G-Quadruplex-Modular CpG Nanoplatform Drives Multi-Pathway Immunity for Abscopal Chemoimmunotherapy.

Conventional cancer immunotherapy suffers from insufficient immune activation, immunosuppressive tumor microenvironment (TME), and rapid CpG adjuvant degradation. To address these challenges, we developed a G-quadruplex (G4)-modular CpG nanoplatform named IONP-G4-DOX/IMT, which uses iron oxide nanoparticles (IONPs) as a stable structural and biocompatible core and G4 as a multifunctional hub. The rationally designed G4 module enables three synergistic functions encompassing enhanced CpG nuclease resistance for sustained TLR9 pathway activation, site-specific loading of doxorubicin (DOX) to trigger potent immunogenic cell death (ICD) and release tumor antigens, and IMT anchoring to activate the cGAS-STING pathway. These three processes are structurally coordinated and functionally synergistic, collectively driving robust dendritic cell maturation, boosting CD4+/CD8+ T cell infiltration, and reducing regulatory T cell accumulation. This cascade of immune modulation effectively reprograms the TME into an immune-permissive state. In murine 4T1 breast cancer models, IONP-G4-DOX/IMT achieves a primary tumor suppression rate of approximately 79.4%, with no significant systemic toxicity. More importantly, it elicits potent long-term antitumor immunity that inhibits contralateral tumor growth, offering a versatile and promising strategy for advanced abscopal chemoimmunotherapy.