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.