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

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.