation is applied, while reducing systemic oxidative exposure. This design logic directly links the precision theme to safety: the more tightly catalysis is gated by tumor-local cues, the higher the therapeutic index in the cirrhotic-liver setting.

A fourth principle is purpose-driven multifunctionality rather than “additive stacking.” Many platforms combine CDT with PTT/PDT, drug delivery, or immunomodulation; however, multimodality becomes precision-relevant only when each module addresses a defined barrier in HCC biology. For instance, photothermal modules should be used not merely for ablation but to (i) accelerate catalytic rates and (ii) lower heat-shock tolerance through ROS-mediated stress, creating a mechanistically coupled synergy rather than parallel effects. Similarly, immunomodulatory modules should be justified by a clear immunological bottleneck: nanozyme-induced ICD can improve antigen availability and dendritic cell priming, while oxygenation can reduce hypoxia-driven immune suppression and improve effector cell persistence; such immune gains are most meaningful when paired with checkpoint blockade or other immunotherapies in a conceptually coherent regimen. Platforms that include drug loading should clarify whether the cargo is intended to overcome a specific resistance mechanism and whether release is microenvironment-triggered to maintain selectivity. This principle also implies that the manuscript should evaluate multimodal platforms by mechanistic alignment and therapeutic necessity, not by the number of incorporated functions.

A fifth principle is safety-by-design integrated at the materials level, which must be treated as a co-equal objective rather than an afterthought, particularly because HCC often develops in chronically inflamed and functionally impaired livers. Translationally credible nanozymes should minimize long-term hepatic accumulation and uncontrolled redox activity through strategies such as using biodegradable or endogenous-element frameworks, strengthening metal coordination to reduce ion leakage, incorporating redox-buffering coatings that quench excessive ROS outside tumors, and designing self-limiting catalytic behaviors that decay after accomplishing the therapeutic task. Safety assessment should explicitly interrogate mechanisms relevant to nanozymes, rather than relying solely on generic histology. In addition, because protein corona formation can mask active sites and alter biodistribution, design and evaluation should account for corona-dependent changes in catalytic accessibility and immune recognition, especially in the liver where clearance is pronounced.

Finally, manufacturability and reproducibility should be incorporated into design decisions early, because precision medicine ultimately requires controllable composition, batch-to-batch consistency of active centers/defect density, and scalable synthesis compatible with regulatory expectations. Collectively, these principles provide a unified blueprint for precision nanozyme development in HCC: define the dominant pathological bottleneck, select an active-center chemistry with the correct catalytic phenotype, engineer site-level selectivity and microenvironment gating for spatiotemporal confinement, build multifunctionality only when modules are mechanistically coupled to HCC barriers, and embed safety and manufacturability into the material architecture from the outset [[225], [226], [227]]. This framework shifts nanozyme research from empirical performance optimization toward rational therapeutic engineering that is transferable across nanozyme classes and adaptable to the heterogeneous HCC microenvironment.

An illustrative example of integrating gene editing with nanotechnology in the context of HCC therapy is provided by a recent CRISPR/Cas9 delivery system designed to enhance sonodynamic therapy (SDT) efficacy in hepatocellular carcinoma. In this work, a lipid nanoparticle was used to encapsulate both a CRISPR/Cas9 system targeting NFE2L2—a key regulator of antioxidant defense and an ROS precursor. Upon ultrasound stimulation, the formulation generated ROS, which disrupted lysosomes and released the CRISPR/Cas9 complex into the nucleus, enabling NFE2L2 knockdown and thereby augmenting SDT efficacy against HCC cells. This strategy not only leverages nanocarrier-mediated gene delivery to overcome intrinsic resistance mechanisms but also uses tumor-triggered ROS generation to coordinate gene editing activation with therapeutic stress, conceptually aligning with precision nanozyme design principles. Although this and similar CRISPR delivery studies in HCC remain at early preclinical stages, they illustrate a future direction in which nanozyme platforms could be extended beyond catalytic or immunomodulatory functions to serve as integrated delivery scaffolds for gene/epigenetic therapies [228]. Nanoparticle-based CRISPR delivery has shown promise in enhancing intracellular uptake, endosomal escape, and tissue targeting for gene editing in cancer models, overcoming several challenges associated with viral vectors and physical delivery methods. In such hybrid strategies, nanozymes could contribute additional control layers, for example, by creating microenvironment-triggered activation of CRISPR payloads through ROS or hypoxia cues, enhancing tumor selectivity and reducing off-target effects [229]. While no bona fide nanozyme–CRISPR combination has yet been reported in HCC, this integrated paradigm merits exploration as a precision therapy that simultaneously addresses genetic drivers, TME adaptation, and catalytic vulnerability.

6. Conclusion

In the ongoing battle against HCC, a malignancy characterized by profound heterogeneity, therapeutic resistance, and high recurrence rates, conventional treatment paradigms have reached a plateau, leaving a significant unmet clinical need. This review systematically charts the rise of nanozymes, nanomaterials endowed with intrinsic enzyme-like activities, as a disruptive and transformative force poised to redefine the therapeutic landscape of HCC. Unlike traditional nanocarriers that function primarily as passive delivery vehicles, nanozymes are active therapeutic agents capable of catalytically manipulating the TME to address the persistent challenges of HCC management. By converting endogenous substrates into cytotoxic products, modulating redox homeostasis, and reshaping the immune milieu, nanozymes offer a multifaceted strategy that circumvents established drug resistance mechanisms and creates potent synergies with existing therapies. The therapeutic versatility of nanozymes, as explored in this review, is particularly striking. Catalytic therapy, which leverages the peroxidase-like activity of nanozymes, exemplifies a highly selective strategy that exploits the unique metabolic state of HCC, particularly its excessive hydrogen peroxide production, to induce localized oxidative damage through chemodynamic therapy. This approach not only initiates conventional apoptotic cell death but also activates non-apoptotic pathways such as ferroptosis and cuproptosis, both of which HCC cells are especially susceptible to, thereby providing an effective means to eradicate tumors resistant to standard treatments. Furthermore, the integration of PTT with nanozyme catalysis has produced profound synergistic effects. Localized hyperthermia accelerates catalytic reactions, while the resulting burst of reactive oxygen species reduces the thermal tolerance of cancer cells, culminating in highly efficient, spatiotemporally controlled tumor ablation. Equally promising is the capacity of nanozymes to function as immunomodulators. By inducing ICD, alleviating hypoxia, and depleting immunosuppressive mediators, nanozymes can systematically dismantle the immunosuppressive TME, transforming immunologically “cold” tumors into “hot,” T cell–inflamed phenotypes responsive to immune checkpoint blockade. The convergence of these therapeutic modalities within multifunctional nanozyme platforms represents the current pinnacle of nanozyme engineering, enabling simultaneous catalytic, photothermal, and immune-activating interventions for a comprehensive anti-tumor strategy.

Despite this compelling preclinical progress, the path to clinical translation remains fraught with formidable challenges that demand rigorous scientific solutions and strategic foresight. The foremost concern is biocompatibility and long-term safety, particularly in the context of the chronically diseased liver where HCC arises. A central paradox lies in the fact that liver-targeted nanozymes are often sequestered by the liver's mononuclear phagocyte system, and prolonged accumulation of non-biodegradable materials poses a risk of hepatotoxicity. This necessitates a shift toward the design of intelligent, biodegradable, and transiently acting nanozymes. Moreover, the dense and fibrotic stroma characteristic of HCC serves as a significant physical barrier to nanozyme penetration, greatly limiting the efficacy of passive targeting strategies. Overcoming this challenge requires the development of advanced delivery systems capable of navigating such hostile microenvironments. In addition, the unpredictable in vivo therapeutic landscape, marked by fluctuating substrate concentrations and adaptive resistance mechanisms, further complicates the reliable prediction of nanozyme performance. This highlights the urgent need for theranostic platforms that can non-invasively monitor the TME and provide real-time feedback on therapeutic efficacy.

Looking forward, the future of nanozyme-based HCC therapy will be defined by integration, precision, and clinical translation. Bridging the current translational gap requires a shift from simplistic subcutaneous tumor models to more clinically relevant systems, such as genetically engineered mouse models, patient-derived xenografts, and orthotopic models established in cirrhotic livers, all of which better capture the complexity of human HCC. The development of next-generation nanozymes must balance efficacy with safety and manufacturability. Promising avenues include nanozymes constructed from endogenous or biodegradable materials, coupled with robust, scalable synthesis protocols aligned with Good Manufacturing Practices to ensure reproducibility. Ultimately, the success of nanozymes will likely rest on their role as adjuvant agents within a multidisciplinary therapeutic framework. Rational integration with targeted therapies, advanced radiotherapies, and personalized immunotherapies may yield unprecedented synergistic effects, overcome resistance, and reduce recurrence.

In conclusion, nanozymes represent a frontier of extraordinary promise in precision nanomedicine for HCC. Their dual role as catalytic and therapeutic agents introduces a fundamentally new paradigm for targeting the intricate biology of this malignancy. Although the hurdles of clinical translation are substantial, they are not insurmountable. Through sustained interdisciplinary collaboration among materials scientists, cancer biologists, immunologists, and clinicians, the transformative potential of nanozymes can be fully realized. By engineering safer, smarter, and more clinically relevant nanozyme platforms, it may be possible to reshape the therapeutic landscape of HCC and provide new hope for patients worldwide.

Consent for publication

All authors have consented to publication.

Funding

This work was supported by grants provided by the Natural Science Foundation of Liaoning Province (20242108) and China Medical University (CMU-A-2505).

CRediT authorship contribution statement

Shu Feng: Conceptualization, Writing – original draft. Ying Xuan: Conceptualization, Investigation. Hong Jin: Conceptualization, Investigation. Meng Cui: Conceptualization. Xinyue Meng: Conceptualization, Formal analysis. Jun Liao: Funding acquisition, Supervision, Writing – review & editing. Jianwei Feng: Supervision, Writing – review & editing.

Declaration of competing interest

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

Contributor Information

Meng Cui, Email: meng_cui@hotmail.com.

Xinyue Meng, Email: mengxinyue88@outlook.com.

Jianwei Feng, Email: fjw1001@126.com.

Data availability

No data was used for the research described in the article.

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Data Availability Statement

No data was used for the research described in the article.

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PERMALINK

Nanozyme for precision treatment of hepatocellular carcinoma

Shu Feng

Ying Xuan

Hong Jin

Meng Cui

Xinyue Meng

Jun Liao

Jianwei Feng

Abstract

Graphical abstract

1. Introduction

Fig. 1.

2. Molecular pathogenesis of HCC

Fig. 2.

2.1. Pathophysiology of hepatocarcinogenesis

2.2. Genetic and epigenetic alterations driving HCC progression

Table 1.

2.3. Dysregulation and network reconstruction of core signaling pathways

2.4. Tumor microenvironment remodeling and metabolic reprogramming

3. Clinical therapeutic strategies and challenges in HCC

Fig. 3.

3.1. Curative-intent therapies for early-stage HCC

Table 2.

3.2. Locoregional therapies for intermediate-stage HCC

3.3. Systemic therapy for advanced-stage HCC

Fig. 4.

4. Nanozyme-based therapies for HCC

Table 3.

4.1. Catalytic therapy

Fig. 5.

Fig. 6.

Fig. 7.

4.2. Nanozyme-enhanced immunotherapy

Fig. 8.

Fig. 9.

4.3. Nanozyme-based photothermal therapy

Fig. 10.

Fig. 11.

4.4. Combination therapy platforms

Fig. 12.

Fig. 13.

Table 4.

5. Challenges and future perspectives in clinical translation

Table 5.

5.1. Biocompatibility and long-term safety

5.2. In vivo behavior and therapeutic uncertainty

5.3. Large-scale manufacturing and regulatory science

5.4. The gap between preclinical models and human pathology

5.5. Generalizable design principles for nanozyme-based precision therapy in HCC

6. Conclusion

Consent for publication

Funding

CRediT authorship contribution statement

Declaration of competing interest

Contributor Information

Data availability

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

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