An Injectable Metal‐Drug Supramolecular Condensate Enables Radiosensitization and Systemic Antitumor Immunity for Post‐Surgical Osteosarcoma Therapy

Vollständiger Abstract

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ABSTRACT Radiotherapy (RT) is widely used as an adjuvant treatment after surgical resection for osteosarcoma, but its efficacy is often limited by insufficient radiosensitization and an immunosuppressive tumor microenvironment that restricts systemic antitumor immunity and promotes recurrence and metastasis. Here we report an injectable metal‐drug supramolecular condensate formed from hafnium ions and alendronate (Hf‐ALN) and loaded with the COX‐2 inhibitor celecoxib (CXB) for synergistic radioimmunotherapy of postoperative osteosarcoma. The condensate forms through coordination‐driven liquid‐liquid phase separation between Hf 4+ ions and alendronate, enabling local retention within postoperative bone defects and sustained therapeutic release. Upon X‐ray irradiation, the Hf component amplifies radiation energy deposition and reactive oxygen species generation, thereby enhancing radiation‐induced DNA damage and immunogenic cell death. Meanwhile, the acidic tumor microenvironment triggers responsive release of CXB and ALN; CXB inhibits the COX‐2/PGE 2 immunosuppressive pathway, while ALN promotes macrophage repolarization toward the M1 phenotype, collectively remodeling the tumor immune microenvironment. This strategy enhances dendritic cell maturation, activates cytotoxic CD8 + T cells, and reduces regulatory T‐cell infiltration. In orthotopic osteosarcoma models, CXB@Hf‐ALN combined with RT suppresses tumor recurrence, preserves bone integrity, inhibits pulmonary metastasis, and prolongs survival with minimal systemic toxicity, offering a promising strategy to improve postsurgical RT outcomes in osteosarcoma.