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

【Abstract】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 via 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 in vitro and in vivo 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.

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