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Tumor‐specific, hypoxia‐activated prodrugs have been developed to alleviate the side effects of chemotherapy drugs. However, the release efficiency of hypoxia‐activated prodrugs is restricted by the degree of tumor hypoxia, which further leads to poor cancer treatment effects. On the other hand, oxygen is consumed gradually in photodynamic therapy (PDT), which aggravates hypoxia at the tumor site. In this study, we combined hypoxia‐activated prodrugs with PDT agents to promote the prodrugs release, thereby improving their bioavailability and therapeutic effects. As a proof of concept, a mitochondria‐targeted molecular prodrug, CS‐P, was designed and synthesized. It can be selectively activated by tumor hypoxia to release chemotherapeutic drugs and photosensitizers, and then further discharge drugs after light irradiation. The design strategy proposed in this paper provides a new idea for enhancing hypoxia‐activated prodrug release and real‐time monitoring prodrug release. [ABSTRACT FROM AUTHOR]

Hypoxia, as a characteristic feature of solid tumor, can significantly adversely affect the outcomes of cancer radiotherapy (RT), photodynamic therapy, or chemotherapy. In this study, a strategy is developed to overcome tumor hypoxia‐induced radiotherapy tolerance. Specifically, a novel two‐dimensional Pd@Au bimetallic core–shell nanostructure (TPAN) was employed for the sustainable and robust production of O2 in long‐term via the catalysis of endogenous H2O2. Notably, the catalytic activity of TPAN could be enhanced via surface plasmon resonance (SPR) effect triggered by NIR‐II laser irradiation, to enhance the O2 production and thereby relieve tumor hypoxia. Thus, TPAN could enhance radiotherapy outcomes by three aspects: 1) NIR‐II laser triggered SPR enhanced the catalysis of TPAN to produce O2 for relieving tumor hypoxia; 2) high‐Z element effect arising from Au and Pd to capture X‐ray energy within the tumor; and 3) TPAN affording X‐ray, photoacoustic, and NIR‐II laser derived photothermal imaging, for precisely guiding cancer therapy, so as to reduce the side effects from irradiation. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has been applied in cancer treatment by utilizing reactive oxygen species to kill cancer cells. However, a high concentration of glutathione (GSH) is present in cancer cells and can consume reactive oxygen species. To address this problem, we report the development of a photosensitizer-MnO2 nanosystem for highly efficient PDT. In our design, MnO2 nanosheets adsorb photosensitizer chlorin e6 (Ce6), protect it from self-destruction upon light irradiation, and efficiently deliver it into cells. The nanosystem also inhibits extracellular singlet oxygen generation by Ce6, leading to fewer side effects. Once endocytosed, the MnO2 nanosheets are reduced by intracellular GSH. As a result, the nanosystem is disintegrated, simultaneously releasing Ce6 and decreasing the level of GSH for highly efficient PDT. Moreover, fluorescence recovery, accompanied by the dissolution of MnO2 nanosheets, can provide a fluorescence signal for monitoring the efficacy of delivery. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS)‐based cancer therapy, such as photodynamic therapy (PDT), is subject to the hypoxia and overexpressed glutathione (GSH) found in the tumor microenvironment (TME). Herein, a novel strategy is reported to continuously and simultaneously regulate tumor hypoxia and reducibility in order to achieve the desired therapeutic effect. To accomplish this, a biocompatible nanoplatform (MnFe2O4@metal–organic framework (MOF)) is developed by integrating a coating of porphyrin‐based MOF as the photosensitizer and manganese ferrite nanoparticle (MnFe2O4) as the nanoenzyme. The synthetic MnFe2O4@MOF nanoplatform exhibits both catalase‐like and glutathione peroxidase‐like activities. Once internalized in the tumor, the nanoplatform can continuously catalyze H2O2 to produce O2 to overcome the tumor hypoxia by cyclic Fenton reaction. Meanwhile, combined with the Fenton reaction, MnFe2O4@MOF is able to persistently consume GSH in the presence of H2O2, which decreases the depletion of ROS upon laser irradiation during PDT and achieves better therapeutic efficacy in vitro and in vivo. Moreover, the nanoplatform integrates a treatment modality with magnetic resonance imaging, along with persistent regulation of TME, to promote more precise and effective treatment for future clinical application. [ABSTRACT FROM AUTHOR]