A Ferrous-Supply-Regenerating Lipid Nanoparticle Integrating RNAi Induces Ferroptosis for Cancer Therapy

Targeting iron-dependent ferroptosis with siRNA has emerged as a promising strategy for cancer treatment. The concept of ferrous-supply regeneration, inspired by electro-Fenton technology, has also gained interest as a non-apoptotic approach to induce ferroptosis. However, integrating both strategies into a single lipid nanoparticle (LNP) remains challenging. To address this, we developed ALSF, a novel LNP in which DSPC is replaced with arachidonic acid (AA) to enable co-delivery of Glutathione Peroxidase 4-siRNA (GPX4-siRNA) and Fe^{3 +}. ALSF facilitates acid- and H₂O₂-dependent iron recycling, continuously regenerating Fe^{2 +} to drive ROS production, while GPX4-siRNA silences GPX4 to induce lipid peroxidation (LPO) and ferroptosis. Elevated H₂O₂ levels in cancer cells promote selective iron recycling, lysosomal disruption, and siRNA escape, enabling effective gene knockdown at lower doses. In vivo, ALSF suppressed tumor growth in a C918 xenograft model with favorable biosafety. This study is the first to integrate a ferrous-supply-regeneration system with siRNA into a single LNP platform, offering a selective ferroptosis-inducing strategy for ocular cancers and other ferroptosis-sensitive malignancies.