Hierarchical Core-Shell Nanoplatform with Sequential Mn²⁺/Co²⁺ Release Enables Dual-Track STING Amplification and Radiosensitization for Potent Radio-Metalloimmunotherapy.

Abstract

Cancer immunotherapy is often hindered by the immunosuppressive tumor microenvironment and the inefficient activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway under hypoxic conditions. To address these challenges, we developed a hierarchical core-shell Au@Co-EGCG/Mn-EGCG (ACM) nanoplatform that synergistically integrates radiosensitization with a dual-track STING amplification strategy. Owing to its high-Z gold core and robust catalase-like activity, the ACM nanostructure effectively alleviates tumor hypoxia and maximizes X-ray energy deposition, leading to an intense burst of reactive oxygen species (ROS) and irreparable DNA damage. This synergy in turn triggers potent immunogenic cell death and substantial mitochondrial DNA (mtDNA) leakage. Critically, the hierarchical release of Mn²⁺ and Co²⁺ ions within tumor cells establishes a "sequential synergistic cascade": Mn²⁺ sensitizes cGAS for enhanced DNA recognition, while Co²⁺ acts as a high-gain amplifier by enhancing the binding affinity of STING for 2', 3'-cyclic GMP-AMP (cGAMP). This molecular relay ignites a systemic surge of pro-inflammatory cytokines, notably IFN-β, effectively converting "cold" tumors into "hot" ones. In vivo, ACM-mediated radiotherapy not only achieves thorough in situ tumor ablation but also elicits a powerful abscopal effect, suppressing distant metastasis through enhanced T-cell infiltration and macrophage repolarization. Collectively, this work establishes a potent radio-metalloimmunotherapy paradigm to overcome radioresistance and systemic cancer progression. STATEMENT OF SIGNIFICANCE: The majority of colorectal cancers are microsatellite stable (MSS) and resistant to immunotherapy due to a "cold" tumor microenvironment. In this study, we introduce a hierarchical core-shell nanoparticle that, upon X-ray irradiation, sequentially releases two metal ions to activate the cGAS-STING pathway cooperatively. Unlike conventional single-agent STING agonists, our design separates the DNA sensitization provided by Mn²⁺ from the signal amplification driven by Co²⁺, creating a synergistic cascade that overcomes hypoxia-induced immunosuppression. This dual-track mechanism transforms resistant MSS tumors into immune-responsive "hot" lesions, eliminating primary tumors and suppressing distant metastases. The work establishes a new paradigm of radio-metalloimmunotherapy, offering a translatable strategy to convert radiation into a systemic immune adjuvant.