Key Takeaways & Executive Findings
- •• Developed a dual-enzyme cascade system integrating iridium single-atom nanozymes with glucose oxidase, optimizing hydrogen peroxide production, acidity, and temperature within the tumor microenvironment to markedly improve catalytic therapy efficacy. • Functionalized the cascade reaction system with cancer cell membranes to achieve homologous targeting and high biocompatibility, ensuring accurate accumulation at tumor sites while minimizing off-target effects. • Demonstrated that GOx catalysis produces abundant H2O2 and lowers local pH, while laser irradiation enables mild-temperature photothermal enhancement, collectively maximizing the catalytic efficiency of Ir SAzymes. • Presented a comprehensive strategy for refining single-atom catalytic kinetics, offering a promising approach for tumor homologous-targeted catalytic therapy with potential clinical translation.
Abstract
Single-atom nanozymes (SAzymes) hold significant potential for tumor catalytic therapy, but their effectiveness is often compromised by low catalytic efficiency within tumor microenvironment. This efficiency is mainly influenced by key factors including hydrogen peroxide (H2O2) availability, acidity, and temperature. Simultaneous optimization of these key factors presents a significant challenge for tumor catalytic therapy. In this study, we developed a comprehensive strategy to refine single-atom catalytic kinetics for enhancing tumor catalytic therapy through dual-enzyme-driven cascade reactions. Iridium (Ir) SAzymes with high catalytic activity and natural enzyme glucose oxidase (GOx) were utilized to construct the cascade reaction system. GOx was loaded by Ir SAzymes due to its large surface area. Then, the dual-enzyme-driven cascade reaction system was modified by cancer cell membranes for improving biocompatibility and achieving tumor homologous targeting ability. GOx catalysis reaction could produce abundant H2O2 and lower the local pH, thereby optimizing key reaction-limiting factors. Additionally, upon laser irradiation, Ir SAzymes could raise local temperature, further enhancing the catalytic efficiency of dual-enzyme system. This comprehensive optimization maximized the performance of Ir SAzymes, significantly improving the efficiency of catalytic therapy. Our findings present a strategy of refining single-atom catalytic kinetics for tumor homologous-targeted catalytic therapy.
1. Introduction
Tumor catalytic therapy, especially single-atom nanozymes (SAzymes)-mediated approaches, has emerged a research hotspot in cancer treatment due to its ability to specifically generate reactive oxygen species (ROS) in tumor tissues [1–3]. The development of atomic nanotechnology has ushered in the era of SAzymes, which provide superior catalytic efficiency and customizable active sites, marking a great advancement over traditional nanoparticle-based catalysts [4, 5]. Recently, highly active SAzymes with well-defined metal–nitrogen–carbon (M–N–C, M = Mn, Fe, Co, Cu, Zn, Ru, etc.) coordination structures have been developed [6–11]. Notably, iridium (Ir) SAzyme demonstrates good biocompatibility and catalytic stability, making them promising candidates for tumor catalytic therapy [12, 13].
SAzyme-based catalytic therapy primarily focuses on regulating ROS level. Various strategies of improving SAzyme performance have been explored to enhance ROS yield, such as defect engineering [14, 15], doping with heterogeneous atoms [13], constructing near-neighbor monometallic atoms [16–19], or coupling with carriers [20–23]. The effectiveness of SAzyme-based therapies depends on both their catalytic activity and their adaptability to variations in the intratumoral microenvironment. Catalytic rates are influenced by factors such as temperature, pH, and hydrogen peroxide (H2O2) levels within tumor tissues [24–27]. Therefore, optimizing these parameters of catalytic process is crucial for efficient catalytic therapy.
In addition to optimizing catalytic kinetics, the development of an efficient delivery system is equally crucial. Current delivery systems for SAzyme encounter limitations, including low targeting efficiency, insufficient tumor accumulation and short blood circulation time. Recently, cancer cell membranes, as emerging biomimetic carriers, show great potential in the development of efficient delivery systems [28–30]. Cancer cell membrane-camouflaged nanoparticles retain key adhesion proteins, antigens, and membrane structures, preserving the surface characteristics and functions of the source cells [31, 32]. This approach enables homologous targeting, improved biocompatibility, extended blood circulation time, and enhanced cellular uptake compared to synthetic alternatives [28, 33]. Despite the significance of optimizing cascade reaction kinetics and enhancing tumor targeting, there have been limited studies exploring SAzyme-based cascade nanoreactors that can achieve high catalytic activity, sustained H2O2 supply, reduced pH level, and heat generation—all of which are vital for effective tumor catalytic therapy.
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Hengke Liu, Shan Lei, Hongyu Li, Jiayingzi Wu, Ting He, Jing Lin, Peng Huang (2025). Refining Single-Atom Catalytic Kinetics for Tumor Homologous-Targeted Catalytic Therapy. Nano-Micro Letters. https://doi.org/10.1007/s40820-025-01735-y
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Frequently Asked Questions
What are single-atom nanozymes (SAzymes) and how do they work in tumor catalytic therapy?
Single-atom nanozymes are nanomaterials with isolated metal atoms dispersed on a support, mimicking the active sites of natural enzymes. In tumor catalytic therapy, they catalyze the conversion of endogenous molecules like hydrogen peroxide into reactive oxygen species (ROS), which are toxic to cancer cells, thereby inducing tumor cell death.
How does the dual-enzyme cascade system improve catalytic therapy efficacy?
The system combines iridium SAzymes with glucose oxidase (GOx). GOx consumes glucose to produce hydrogen peroxide and gluconic acid, lowering pH, which enhances the catalytic activity of Ir SAzymes. Additionally, laser irradiation induces mild hyperthermia, further boosting the catalytic efficiency, leading to improved ROS generation and therapeutic outcomes.
What is the role of cancer cell membrane coating in this strategy?
The cancer cell membrane coating provides homologous targeting, allowing the nanoparticles to specifically recognize and accumulate in tumor tissues. It also improves biocompatibility, prolongs blood circulation, and reduces off-target effects, thereby enhancing the safety and efficacy of the therapy.
What are the key factors limiting SAzyme catalytic efficiency in tumors?
The main limiting factors are the low availability of hydrogen peroxide (H2O2), acidic pH conditions, and suboptimal temperature within the tumor microenvironment. These factors can reduce the catalytic activity of SAzymes, thereby compromising the effectiveness of catalytic therapy.
What is the significance of this study for cancer treatment?
This study presents a comprehensive strategy to refine single-atom catalytic kinetics by simultaneously optimizing H2O2 supply, pH, and temperature, while achieving tumor-specific targeting via biomimetic coating. This approach significantly enhances the efficiency of catalytic therapy, offering a promising avenue for effective and safe cancer treatment.
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