Tumor lysate-cloaked CuMOF-sorafenib nanoassembler: A synergistic cuproptosis-ferroptosis nanoweapon against tumors

Clinical tumor management is hindered by insufficient therapeutic efficacy and systemic side effects. Ferroptosis and cuproptosis, emerging metal ion-disruption-driven regulated cell death pathways, hold significant therapeutic potential. However, their combined efficacy is constrained by the tumor microenvironment (TME), where elevated levels of glutathione (GSH) and glutathione peroxidase 4 (GPX4) effectively mitigate reactive oxygen species (ROS) and lipid peroxidation. To overcome these barriers, we developed a biomimetic Cu-MOF-sorafenib nanoassembler (CMSP) for synergistic cuproptosis-ferroptosis-based anticancer therapy. CMSP comprises sorafenib (SOF)-loaded Cu-MOFs coated with tumor cell lysate-derived proteins. It exerts robust antitumor effects through three interconnected mechanisms: i) The tumor lysate coating facilitates homotypic targeting and immune evasion, thereby enhancing tumor-specific accumulation; ii) The acidic TME triggers the release of copper ions, which amplify ROS generation <i>via</i> Fenton-like reactions, while SOF inhibits System Xc^-, thereby depleting GSH and downregulating GPX4 expression; iii) Copper ions induce the aggregation of lipoylated proteins, initiating cuproptosis, while SOF synergistically promotes lipid peroxidation, driving ferroptosis. Both <i>in vitro</i> and <i>in vivo</i> studies demonstrate the efficient tumor accumulation, growth suppression, and metastasis inhibition of CMSP. By integrating biomimetic targeting, oxidative stress amplification, and dual-pathway synergy, CMSP presents a promising strategy to advance the development of personalized antitumor nanomedicines.