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Since there are several limitations in cancer treatment for traditional chemotherapy, such as side effects, poor prognosis and drug resistance, developing new combined therapy is urgently needed. In this work, a biocompatible, simple and tumor microenvironment-responsive nanotheranostics (PCN-Oxpt/PEG) was built to favor the chemotherapy/ferroptosis/immunomodulation synergism in cancer. This nanotheranostics is constructed by modifying oxaliplatin prodrug and PEG on Fe(III) − porphyrin metal-organic frameworks (PCN(Fe) MOFs). After intravenous injection, the cloak of PEG leads to long circulation, and the Fe(III)-porphyrin MOFs enables dual-model guidance with fluorescence (FL) and magnetic resonance imaging (MRI). Inside the tumor, the intracellular H 2 O 2 would be transferred into hydroxyl radicals (•OH) by iron ions released from MOFs, which could trigger the lethal ferroptosis to cancer cells. Meanwhile, oxaliplatin(II) transformed from the loaded oxaliplatin prodrug would result in the chemotherapy, as well as immunogenic cell death (ICD), and the prodrug strategy could also avoid the occurring of liver damage by the direct administration of oxaliplatin(II). It was noticed that the ferroptosis effect was enhanced by triple-assistance during the combined therapy, as followed: (1) glutathione (GSH) would be consumed in the process of oxaliplatin(II) generation from oxaliplatin prodrug; (2) the increased CD8+ T cells induced by ICD were able to produce interferon-γ (IFN-γ), which could inhibit the transport of cystine by tumor cells, and impair the activation of glutathione peroxidase 4 (GPX4); (3) the amount of H 2 O 2 could be increased by the internalized oxaliplatin and thus further promote the Fenton reaction and ferroptosis. Both in vivo and in vitro results revealed that tumor growing was significantly inhibited by PCN-Oxpt/PEG, taken together, the concomitant of oxaliplatin-mediated chemotherapy and ICD with triple-enhanced ferroptosis offer great prospect in the clinical treatment of cancer. [Display omitted] • A novel nanoplatform (PCN-Oxpt/PEG) was designed for eliminating tumor with combined therapy. • The designed nanoplatform enables dual-model imaging (FL and MRI) to guide antitumor therapy. • Immunosuppressive tumor micro-environment could be remodeled by PCN-Oxpt/PEG, which would enhance ferroptosis efficiently. [ABSTRACT FROM AUTHOR]

The therapeutic application of chemodynamic therapy (CDT) is severely limited by the insufficient intracellular H 2 O 2 and acidity in tumor. Herein, an acid-sensitive nanoplatform (ZIF67-ICG/TAM@GOx) to promote H 2 O 2 and acidity enhancement through intracellular cyclic amplification for enhanced CDT is rationally designed. Notably, the acidic conditions of the tumor microenvironment (TME) can turn on the switch of the nanoplatform, setting free the loaded tamoxifen (TAM) and indocyanine green (ICG). The mitochondrial respiration inhibitor TAM and the superoxide dismutase-mimicking ZIF67 synergistically lead to an increase in the content of O 2 and H 2 O 2 , accelerating the depletion of β- d -glucose by GOx to generate gluconate and H 2 O 2. The gluconate in turn boosts the acidity to facilitate the collapse of nanoparticles, further significantly promoting the accumulation of intracellular H 2 O 2 through a positive circulation. Consequently, the amplificated endogenous H 2 O 2 is catalyzed by Co2+ to liberate hydroxyl radicals (•OH). Besides, ICG-mediated photothermal therapy (PTT) and GOx-induced starvation therapy along with CDT realize the synergistic cancer treatment. Importantly, in vitro and in vivo experiments verified that the nanoplatform performed superior specificity and excellent therapeutic responses. The smart nanoplatform overcomes H 2 O 2 and acidity deficiency simultaneously for intensive CDT, providing new prospects for the development of biocompatible cancer synergistic therapy strategies. In the tumor microenvironment, the released TAM, GOx and ZIF67 synergistically lead to a positive circulation for self-amplified CDT, cooperating with PTT and starvation to realize the synergistic cancer treatment. [Display omitted] • An acidic sensitive nanoplatform (ZIF67-ICG/TAM@GOx) is constructed for specific tumor therapy. • The combination of TAM, ZIF67 and GOx enabled positive circulation to accumulate H 2 O 2 and acidity for boosting CDT. • The disruption of H 2 O 2 homeostasis made the approach of "expanding source and cost-saving" for the increase of H 2 O 2. • The self-amplified CDT along with PTT, GOx-induced starvation realized a novel synergistic cancer therapy strategy. [ABSTRACT FROM AUTHOR]