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With the development of redox-related therapy modalities in cancer therapy, photodynamic therapy (PDT) has gradually become the most widely used type in the clinic. However, the hypoxic tumor microenvironment restricted the curative effect of PDT. Here, a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy was designed to alleviate tumor hypoxia on the basis of PDT. Specifically, the oxygen producer MnO 2 , oxygen consumption inhibitor atovaquone (ATO) and photosensitizer hypericin (HY) were loaded in SHRN. MnO 2 reacted with excess H 2 O 2 in the tumor microenvironment to increase oxygen generation, while ATO inhibited electron transfer in the aerobic respiratory chain to decrease oxygen consumption. Then, HY utilized this sufficient oxygen to produce ROS under irradiation to enhance the PDT effect. In vitro and in vivo assays confirmed that SHRN exhibits powerful and overall antitumor PDT effects. This formulation may provide an alternative strategy for the development of PDT effects in hypoxic tumor microenvironments. We constructed a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy to alleviate tumor hypoxia on the basis of photodynamic therapy (PDT). This work uniquely aimed at not only increased O 2 generation in hypoxic tumor microenvironment but also reduced O 2 consumption. Moreover, we designed a nanodrug delivery system to enhance the tumor permeability of SHRN. In vitro and in vivo assays all confirmed that SHRN exhibited powerful and overall antitumor effects. This formulation may provide an alternative strategy for the development of the PDT effect in hypoxic solid tumor. [Display omitted] [ABSTRACT FROM AUTHOR]

• Pyroelectric BaTiO 3 (BTO) nanomaterials have a build-in electric field that can prevent the electron-hole recombination. • Temperature variation on BTO nanomaterials facilitate the free hole release and O 2 -independent hydroxyl radical generation. • NIR laser irradiated plasmonic Au cores in Au@BTO CSNSs can heat pyroelectric BTO shell, leading to efficient ROS production. • Biocompatible p Au@BTO CSNSs exhibit excellent in vitro and in vivo PDT and PTT performance for hypoxic tumor therapy. [Display omitted] Photodynamic therapy (PDT) has attracted considerable attention for tumor treatment, however, its efficacy is dramatically limited by the low reactive oxygen species (ROS) generation efficiency at hypoxic tumor microenvironment. Herein, new plasmon-pyroelectric gold (Au)@barium titanate (BTO) core-shell (CS) nanostructures (NSs) were designed to produce a temperature-mediated oxygen (O 2)-independent PDT for hypoxic tumor therapy. Upon 808 nm laser irradiation, the plasmonic heating of Au cores was excited and transferred a heat to pyroelectric BTO shell, where the temperature elevation could decrease spontaneous polarization of BTO, leading to abundant hole released from the BTO surface and promoting to hydroxyl radical formation through an O 2 -independent approach. Simultaneously, Au@BTO CSNSs still remain excellent photothermal performance originating from Au cores. Actually, 808 nm laser irradiated and polyethylene glycol modified Au@BTO CSNSs could exhibit promising phototherapeutic effects on 4T1 cells at hypoxic conditions and 4T1 tumor-bearing mice, showing great potential for hypoxic tumor therapy. [ABSTRACT FROM AUTHOR]