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

Iodine-131 (¹³¹I), 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, ¹³¹I-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 ¹³¹I radiotherapy. In subcutaneous tumors, ¹³¹I-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, ¹³¹I-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.