Titanium Sulfide Nanosheets Serve as Cascade Bioreactors for H2S‐Mediated Programmed Gas–Sonodynamic Cancer Therapy

Abstract Gas‐mediated sonodynamic therapy (SDT) has the potential to become an effective strategy to improve the therapeutic outcome and survival rate of cancer patients. Herein, titanium sulfide nanosheets (TiS X NSs) are prepared as cascade bioreactors for sequential gas–sonodynamic cancer therapy. TiS X NSs themselves as hydrogen sulfide (H 2 S) donors can burst release H 2 S gas. Following H 2 S generation, TiS X NSs are gradually degraded to become S‐defective and partly oxidized into TiO X on their surface, which endows TiS X NSs with high sonodynamic properties under ultrasound (US) irradiation. In vitro and in vivo experiments show the excellent therapeutic effects of TiS X NSs. In detail, large amounts of H 2 S gas and reactive oxygen species (ROS) can simultaneously inhibit mitochondrial respiration and ATP synthesis, leading to cancer cell apoptosis. Of note, H 2 S gas also plays important roles in modulating and activating the immune system to effectively inhibit pulmonary metastasis. Finally, the metabolizable TiS X NSs are excreted out of the body without inducing any significant long‐term toxicity. Collectively, this work establishes a cascade bioreactor of TiS X NSs with satisfactory H 2 S release ability and excellent ROS generation properties under US irradiation for programmed gas–sonodynamic cancer therapy.