A cascaded amplification carrier-free nanoplatform for synergistic photothermal/ferroptosis therapy via dual antioxidant pathway disruption in cervical cancer

Abstract

Cellular defense mechanisms against ferroptosis are primarily mediated by antiferroptotic regulators, particularly glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Notably, singlet oxygen (1O2) generated through photoactivation of organic small-molecule photosensitizers (PSs) has been demonstrated to deplete both glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH). This dual depletion mechanism effectively disrupts the GSH/GPX4 redox axis and the NADPH/FSP1/ubiquinone (CoQ) antioxidant system, thereby potentiating ferroptosis. In this study, we engineered a tumor-targeting amphiphilic iridium-based photosensitizer nanoplatform (Ir-TCF3P-FA NPs) for synergistic photothermal-ferroptosis therapy. Specifically, GSH depletion and NADPH oxidation by 1O2 produced via Ir-TCF3P-FA NPs at 450 nm can suppress the expression of GPX4 and FSP1, amplifying ferroptosis. Additionally, TCF3P exhibited high photothermal conversion efficiency at 808 nm, which not only can enhance photothermal therapy (PTT) efficacy but also facilitated 1O2 generation. The Ir-TCF3P-FA NPs enable effective tumor-targeted delivery and fluorescence/photoacoustic imaging for in vivo distribution tracking. In vivo studies revealed that dual-laser irradiation of Ir-TCF3P-FA NPs provided potent therapeutic efficacy, significantly inhibiting human cervical cancer progression in murine models. This cascaded amplification carrier-free nanoplatform holds promise for clinical multimodal treatment of cervical cancer.