Light Activated Induction of Cuproptosis in Resistant Cancer Cells Using Polymeric BODIPY Nanoparticles for Photoactivated Chemotherapy

ABSTRACT Although advancements in anticancer treatments have progressed over the last decades, cancer continues to be a major cause of death globally. One of the most commonly employed techniques is chemotherapy in which cytotoxic drugs are systemically administered. Despite their undoubtful clinical success, the vast majority of these agents induce apoptosis in cancer cells and are prone to the development of drug resistance. To overcome this challenge, alternative cell death mechanisms have gained increasing attention, including the recently discovered mechanism of cuproptosis, a copper‐dependent form of regulated cell death. However, most cuproptosis‐inducing compounds suffer from poor solubility, limited tumor selectivity, and suboptimal pharmacological properties. Herein, a photo‐responsive nanoparticle platform that induces copper‐driven cuproptotic cell death with high precision is reported. The nanoparticles remain stable and therapeutically inactive in the dark, but upon exposure to red light, they rapidly degrade into molecular species that trigger a potent cytotoxic response in the nanomolar range in drug‐resistant human breast cancer cells, highlighting its effectiveness against difficult‐to‐treat tumors. This strategy provides high spatial and temporal control over anticancer therapy, minimizing off‐target effects and enabling therapeutic precision.