Alkaline Phosphatase‐Activated NIR‐II AIEgens Nanosystem for Surgical and Postoperative Closed‐Loop Therapy of Advanced Osteosarcoma

ABSTRACT In advanced osteosarcoma, tumor invasion often prevents complete resection, and immunotherapy is limited by the tumor's immunosuppressive nature, making residual lesions a key source of recurrence. To address this, we developed an ALP‐responsive theranostic nanoplatform (SGPF) integrating an AIEgens (STEA) and HSP90 inhibitor (Ganetespib) for imaging‐guided resection and multimodal therapy. Selenium‐doped STEA enables NIR‐IIb imaging and enhanced phototherapy via narrowed HOMO‐LUMO gaps and nonradiative decay optimization. At tumor sites, ALP‐triggered nanomicelle cleavage releases STEA and Ganetespib while vaporizing perfluorohexane to relieve hypoxia. NIR irradiation induces pyroptosis via caspase‐3/GSDME activation and immunogenic cell death, while Ganetespib suppresses glycolysis (HK2/PKM2 downregulation) to reverse lactate‐driven immunosuppression. This dual‐action strategy synergistically enhances T‐cell infiltration and ablates residual/metastatic lesions, offering a transformative approach for unresectable Osteosarcoma.