A copper missile triggered power coalescence and death vortex within tumor cell mitochondria for synergistic cuproptosis/phototherapy/chemotherapy

The importance of copper homeostasis in mitochondria and copper-triggered modality of mitochondrial cell death have been confirmed. However, the existing copper-based nanoplatforms are focused on synergistic therapies while the intracellular therapeutic targets are relatively scattered. Effective integration of all targets within mitochondria to generate power coalescence remains a challenge. Herein, we developed a novel copper-based delivery system to trigger power coalescence and death vortex within tumor cell mitochondria. Specifically, a mitochondrial targeting "copper missile" loaded with curcumin (termed as Cur@CuS-TPP-HA, CCTH) was designed for cuproptosis/phototherapy/chemotherapy synergistic anti-tumor therapy. Once the CCTH NPs are shuttled to the mitochondria, near-infrared (NIR) irradiation initiates the release of copper ions and curcumin for