Small (Weinheim an der Bergstrasse, Germany)Jul 30, 2026

Lipid nanoparticles that restore iron supply and use RNA interference to trigger iron-dependent cell death for cancer treatment

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 3, 2026

Abstract

ALSF, a novel lipid nanoparticle, enabled effective co-delivery of GPX4-siRNA and Fe³⁺ for cancer treatment.

The lipid nanoparticle replaces DSPC with arachidonic acid to facilitate simultaneous delivery.
ALSF promotes acid- and H₂O₂-dependent iron recycling to generate Fe²⁺, enhancing reactive oxygen species production.
Silencing of GPX4 by siRNA leads to increased lipid peroxidation and induction of ferroptosis.
Elevated H₂O₂ levels in cancer cells enhance iron recycling and aid in siRNA escape from lysosomes.
In vivo experiments showed that ALSF suppressed tumor growth in a C918 xenograft model while demonstrating favorable biosafety.

Simplified

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.

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Lipid nanoparticles that restore iron supply and use RNA interference to trigger iron-dependent cell death for cancer treatment

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