Bone‐Targeted Nanosystems Induce Multiple Types of Cell Death and Suppress Osteoclasts via Sonodynamic Sensitization Therapy to Treat Bone Metastatic Tumors

Sonodynamic therapy (SDT) has enormous potential to eradicate tumors in situ and reshape antitumor immunity, but the efficacy of SDT is constrained by sonosensitizer performance and the intensity of the induced immune response. In the present study, a metal–organic framework (MOF) sonosensitizer (PN20@Rx) for treating bone metastases was designed through alendronate sodium (ALN)‐mediated defect engineering. This strategy significantly increased sonocatalytic efficiency by narrowing the interstitial spaces and optimizing the sonic‐to‐electrical energy conversion. Furthermore, PN20@Rx exhibited multiple nanoenzyme activities and bone‐targeting properties, simultaneously depleting glutathione (GSH), generating hydroxyl radicals (•OH), and producing oxygen (O 2 ). In a bone metastasis model, upon ultrasound (US) stimulation, PN20@Rx effectively cleared 4T1 cells within mouse tibiae, inhibited tumor‐associated bone destruction, and induced multiple regulated cell death (RCD) pathways and immunogenic cell death (ICD). PN20@Rx simultaneously downregulated the expression of the CD47 immune checkpoint protein on tumor cell surfaces, thereby converting the tumor from an immune “cold” state to an immune “hot” state and effectively suppressing lung metastasis. The present study provides a unique sonocatalytically enhanced strategy and novel insights for MOF‐based clinical tumor immunotherapy.