Titanium Sulfide Nanosheets Serve as Cascade Bioreactors for H₂ S-Mediated Programmed Gas-Sonodynamic Cancer Therapy

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 (H₂ S) donors can burst release H₂ S gas. Following H₂ 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 H₂ S gas and reactive oxygen species (ROS) can simultaneously inhibit mitochondrial respiration and ATP synthesis, leading to cancer cell apoptosis. Of note, H₂ 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 H₂ S release ability and excellent ROS generation properties under US irradiation for programmed gas-sonodynamic cancer therapy.