Schottky Heterojunction Facilitates Osteosarcoma Ferroptosis and Enhances Bone Formation in a Switchable Mode

Effective antitumor agents with concurrent osteogenic properties are essential for comprehensive osteosarcoma (OS) treatment. However, the current clinical therapeutic strategies of OS fail to completely eradicate tumors while simultaneously encouraging bone formation. To address this issue, a switchable strategy for dynamic OS ablation and static bone regeneration is developed by integrating piezoelectric BaTiO3 (BTO) with atomic‐thin Ti3C2 (TC) through a Schottky heterojunction, resulting in the formation of TC@BTO. Under sequential ultrasound and near‐infrared irradiation, the optimized carrier transport of TC@BTO, based on Schottky heterojunction, exhibits excellent characteristics of photothermal conversion and reactive oxygen species generation. This results in ferroptosis of tumor cells and eventual elimination of OS. Moreover, in the static state, the interfacial Schottky heterojunction facilitates the carriers’ directed transfer from the semiconductor to the metal. The Schottky heterojunction‐enhanced static electrical stimulation enhances the osteogenic differentiation of bone marrow‐derived mesenchymal stem cells and repair of bone defects. Furthermore, RNA‐sequencing analysis reveals that static TC@BTO promotes bone regeneration by activating Wnt signaling pathway, and remarkably, pharmacological inhibition of Wnt signaling suppresses the TC@BTO‐induced osteogenesis. Overall, this work broadens the biomedical potential of Schottky heterojunction‐based therapies and provides a comprehensive strategy for overall OS ablation and bone regeneration. Lv et al develop a Schottky heterojunction‐based multifunctional nano‐switch (TC@BTO) for the treatment of osteosarcoma. In dynamic state, under sequential ultrasound and near‐infrared irradiation, TC@BTO induces robust osteosarcoma elimination by generating reactive oxygen species and facilitating ferroptosis; in static state, without any irradiation, TC@BTO initiates osteogenic differentiation of BMSCs and repair of bone defects by activating Wnt‐signaling pathway.