Photosensitizing Lipid Nanoparticles for Ferroptosis‐Enhanced Photodynamic Cancer Therapy via GPX4 Silencing

Ferroptosis, a regulated form of non-apoptotic cell death driven by iron-dependent lipid peroxidation, has emerged as a promising approach for overcoming therapy-resistant cancers. A multifunctional lipid nanoparticle (LNP) platform was developed to integrate ferroptosis induction with photodynamic therapy (PDT) for synergistic anticancer effects. By partially substituting cholesterol in conventional DLin-MC3-DMA (MC3)-based LNPs with cholesterol-polyethylene glycol (PEG)-pheophorbide a (CPP), we engineered photosensitizing lipid nanoparticles (PLNPs) capable of delivering glutathione peroxidase 4 (GPX4)-targeting small interfering RNA (siRNA). Upon laser irradiation, the PLNPs generate reactive oxygen species (ROS) through PDT, while siRNA-mediated GPX4 silencing promotes ferroptosis by disrupting cellular antioxidant defenses. The PLNPs demonstrate favorable physicochemical characteristics, efficient gene silencing, and potent ROS production. In vitro experiments in 4T1 and EO771 breast cancer cells reveal enhanced cytotoxicity under combined treatment, underscoring the synergistic interaction between PDT-induced oxidative stress and ferroptotic cell death. In vivo, the PLNPs exhibit prolonged tumor retention, effective GPX4 knockdown, and significant tumor growth inhibition, with minimal systemic toxicity. Overall, this work introduces a dual-function nanoplatform that potentiates photodynamic cancer therapy through ferroptosis induction and offers a versatile strategy for developing next-generation combination treatments targeting aggressive tumors.