Engineered nanoplatform mediated gas therapy enhanced ferroptosis for tumor therapy in vivo

The high glutathione (GSH) environment poses a significant challenge for inducing ferroptosis in tumor cells, necessitating the development of nanoplatforms that can deplete intracellular GSH. In this study, we developed an engineered nanoplatform (MIL-100@Era/L-Arg-HA) that enhances ferroptosis through gas therapy. First, we confirmed that the Fe element in the nanoplatform undergoes valence changes under the influence of high GSH and H₂O₂ in tumor cells. Meanwhile, L-Arg generates NO gas in the presence of intracellular H₂O₂, which reacts with GSH. Additionally, Erastin depletes GSH by inhibiting the cystine/glutamate antiporter system, reducing cystine uptake and impairing GPX4, while also increasing intracellular H₂O₂ levels by activating NOX4 protein expression. Through these combined GSH-depletion mechanisms, we demonstrated that MIL-100@Era/L-Arg-HA effectively depletes GSH levels, disrupts GPX4 function, and increases intracellular lipid ROS levels <i>in vitro</i>. Furthermore, this nanoplatform significantly inhibited tumor cell growth and extended the survival time of tumor-bearing mice <i>in vivo</i>. This engineered nanoplatform, which enhances ferroptosis through gas therapy, shows significant promise for ferroptosis-based cancer therapy and offers potential strategies for clinical tumor treatment.