Nitric oxide dual-enhanced nanosystem boosts ferroptosis-chemotherapy synergy for tumor therapy

Compared with apoptosis, ferroptosis has attracted extensive interest owing to its highly efficient anti-tumor activity. However, ferroptosis is strictly dependent on the accumulation of lipid peroxides (LPOs), which requires the excessive production of reactive oxygen species (ROS) and downregulation of glutathione (GSH) levels in tumor cells. Therefore, enhancing intracellular lipid peroxidation represents a promising strategy to potentiate ferroptosis against tumors. Herein, we report a nitric oxide (NO)-releasing nanodevice with dual functions to synergistically induce ferroptosis and apoptosis for tumor elimination. Mesoporous Fe₃O₄ nanoparticles were modified with arginine (Arg), a natural amino acid that not only facilitates tumor-targeted homing of the nanosystem but also serves as an endogenous NO donor. Notably, NO can simultaneously enhance both apoptosis and ferroptosis through distinct molecular mechanisms. The doxorubicin (DOX)-loaded Arg-modified mesoporous Fe₃O₄ nanosystem (Arg-AFe₃O₄@DOX) was systematically evaluated, and results demonstrated that it efficiently induced apoptosis and ferroptosis in tumor cells. In vivo studies further confirmed that Arg-AFe₃O₄@DOX administration significantly improved anti-tumor efficacy compared with monotherapy, with no obvious systemic toxicity observed.