W-Doped TiO₂ Nanorods for Multimode Tumor Eradication in Osteosarcoma Models under Single Ultrasound Irradiation

Sonosensitizers play crucial roles in the controlled production of reactive oxygen species (ROS) under ultrasound (US) irradiation with high tissue-penetration depth for noninvasive solid tumor therapy. It is desirable to fabricate structurally simple yet multifunctional sonosensitizers from ultrafine nanoparticles for ROS-based multimode therapy to overcome monomode limitations such as low ROS production yields and endogenous reductive glutathione (GSH) to ROS-based treatment resistance. We report the facile high-temperature solution synthesis of ultrafine W-doped TiO₂ (W-TiO₂) nanorods for exploration of their sonodynamic, chemodynamic, and GSH-depleting activities in sonodynamic-chemodynamic combination tumor therapy. We found that W⁵⁺ and W⁶⁺ ions doped in W-TiO₂ nanorods play multiple roles in enhancing their ROS production. First, W doping narrows the band gap from 3.2 to 2.3 eV and introduces oxygen and Ti vacancies for enhancing their sonodynamic performance. Second, W⁵⁺ doping endows W-TiO₂ nanorods with Fenton-like reaction activity to produce •OH from endogenous H₂O₂ in the tumor. Third, W⁶⁺ ions reduce endogenous GSH to glutathione disulfide (GSSG) and, in turn, form W⁵⁺ ions that further enhance their chemodynamic activity, which greatly modifies thae oxidation-reduction tumor microenvironment in the tumor. In vivo experiments display the excellent ability of W-TiO₂ nanorods for enhanced tumor eradication in human osteosarcoma models under single US irradiation. Importantly, the ultrafine nanorod morphology facilitates rapid excretion from the body, displaying no significant systemic toxicity. Our work suggests that multivalent metal doping in ultrafine nanomaterials is an effective and simple strategy for the introduction of new functions for ROS-based multimode therapy.