Self-Adaptive MoO3−x Subnanometric Wires Incorporated Scaffolds for Osteosarcoma Therapy and Bone Regeneration

Residual tumor cells and bone tissue defects are two critical challenges in clinical osteosarcoma treatment. Herein, a subnanomedicine concept is proposed by developing a self-adaptive functional tissue engineering scaffold constructed by integrating MoO_3−x subnanometric wires onto 3D printing bioactive glass scaffolds. The MoO_3−x subnanometric wires are synthesized by a one-pot hydrothermal method, which aggregate in an acidic tumor microenvironment and react with hydrogen peroxide to produce reactive oxygen species for specific chemodynamic therapy. However, they can degrade rapidly under physiological conditions without causing toxicity. Moreover, self-adaptively enhanced photothermal conversion enables tumor-targeting photothermal therapy while enhancing chemodynamic therapy. Additionally, the Mo⁵⁺-Mo⁶⁺ transition enables lipid peroxide accumulation and glutathione depletion, thereby resulting in the deactivation of glutathione peroxidase 4 protein and ferroptosis through Western blot analysis, confocal laser scanning microscopy observation, and mRNA transcriptome analysis. In addition to its robustness against osteosarcoma, the constructed scaffolds can stimulate rat bone mesenchymal stem cell differentiation and proliferation as well as promote osteogenesis in bone defects. Therefore, this multifunctional scaffold not only validates the subnanomedicine concept but also provides a promising clinical strategy for bone tissue engineering.