iRGD-NaGd(MoO4)2: A Tumor-Targeted Magnetic Resonance Contrast Agent Activating Immunotherapy via the cGAS-STING Pathway

Because of the high incidence and mortality of cancer, there is an urgent need for more effective tumor diagnostic imaging and treatment strategies. Single-molecule therapeutics have emerged as a promising strategy to address the limitations of independent imaging and therapeutic modalities, thereby significantly reducing adverse side effects for patients. For the first time, we successfully synthesized NaGd(MoO₄)₂ nanoparticles via a homogeneous precipitation method in polyol media, which serve as a single-molecule agent for MRI imaging and metallic immunotherapy. With the addition of iRGD, we obtained iRGD-NaGd(MoO₄)₂. The iRGD-NaGd(MoO₄)₂ nanoparticles exhibit excellent tumor-targeting capability and significantly enhance T1-weighted MRI contrast with a longitudinal relaxivity of 4.95 mM^–1 s^–1. In terms of antitumor immunotherapy, iRGD-NaGd(MoO₄)₂ not only directly activates the cGAS-STING pathway but also induces ferroptosis in tumor cells, resulting in the generation of aberrant dsDNA and thereby indirectly activating the STING pathway. The dual pathway elicits a tumor-specific immune response, plays a significant role in promoting the maturation of DC cells, activates DC and T cells to secrete high levels of TNF-α, IL-6 and other cytokines, and regulates the polarization of macrophages from M2 phenotype to M1 phenotype. This mechanism significantly suppresses tumor growth. Beyond the metallic immunotherapy induced by Mn²⁺, Zn²⁺, and Co²⁺, this study provides robust validation of MoO4^2– as an effective cGAS-STING agonist. Moreover, this study achieved the synergy of multiple disciplines including biomaterials, tumor immunotherapy and medical imaging. This not only promotes the innovative integration in various fields, but also provides new treatment strategies and imaging tools for cancer treatment, which has important clinical application prospects.