Homing Effect Directed Cuprous Delivery Activates Cuproptosis Against Nasopharyngeal Carcinoma and Metastasis

Abstract Cuproptosis, a newly discovered cell death mechanism driven by cuprous ions (Cu(I)), faces challenges in achieving efficient pathway activation due to limitations in tumor cell targeting and intracellular copper accumulation. To address these, a NIR‐triggered nanoplatform (Cu(I)‐TA@HG) is developed for precise Cu(I) delivery to metastatic nasopharyngeal carcinoma (NPC) cells, thereby inducing potent cuproptosis. Drawing inspiration from the critical role of membrane proteins in cancer metastasis, tumor‐homing nanovesicles derived from GAS6‐overexpressing cell membranes (HG‐CMs) are engineered. These membranes exhibit enhanced affinity for the AXL receptor, which is frequently overexpressed in metastatic NPC. The HG‐CMs encapsulated cuprous‐loaded nanoparticles (Cu(I)‐TA), facilitating specific recognition via the GAS6‐AXL axis and promoting highly targeted NPC delivery while minimizing off‐target effects. Upon reaching the tumor, the Cu(I)‐TA@HG can effectively trigger cuproptosis through the synergistic effect originating from the GAS6‐AXL axis‐directed cell targeting and TA‐interfering copper ion excretion. Crucially, in vivo experiments demonstrate that this nanoplatform not only eradicates primary tumor sites but also effectively eliminates early metastatic lesions, leading to significant suppression of lung metastasis in an NPC model. This work establishes a strategic foundation for the rational design of nanotherapeutics that exploit cuproptosis for the treatment of aggressive and metastatic cancers.