Chemodynamic Therapy Enhanced 131 I‐Radiotherapy for Efficient Inhibition on Cancer Growth and Metastasis

Abstract Iodine‐131 ( 131 I), a cornerstone of thyroid cancer therapy, suffers from limited efficacy in other cancers due to poor tumor accumulation and hypoxia‐driven radiotherapy resistance. To overcome these challenges, 131 I‐M@HI, a theranostic nanoparticle was engineered that synergizes radiotherapy with chemodynamic therapy (CDT). This platform integrated Mn(III) porphyrin and indocyanine green self‐assembled on albumin, enabling dual‐mode fluorescence/MRI‐guided imaging, tumor/sentinel lymph node‐targeted accumulation, and hypoxia modulation. The Mn(III) porphyrin catalyzes intratumoral hydrogen peroxide into cytotoxic hydroxyl radicals for CDT while alleviating hypoxia to amplify 131 I radiotherapy. In subcutaneous tumors, 131 I‐M@HI achieved >85% tumor inhibition by inducing immunogenic cell death, marked by calreticulin exposure and high mobility group box 1 release, and triggered systemic anti‐tumor immunity. Strikingly, in a breast cancer metastasis model, 131 I‐M@HI selectively eradicated sentinel lymph node metastases, reducing lung metastatic nodules by >90%, representing a critical advancement for preventing metastatic spread. This work pioneers a multifunctional nanoplatform that not only enhances radiotherapy but also redefines precision metastasis inhibition, offering a transformative strategy for advanced cancer therapy.