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 Fe3 +. ALSF facilitates acid- and H2O2-dependent iron recycling, continuously regenerating Fe2 + 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.