Microwave‐Responsive AIE Nanocomposite Induces Immunogenic Senescence for Imaging‐Guided Therapy and Bone Repair in Osteosarcoma

Abstract

ABSTRACT Osteosarcoma remains challenging due to incomplete tumor resection, local recurrence, and limited immunostimulatory efficacy of current microwave (MW)‐based therapies. Here, we develop a multifunctional theranostic nanoplatform, GPC3@TTBC, by conjugating an osteosarcoma‐targeting anti‐GPC3 peptide onto aggregation‐induced emission (AIE) nanoparticles. GPC3@TTBC enables selective tumor accumulation and high‐contrast near‐infrared fluorescence imaging, allowing precise tumor margin delineation and superior tumor‐to‐background resolution compared with clinically used dyes, including effective visualization in patient‐derived xenograft models. Upon MW irradiation, lysosome‐localized GPC3@TTBC generates robust nonthermal reactive oxygen species (ROS) through enhanced charge separation and electron transfer, resulting in substantial tumor cell apoptosis while simultaneously inducing a prominent immunogenic senescence‐associated phenotype and senescence‐associated secretory phenotype (SASP) response. Importantly, MW + GPC3@TTBC suppressed tumor cell migration and invasion in vitro and reduced pulmonary metastatic lesions in vivo. Meanwhile, the SASP promoted dendritic cell maturation and cytotoxic T lymphocyte activation, thereby enhancing antitumor immune responses and remodeling the tumor immune microenvironment. Beyond tumor eradication, GPC3@TTBC facilitates osteogenic microenvironment reconstruction and bone regeneration after tumor clearance, while exhibiting favorable biosafety. Collectively, GPC3@TTBC integrates targeted fluorescence‐guided imaging, MW‐enhanced ROS generation, immunogenic senescence induction, and bone regeneration, providing a comprehensive theranostic strategy for precise osteosarcoma treatment.