Cuproptosis-InducingFunctional Nanocomposites forEnhanced and Synergistic Cancer Radiotherapy

Radiotherapy is crucial in local cancer management and needs advancements. Tumor cells elevate intracellular copper levels to promote growth and resist radiation; thus, targeted copper delivery to mitochondria could enhance radiotherapy by inducing cuproptosis in tumor cells. In this study, we engineered a multifunctional nanoliposome complex, termed Lipo-Ele@CuO₂, which encapsulates both copper peroxide (CuO₂) and the copper chelator elesclomol, which can delivery Cu ions to the mitochondria. The Lipo-Ele@CuO₂ complex induces mitochondria-mediated cuproptosis in tumor cells and synergistically enhances the efficacy of radiotherapy. CuO₂ acts as a copper donor and exhibits inherent sensitivity to acidic environments. Additionally, it depletes intracellular glutathione, thereby sensitizing cells to cuproptosis. Leveraging its pH-responsive properties in the acidic tumor microenvironment, the Lipo-Ele@CuO₂ facilitate the controlled release of elesclomol, efficiently delivering copper ions to mitochondria at tumor sites. The combined <i>in vitro</i> and <i>in vivo</i> studies demonstrate that Lipo-Ele@CuO₂-based therapy significantly improves antitumor efficacy and exhibits excellent safety profiles, effectively inducing cuproptosis in tumor cells and boosting the effectiveness of radiotherapy. Furthermore, metabolomic and transcriptomic analyses reveal that this combination therapy precipitates significant alterations in tumor energy metabolism, notably repressing genes related to iron–sulfur cluster assembly and glycolysis, thereby confirming the induction of cuproptosis. This therapeutic strategy provides a viable approach for addressing clinical radiotherapy resistance and demonstrates significant translational potential.