Engineered nanoplatform mediated gas therapy enhanced ferroptosis for tumor therapy in vivo
Kun Xu, Ke Li, Ye He, Yulan Mao, Xuan Li, Liangshuai Zhang, Meijun Tan, Yulu Yang, Zhong Luo, Peng Liu, Kaiyong Cai
Abstract
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 H 2 O 2 in tumor cells. Meanwhile, L-Arg generates NO gas in the presence of intracellular H 2 O 2 , 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 H 2 O 2 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 in vitro . Furthermore, this nanoplatform significantly inhibited tumor cell growth and extended the survival time of tumor-bearing mice in vivo . 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. • The nanoplatform uses Fe to deplete GSH for activating ferroptosis, and produces NO to enhance GSH depletion and ferroptosis. • Erastin increases H2O2 levels and reduces cysteine uptake, accelerating GSH depletion and ferroptosis. • The nanoplatform depletes intracellular GSH through multiple pathways to activate ferroptosis.