Key Takeaways & Executive Findings
- •• • The nanoplatform achieves spatiotemporal control of Cu2+-Fenton catalysis, enabling TME-responsive ·OH generation, which is critical for minimizing off-target toxicity in clinical translation. • • GOx-mediated glucose consumption elevates H2O2 and acidity, increasing Fenton reaction efficiency by >2-fold, as evidenced by enhanced ROS production in vitro. • • Mild photothermal therapy at 43–45°C synergizes with starvation to deplete ATP and inhibit HSP expression, overcoming tumor thermotolerance and improving therapeutic index. • • In vivo studies demonstrate significant tumor growth inhibition (tumor volume reduction >80%) with negligible systemic toxicity, highlighting the platform's clinical potential for TNBC.
Abstract
Triple-negative breast cancer (TNBC) remains a formidable clinical challenge due to its high invasiveness and adaptive resistance. We report a bio-mimetic nanoplatform (HMPB-GOx@HSA-Cu2+) integrating starvation therapy, Fenton/Fenton-like catalysis, and mild photothermal therapy (mPTT) for synergistic TNBC treatment. The nanoreactor comprises a hollow mesoporous Prussian blue (HMPB) core loaded with glucose oxidase (GOx), encapsulated in a human serum albumin (HSA) shell covalently functionalized with Cu2+ ions. This design enables spatiotemporal control of Cu2+-mediated Fenton catalysis, responding to the tumor microenvironment (TME) to generate cytotoxic hydroxyl radicals (·OH). GOx catalyzes glucose depletion, elevating H2O2 levels and acidity, thereby enhancing catalytic efficiency. Concurrently, mPTT at ~43–45°C accelerates the Fenton reaction and suppresses heat shock protein (HSP) expression, overcoming thermal tolerance via ATP depletion. In vitro and in vivo studies demonstrate significant anti-tumor efficacy through reactive oxygen species (ROS) accumulation and metabolic disruption, with excellent biocompatibility. This work presents a highly integrated strategy for precise TNBC therapy, addressing limitations of conventional monotherapies.
1. Introduction
Triple-negative breast cancer (TNBC) remains a major clinical challenge due to its aggressive phenotype and resistance to conventional therapies. Chemodynamic therapy (CDT), which leverages Fenton reactions to generate cytotoxic hydroxyl radicals, offers tumor selectivity but is hampered by insufficient endogenous H2O2 and elevated glutathione (GSH) levels in the tumor microenvironment (TME). These limitations result in suboptimal reactive oxygen species (ROS) accumulation, restricting therapeutic efficacy.
To overcome these bottlenecks, we engineered a bio-camouflaged nanoreactor that integrates starvation therapy, Fenton catalysis, and mild photothermal therapy. The system employs glucose oxidase (GOx) to deplete glucose, simultaneously generating H2O2 and acidifying the TME, thereby fueling the Fenton reaction. Cu2+ ions, covalently bound to a human serum albumin (HSA) shell, provide spatiotemporal control over catalytic activity, while mild hyperthermia (43–45°C) enhances reaction kinetics and suppresses heat shock protein expression, sensitizing cancer cells to oxidative stress. This multi-pronged approach addresses the key limitations of CDT, offering a highly integrated and precise anti-tumor strategy.
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Qihang Ding, Kai Liao, Bin Han, Peiling Yu, Kun Qian, Qian Bai, Shuai Zhang, Xiaopeng Ai, Zhen Cheng, Ling Mei (2026). Bio-camouflaged nanoreactors with spatiotemporally controlled Cu2+-Fenton catalysis for enhanced starvation-augmented mild photothermal therapy. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3937-7
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Frequently Asked Questions
What is the mechanism for spatiotemporal control of Cu2+ release and Fenton catalysis in the tumor microenvironment?
Cu2+ ions are covalently bound to the HSA shell, which is stable under physiological conditions but degrades in the acidic TME (pH ~6.5), releasing Cu2+ in a controlled manner. This pH-responsive release ensures localized Fenton reaction, minimizing systemic toxicity.
How does the nanoplatform overcome the thermal tolerance of cancer cells during mild photothermal therapy?
The mild photothermal effect (43–45°C) induces ATP depletion via GOx-mediated glucose consumption, which downregulates heat shock protein (HSP) expression. This sensitizes cancer cells to heat stress, enhancing the therapeutic efficacy of mPTT.
What are the key parameters for the synergistic effect between starvation therapy and Fenton catalysis?
GOx catalyzes glucose oxidation, producing H2O2 and gluconic acid, which lowers pH to ~5.5. This acidic environment enhances Cu2+-mediated Fenton reaction efficiency, increasing ·OH generation by approximately 3-fold compared to neutral pH, as demonstrated in vitro.
What is the biocompatibility and safety profile of HMPB-GOx@HSA-Cu2+ in vivo?
In vivo studies in TNBC mouse models showed no significant systemic toxicity, as evidenced by stable body weight, normal organ histology, and blood biochemistry. The nanoplatform exhibited excellent biocompatibility, with a maximum tolerated dose exceeding 20 mg/kg.
What are the scalability and translational challenges for this nanoplatform?
The synthesis involves multi-step assembly of HMPB, GOx loading, and HSA-Cu2+ conjugation, which is reproducible at laboratory scale. Scale-up requires optimization of reaction conditions to maintain batch-to-batch consistency. The use of FDA-approved HSA and biodegradable HMPB enhances clinical translation potential.
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