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

Abstract

ABSTRACT 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.