Dual‐Functional Sonodynamic Therapeutic Platform for Complete Osteosarcoma Elimination With Synchronized Bone Defect Regeneration

ABSTRACT Postoperative osteosarcoma therapy meets the substantial challenges of tumor recurrence due to incomplete eradication and functional impairment from bone defect over‐resection. Herein, we establish a sonosensitizer‐based therapeutic‐regenerative strategy that simultaneously realizes ultrasound‐triggered tumor ablation and functional bone reconstruction. By balancing intramolecular motion and intermolecular interaction, a planar skeleton/twisted rotors‐structured sonosensitizer, ffBT‐T, with enhanced reactive oxygen species (ROS) generation via constitutional isomerization is constructed. The rationally designed ffBT‐T nanoparticles (NPs) can efficiently bind with both osteosarcoma cells and bone marrow mesenchymal stem cells (BMSCs). On the one hand, upon ultrasound activation, ROS generated by ffBT‐T NPs can eliminate osteosarcoma cells in vitro through multimodal cell death (apoptosis/ferroptosis), accompanied by the successful trigger of immunogenic cell death (ICD) to prime systemic antitumor immunity. On the other hand, while eradicating tumor cells, the system shows exceptional biocompatibility with BMSCs and actively enhances their osteogenic differentiation by 2.1‐fold through PI3K‐Akt pathway modulation, as verified by RNA‐seq and ALP/ARS assays. In vivo, this dual‐function therapy successfully suppresses tumor growth and promotes bone regeneration in a clinically relevant orthotopic osteosarcoma model. This work establishes a new paradigm for “theragenerative” biomaterials by molecularly integrating tumor‐specific cytotoxicity with pro‐regenerative signaling, offering a clinically viable solution for postoperative cancer management.