CaSO₄-mediated remote drug loading enables synergistic cancer chemotherapy and ion-interference therapy

As an emerging cancer therapeutic modality, ion-interference therapy (IIT), mediated by the elevated levels of intracellular calcium ions (Ca²⁺), hasgarneredsignificant research attention in the field of cancer theranostics. However, most reported IIT strategies have heavily relied on Ca-based inorganic compounds, such as calcium peroxide and calcium carbonate,whose biosafety remains under investigation due to their high density and uncertainbiodegradability.This study describes a novel strategy for efficiently encapsulating doxorubicin (DOX) andCa²⁺ using the CaSO₄ gradient method fordrugremote loading. In breast cancer cell models, we demonstrated a synergistic anticancer effect between Ca²⁺ and DOX, and elucidated the reactive oxygen species(ROS)-based antitumor mechanisms. This research represents the first instance of nanomedicine inducing combined chemotherapy/ion-interference therapy for cancer treatment without the use of insoluble inorganic compounds, thus offering enhanced biosafety.