A Golgi-Targeted Cu-MOF Nanoplatform Overcomes ATP7B-Mediated Copper Efflux to Amplify Chemo–Cuproptosis Synergy against Colorectal Cancer

Abstract Colorectal cancer (CRC) remains difficult to treat because of tumor heterogeneity and an immunosuppressive microenvironment. Although combining chemotherapy with cuproptosis offers complementary antitumor effects, its efficacy is constrained by poor tumor-selective delivery and ATP7B-associated copper efflux. We developed YC@BS-MOF, a yuanhuacine (YC)-loaded copper metal–organic framework (MOF) with Golgi-targeting capability, to integrate chemotherapy, photodynamic therapy, and cuproptosis. Composed of Cu2+ nodes and Golgi-targeting BS-TCPP photosensitizing ligands, BS-MOF acted as a copper reservoir and, upon light irradiation, induced Golgi disruption that impaired ATP7B-associated Cu handling and promoted intracellular copper retention. Copper retention amplified YC-mediated apoptosis and copper-dependent oxidative stress, leading to enhanced cuproptosis, immunogenic cell death, and activation of the immune microenvironment. Biodistribution analyses showed increased YC tumor accumulation, and in vivo studies demonstrated potent tumor suppression, immune remodeling, and favorable biosafety. This work establishes Golgi-directed regulation of copper trafficking as a subcellular strategy to potentiate chemo–cuproptosis for CRC treatment.