A precise theranostic nanoplatform amplifies anti-tumor efficacy via copper ionophores and sonodynamic therapy

Tumor heterogeneity and therapeutic resistance remain major challenges in cancer treatment. Sonodynamic therapy (SDT), a noninvasive therapeutic modality with deep tissue penetration capability, has shown considerable promise in tumor therapy. However, its efficacy is often limited by insufficient reactive oxygen species (ROS) generation and the lack of real-time treatment monitoring. Cuproptosis, a recently identified copper-dependent form of regulated cell death, is closely associated with mitochondrial metabolic dysfunction and offers new opportunities for synergistic cancer therapy. Herein, we report a multifunctional nanoplatform (ICCP NPs) that integrates SDT, cuproptosis induction, and near-infrared (NIR) fluorescence imaging for precise and visualized cancer theranostics. The nanoplatform utilizes CuS nanocarriers to co-encapsulate the sonosensitizer chlorin e6 (Ce6) and the near-infrared fluorescent dye IR808, with surface modification by DSPE-PEG₂₀₀₀ to improve stability and biocompatibility. Upon ultrasound activation, the sonosensitizer Ce6 generates abundant ROS, while Cu²⁺ released in the acidic tumor microenvironment further produces ROS via Fenton-like reactions, resulting in intracellular ROS level approximately 20-fold higher than that of the control. The abundant Cu²⁺ also induces aggregation of lipoylated proteins and depletion of iron-sulfur proteins, thereby triggering cuproptosis. The synergistic action of ROS and cuproptosis efficiently kill tumor cells and promote immunogenic cell death, leading to immune system activation. Specifically, ICCP NPs significantly enhance dendritic cell maturation (∼8-fold), increase CD4⁺ T cell infiltration (∼5.5-fold), and boost CD8⁺ T cell infiltration (∼6.5-fold), thereby reversing the immunosuppressive tumor microenvironment. Furthermore, the NIR fluorescence enables real-time tumor imaging, facilitating tumor localization, accumulation tracking, and therapeutic guidance. In conclusion, ICCP NPs offer a versatile and effective strategy for multimodal precision cancer therapy.