A Sono‐Responsive Nanoplatform Integrating STING Activation and CXCR4 Blockade for Synergistic Immunotherapy of Glioblastoma

Abstract Glioblastoma (GBM), an aggressive brain tumor with a highly immunosuppressive microenvironment, remains a therapeutic challenge due to its resistance to conventional treatments. In this study, a novel multi‐function therapeutic platform that integrates ultrasound‐triggered sonodynamic therapy (SDT), STING pathway activation, and CXCR4 inhibition for synergistic immunotherapy of GBM is presented. Through systematic comparison of a series of organic molecules with subtle substituted atom alterations, a new selenium‐containing compound is identified with outstanding sonodynamic properties. The high‐performance sonosensitizer is co‐assembled with a STING agonist prodrug, which is further cloaked with glioma cell membrane and CXCR4‐targeting peptides for dual homing and immune modulation. Under ultrasound irradiation, the nanoplatform triggers robust reactive oxygen species production, in combination with the self‐accelerating STING agonist release, significantly stimulating both innate and adaptive immune responses while disrupting the CXCL12/CXCR4 signaling axis to suppress immunosuppressive cell infiltration. This tripartite strategy, which integrates SDT‐mediated tumor ablation, STING‐induced systemic immunity, and CXCR4 blockade, synergistically suppresses primary tumor growth, prevents postoperative recurrence, and extends survival in GBM‐bearing mice. This approach presents a promising sono‐triggered multimodal paradigm for overcoming GBM's immunosuppressive barriers and enhancing therapeutic outcomes.