Inducing ferroptosis and reversing immune evasion for the suppression of melanoma lung metastasis via neferine-loaded controlled-release system.

Although melanoma is sensitive to ferroptosis, the upregulation of programmed cell death ligand 1 (PD-L1) induced by ferroptosis contributes to immune evasion. This study demonstrates that Neferine (Nef) effectively inhibits PD-L1 expression in melanoma, reversing immune evasion induced by ferroptosis. Utilizing the coordination network between phenolic hydroxyl groups in Nef and iron within metal-organic frameworks (MOFs), we engineered a drug delivery system Nef@MOF, to achieve stable delivery and controlled release of Nef. In the acidic tumor microenvironment, the coordination network disassembles, enabling sustained release of Nef and Fe3+, providing stable energy for ferroptosis and suppressing PD-L1 upregulation, thus enhancing T cell-mediated tumor immune surveillance and killing. Furthermore, the homologous cell membrane was coated on the surface of Nef@MOF to construct a targeted controlled-release system Nef@MOF@C, and this system effectively inhibited the progression of both primary and lung metastatic melanoma in murine models. This controlled release strategy not only enhances the ferroptosis effect but also optimizes immune therapy, providing a promising method for developing targeted immunotherapeutic drugs for metastatic tumors.