Ginsenoside Rk1-Loaded Manganese-Doped Hollow Titania for Enhancing Tumor Sonodynamic Therapy via Upregulation of Intracellular Reactive Oxygen Species

Amplifying the intracellular reactive oxygen species (ROS) level remains an urgent challenge for efficient sonodynamic therapy (SDT) of tumors. Herein, by loading ginsenoside Rk1 with manganese-doped hollow titania (MHT), a Rk1@MHT sonosensitizer was conceived to strengthen the outcome of tumor SDT. The results verify that manganese-doping remarkably elevates the UV-visible absorption and decreases the bandgap energy of titania from 3.2 to 3.0 eV, which improves ROS production under ultrasonic irradiation. Immunofluorescence and Western blot analysis demonstrate that ginsenoside Rk1 can block the critical protein of the glutathione synthesis pathway, glutaminase, thus enhancing intracellular ROS by eliminating the endogenous glutathione-depleted pathway of ROS. Manganese-doping confers the nanoprobe T₁-weighted MRI function (r₂/r₁ = 1.41). Moreover, the in vivo tests confirm that Rk1@MHT-based SDT eradicates liver cancer in tumor-bearing mice via dual upregulation of intracellular ROS production. In summary, our study provides a new strategy for designing high-performance sonosensitizer to achieve noninvasive cancer treatment.