Iron Single Atom Nanozyme-Mediated GPX4 Inhibitor Delivery for Self-Enhanced Ferroptosis

Abstract

Ferroptosis, an iron-dependent regulated cell death modality driven by lipid peroxidation (LPO) and mitochondrial dysfunction, represents a promising therapeutic target for tumors, given cancer cells’ elevated iron demand, reactive oxygen species (ROS) levels, and reliance on glutathione peroxidase 4 (GPX4) for redox homeostasis. While single-atom nanozymes (SANs) have emerged as potent catalytic tools for ROS-driven ferroptosis induction, their efficacy is hampered by the abundant glutathione and ROS-scavenging GPX4, which suppress sustained LPO accumulation. To address this bottleneck, we engineer a proof-of-concept Fe-based SAN (Fe-SAN) with well-defined Fe–N₄ active sites and further encapsulate the GPX4 inhibitor Fin56 to construct the Fe-SAN@F nanoplatform. Fe-SAN@F showed dual catalytic activities: robust peroxidase-like activity that converts endogenous hydrogen peroxide into cytotoxic ^•OH to trigger LPO and glutathione oxidase-like activity that depletes intracellular GSH to inactivate GPX4. Meanwhile, the loaded Fin56 exerts synergistic GPX4 inhibition, amplifying the ROS cascade. In vitro and in vivo assays confirm that Fe-SAN@F induces irreversible tumor ferroptosis via the combined effects of LPO accumulation, GSH depletion, and GPX4 inactivation, effectively suppressing tumor proliferation. This work establishes a novel SAN-based catalytic therapy paradigm for remodeling the TME and boosting ferroptosis, providing a rational design strategy for next-generation precision antitumor nanozymes.