Abstract

Background: Single-atom nanozymes (SAzymes) generally trigger catalytic reactions in situ within tumor cells, generating toxic reactive oxygen species (ROS) that induce cell death through oxidative stress, thereby achieving catalytic tumor therapy. However, therapeutic efficacy is often limited by insufficient ROS levels and intrinsic cellular antioxidant defenses. Results: This study developed a spherical mesoporous iron-based single-atom nanozyme (Fe-SAzyme) modified with polyethylene glycol (PEG) and (4-carboxybutyl)triphenylphosphonium bromide (TPP), achieving photothermal amplification of catalytic activities to deliver antitumor therapeutic effects. Fe-SAzyme exhibited triple enzyme-mimetic activities-peroxidase-like, glutathione peroxidase-like, and catalase-like activity. It simultaneously generated ROS and oxygen while oxidizing glutathione to oxidized glutathione. This elevation in ROS levels and weakening of antioxidant defenses disrupted intracellular redox homeostasis, ultimately triggering a process known as ferroptosis. Density functional theory (DFT) calculations revealed that Fe-SAzyme exhibited a low energy barrier for hydroxyl radical generation and possessed a viable cyclic catalytic pathway. Additionally, Fe-SAzyme-TPP exhibited exceptional photothermal conversion capabilities under second near-infrared (NIR-II) irradiation, enabling its use in photothermal therapy (PTT), while simultaneously enhancing catalytic activity and thereby significantly improving tumor treatment efficacy. In vitro and in vivo experiments demonstrated that PEG and TPP-modified Fe-SAzyme exhibited outstanding antitumor efficacy, along with enhanced biocompatibility and targeting capabilities. Under NIR-II irradiation, photothermal therapy synergized with catalytic activities, significantly amplifying tumor suppression effects. Conclusion: This study proposed a combined antitumor strategy based on iron-based SAzymes, utilizing photothermal amplification to enhance cataly