An NIR‐II Photothermally Triggered “Oxygen Bomb” for Hypoxic Tumor Programmed Cascade Therapy

Abstract Hypoxia, as a characteristic feature of solid tumors, has a close relationship with tumor resistance to photodynamic therapy (PDT) and chemotherapy. Perfluorocarbon (PFC) is reported to relieve hypoxic in solid tumors by acting as an oxygen carrier via several nanostructures. However, the oxygen delivery process is mostly driven by a concentration gradient, which is uncontrollable. Herein, a photothermally controlled “oxygen bomb” PSPP‐Au₉₈₀‐D is designed by encapsulating a PFC core within a functionalized bilayer polymer shell. Near‐infrared second window photothermal agent gold nanorods with excellent photo‐to‐heat energy‐conversion ability are fabricated on the surface of the polymer shell via an innovative modified two‐step seedless ex situ growth process to thermally trigger O₂ release. Then, a programmed cascade therapy strategy is customized for hypoxic orthotopic pancreatic cancer. First, PSPP‐Au₉₈₀‐D is irradiated by a 980 nm laser to photothermally trigger O₂ infusing into the hypoxic tumor microenvironment, which is accompanied by local hyperemia and doxorubicin release. Subsequently, a 680 nm laser is used to generate singlet oxygen in the oxygenated tumor microenvironment for PDT. This choreographed programmed cascade therapy strategy will provide a new route for suppressing hypoxic tumor growth under mild conditions based on controllable and effective oxygen release.