Layered Double Hydroxides for Radium-223 Targeted Alpha Therapy with Elicitation of the Immune Response

Abstract

Targeted Alpha therapy (TAT) has promising application prospects in tumor therapy. It is very appealing to design alpha-emitting radiopharmaceuticals that can modulate the immune microenvironment to overcome the limitations of immunotherapy. Herein, Mg/Al layered double hydroxide nanomaterials (LDH) are utilized to load the alpha-emitting nuclide Radium-223 (²²³Ra), achieving precise delivery of ²²³Ra to the tumor microenvironment. Dual-modal imaging is employed to dynamically monitor the in vivo distribution of ²²³Ra-LDH, ensuring its prolonged retention at the tumor site. In vitro experimentsshowed that ionizing radiation from alpha-emitting nuclides effectively reduced glutathione (GSH) and produced large amounts of reactive oxygen species (ROS), which damaged mitochondria and released free calcium (Ca²⁺), thereby aggravating tumor cell death. Additionally,  DNA double-strand breaks induced by alpha-emitting radiation triggered the STING signaling pathway, which in turn effectively induced immunogenic cell death (ICD) and promoted immune cell maturation and activation. The synergistic effect with immunotherapy triggered a powerful systemic antitumor immune response. Overall, this study develops a novel TAT therapeutic strategy with sufficient antitumor immunity.