Ferroptosis-Enhanced Radiopharmaceutical Therapy via a Manganese-Based Nanoplatform

Radiopharmaceutical therapy (RPT) is a therapeutic strategy that delivers radionuclides in a targeted manner to achieve precise radiation-induced killing of tumor cells. While RPT primarily induces tumor cell death through apoptosis, resistance to apoptosis has been identified as a key mechanism underlying the radioresistance. Therefore, integrating nonapoptotic cell death pathways with RPT offers a promising strategy to enhance its therapeutic efficacy. In this study, we employed biomineralization to fabricate a manganese dioxide nanocarrier based on human serum albumin (MnO₂@HSA), which was further labeled with the radionuclide iodine-131 (¹³¹I) to construct a novel radioactive nanoplatform (MnO₂@HSA-¹³¹I). In vitro experiments demonstrated that the MnO₂ component in the platform exhibited catalytic activity, depleting intracellular glutathione (GSH) and releasing Mn²⁺, which in turn catalyzed the Fenton-like conversion of hydrogen peroxide (H₂O₂) into highly cytotoxic hydroxyl radicals (·OH). In subsequent cellular- and animal-level antitumor studies, MnO₂@HSA-¹³¹I exhibited potent tumor-inhibitory effects. RNA sequencing suggested that ferroptosis may play a pivotal role in the therapeutic mechanism. Further validation confirmed that MnO₂@HSA-¹³¹I promoted reactive oxygen species (ROS) generation, accelerated GSH depletion, and downregulated glutathione peroxidase 4 (GPX4) expression, thereby inducing ferroptosis and synergizing with ¹³¹I-mediated radiotherapy. The nanoplatform also demonstrated excellent biocompatibility and negligible systemic toxicity in vivo, supporting its potential for safe clinical application. This manganese-based radioactive nanodrug provides a novel strategy and theoretical basis for radiopharmaceutical tumor therapy.