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Fenton reaction‐mediated chemodynamic therapy (CDT) can kill cancer cells via the conversion of H2O2 to highly toxic HO•. However, problems such as insufficient H2O2 levels in the tumor tissue and low Fenton reaction efficiency severely limit the performance of CDT. Here, the prodrug tirapazamine (TPZ)‐loaded human serum albumin (HSA)–glucose oxidase (GOx) mixture is prepared and modified with a metal–polyphenol network composed of ferric ions (Fe3+) and tannic acid (TA), to obtain a self‐amplified nanoreactor termed HSA–GOx–TPZ–Fe3+–TA (HGTFT) for sustainable and cascade cancer therapy with exogenous H2O2 production and TA‐accelerated Fe3+/Fe2+ conversion. The HGTFT nanoreactor can efficiently convert oxygen into HO• for CDT, consume glucose for starvation therapy, and provide a hypoxic environment for TPZ radical‐mediated chemotherapy. Besides, it is revealed that the nanoreactor can significantly elevate the intracellular reactive oxygen species content and hypoxia level, decrease the intracellular glutathione content, and release metal ions in the tumors for metal ion interference therapy (also termed “ion‐interference therapy” or “metal ion therapy”). Further, the nanoreactor can also increase the tumor’s hypoxia level and efficiently inhibit tumor growth. It is believed that this tumor microenvironment‐regulable nanoreactor with sustainable and cascade anticancer performance and excellent biosafety represents an advance in nanomedicine.

Compared with conventional tumor photothermal therapy (PTT), mildtemperature PTT brings less damage to normal tissues, but also tumor thermoresistance, introduced by the overexpressed heat shock protein (HSP). A high dose of HSP inhibitor during mild-temperature PTT might lead to toxic side effects. Glucose oxidase (GOx) consumes glucose, leading to adenosine triphosphate supply restriction and consequent HSP inhibition. Therefore, a combinational use of an HSP inhibitor and GOx not only enhances mildtemperature PTT but also minimizes the toxicity of the inhibitor. However, a GOx and HSP inhibitor-encapsulating nanostructure, designed for enhancing its mild-temperature tumor PTT efficiency, has not been reported. Thermosensitive GOx/indocyanine green/gambogic acid (GA) liposomes (GOIGLs) are reported to enhance the efficiency of mild-temperature PTT of tumors via synergistic inhibition of tumor HSP by the released GA and GOx, together with another enzyme-enhanced phototherapy effect. In vitro and in vivo results indicate that this strategy of tumor starvation and phototherapy significantly enhances mild-temperature tumor PTT efficiency. This strategy could inspire people to design more delicate platforms combining mildtemperature PTT with other therapeutic methods for more efficient cancer treatment.

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Photothermal therapy (PTT) usually requires hyperthermia >50 °C for effective tumor ablation, which inevitably induces heating damage to the surrounding normal tissues/organs. Moreover, low tumor retention and high liver accumulation are the two main obstacles that significantly limit the efficacy and safety of many nanomedicines. To solve these problems, a smart albumin‐based tumor microenvironment‐responsive nanoagent is designed via the self‐assembly of human serum albumin (HSA), dc‐IR825 (a cyanine dye and a photothermal agent), and gambogic acid (GA, a heat shock protein 90 (HSP90) inhibitor and an anticancer agent) to realize molecular targeting‐mediated mild‐temperature PTT. The formed HSA/dc‐IR825/GA nanoparticles (NPs) can escape from mitochondria to the cytosol through mitochondrial disruption under near‐infrared (NIR) laser irradiation. Moreover, the GA molecules block the hyperthermia‐induced overexpression of HSP90, achieving the reduced thermoresistance of tumor cells and effective PTT at a mild temperature (<45 °C). Furthermore, HSA/dc‐IR825/GA NPs show pH‐responsive charge reversal, effective tumor accumulation, and negligible liver deposition, ultimately facilitating synergistic mild‐temperature PTT and chemotherapy. Taken together, the NIR‐activated NPs allow the release of molecular drugs more precisely, ablate tumors more effectively, and inhibit cancer metastasis more persistently, which will advance the development of novel mild‐temperature PTT‐based combination strategies.