Activatable Plasmonic Versatile Nanoplatform for Glutathione-Depletion Augmented Ferroptosis and NIR-II Photothermal Synergistic Therapy

Ferroptosis-based therapy exhibits promising prospects for the treatment of malignant tumors. However, the practical therapeutic benefits of ferroptosis-based antitumor therapy are usually restricted by excess endogenous antioxidants and relatively sluggish ROS production kinetics. Here, an activatable plasmonic versatile nanoplatform (AuSi@FePB) with glutathione (GSH)-depletion capacity is reported for synergistic ferroptosis therapy and second near-infrared window photothermal therapy (NIR-II PTT). The nanoplatform exhibits stability in physiological conditions, but in the tumor microenvironment, its Fe-PDA shell gradually disintegrates to increase intracellular ferrous supply for elevated ROS generation and GSH-depletion in response to overexpressed GSH, leading to amplified ferroptosis of tumor cells. The integration of NIR-II laser irradiation facilitates the generation of localized heat, which not only effectively triggers photothermal therapy but also significantly enhances the Fenton reaction, thereby promoting ferroptotic cell death in tumor cells. While the oxidative damage can also downregulate the heat repair effect, thereby facilitating the PTT efficacy. More importantly, such synergism not only results in the elimination of the primary tumor but also triggers a systemic antitumor immune response, facilitating the regression of nontreated distant tumors and impeding the occurrence of lung metastasis. The in vivo therapeutic mechanism was further verified by transcriptome sequencing, demonstrating that synergistic GSH-depletion augmented ferroptosis therapy and NIR-II PTT are an effective combination antitumor strategy. This study presents a promising perspective for cancer treatment based on ferroptosis and also sheds new light on novel therapeutic platforms for future cancer therapy.