A Photo‐Activated Thermoelectric Catalyst for Ferroptosis‐/Pyroptosis‐Boosted Tumor Nanotherapy

Abstract Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) has gradually come into the limelight for oncological treatment due to its noninvasiveness, high specificity, and low side effects. However, upregulated heat‐shock proteins (HSPs) and reactive oxygen species (ROS)‐defensing system such as glutathione (GSH) or MutT homolog 1 (MTH1) protein in tumor microenvironment counteract the efficiency of single‐modality therapy either PTT or PDT. Herein, the well‐defined bismuth telluride nanoplates (Bi₂Te₃ NPs) are engineered with a high‐performance photo‐thermo‐electro‐catalytic effect for tumor‐synergistic treatment. Upon near‐infrared light illumination, Bi₂Te₃ NPs induce a significant temperature elevation for PTT, which effectively inhibits MTH1 expression. Especially, heating and cooling alteration caused temperature variations result in electron–hole separation for ROS generation, which not only damages HSPs to reduce the thermotolerance for enhance PTT, but also arouses tumor cell pyroptosis. Additionally, Bi₂Te₃ NPs conspicuously reduce GSH, further improving ROS level and leading to decrease glutathione peroxidase 4 (GPX4) activity, which triggers tumor cell ferroptosis. Due to the photo‐thermo‐electro‐catalytic synergistic therapy, Bi₂Te₃ NPs are gifted with impressive tumor suppression on both ectopic and orthotopic ocular tumor models. This work highlights a high‐performance multifunctional energy‐conversion nanoplatform for reshaping tumor microenvironment to boost the tumor‐therapeutic efficacy of phototherapy.