Copper–verteporfin coordination nanoparticles to reverse ferroptosis resistance in pancreatic cancer therapy

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has attracted attention for cancer treatment. However, ferroptosis resistance in pancreatic cancer, mediated by the hyperactivated system Xc^-/SLC7A11/GSH/GPX4 axis and YAP-driven SLC7A11 overexpression, remains a major therapeutic challenge. To overcome this, we screened various metalloporphyrins and identified Cu-based verteporfin as an effective YAP inhibitor, so that a tumor-targeted nanosystem termed CuVP-F127-IKE-Mem is developed, which integrates the YAP inhibitor copper-verteporfin metalloporphyrin and the ferroptosis inducer imidazole ketone erastin (IKE) into cancer cell membrane-coated nanoparticles. This system exhibits pH-responsive dissociation in the acidic tumor microenvironment, leading to YAP activity suppression and SLC7A11 transcription downregulation by the released verteporfin to block antioxidant synthesis, while IKE concurrently inhibits SLC7A11 function. This dual action synergistically disrupts redox homeostasis by crippling the system Xc^-/SLC7A11/GSH/GPX4 defense axis. In pancreatic cancer, CuVP-F127-IKE-Mem significantly enhances ferroptosis sensitivity, suppresses YAP/SLC7A11 signaling, and exhibits potent tumor growth inhibition in vivo. This YAP-targeted transcriptional regulation strategy establishes a new paradigm for overcoming ferroptosis resistance.