Multifunctional Bismuth Nanoplatforms Augment Radioactive Iodine Therapy in Anaplastic Thyroid Cancer

Introduction: Radioactive iodine (RAI) therapy is a highly specific targeted treatment for thyroid cancer. However, the intrinsic low energy of ¹³¹I limits its efficacy in tumor eradication. Additionally, certain thyroid cancers exhibit a loss of sodium/iodine symporter (NIS) function due to severe dedifferentiation, compromising the therapeutic effectiveness of RAI. Methods: Our work was based on two distinct RAI-sensitizing strategies: (1) the generation of secondary electrons by irradiated metallic nanomaterials to promote hydrolysis and enhance reactive oxygen species (ROS) production, and (2) drug-induced reversal of the dedifferentiated phenotype of tumor cells to restore iodine uptake. Accordingly, we developed a multifunctional nanoplatform, termed Bi@Digoxin, by loading digoxin onto bismuth nanoparticles (BiNPs). The physicochemical properties of Bi@Digoxin were systematically characterized. Furthermore, its therapeutic efficacy was rigorously evaluated through in vitro and in vivo experiments, demonstrating significant treatment outcomes. Results: The experiments demonstrate that Bi@Digoxin enhances the efficacy of RAI in Anaplastic thyroid cancer (ATC) through a triple synergistic mechanism: utilizing nanocarriers for efficient delivery of Digoxin to restore NIS function in tumor cells, reversing RAI resistance in ATC; leveraging the high atomic number property of bismuth (Bi) to enhance radiation energy deposition, promoting ROS bursts and DNA double-strand breaks; and combining near-infrared (NIR) laser-triggered controlled drug release with photothermal ablation to significantly inhibit tumor growth. Conclusion: Bi@Digoxin significantly enhances the therapeutic efficacy of RAI, offering a novel synergistic treatment strategy for ATC that combines biosafety and scalable production, with significant potential for clinical translation.