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 H 2 O 2 ‐dependent iron recycling, continuously regenerating Fe 2 + to drive ROS production, while GPX4‐siRNA silences GPX4 to induce lipid peroxidation (LPO) and ferroptosis. Elevated H 2 O 2 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.