Tumor Microenvironment-Modulated Nanozymes for NIR-II-Triggered Hyperthermia-Enhanced Photo-Nanocatalytic Therapy via Disrupting ROS Homeostasis

Purpose: Reactive oxygen species (ROS) are a group of signaling biomolecules that play important roles in the cell cycle. When intracellular ROS homeostasis is disrupted, it can induce cellular necrosis and apoptosis. It is desirable to effectively cascade-amplifying ROS generation and weaken antioxidant defense for disrupting ROS homeostasis in tumor micro environment (TME), which has been recognized as a novel and ideal antitumor strategy. Multifunctional nanozymes are highly promising agents for ROS-mediated therapy. Methods: This study constructed a novel theranostic nanoagent based on PEG@Cu2-xS@Ce6 nanozymes (PCCNs) through a facile one-step hydrothermal method. We systematically investigated the photodynamic therapy (PDT)/photothermal therapy (PTT) properties, catalytic therapy (CTT) and glutathione (GSH) depletion activities of PCCNs, antitumor efficacy induced by PCCNs in vitro and in vivo. Results: PCCNs generate singlet oxygen (O-1(2)) with laser (660 nm) irradiation and use catalytic reactions to produce hydroxyl radical (center dot OH). Moreover, PCCNs show the high photothermal performance under NIR II 1064-nm laser irradiation, which can enhance CTT/PDT efficiencies to increase ROS generation. The properties of O-2 evolution and GSH consumption of PCCNs achieve hypoxia-relieved PDT and destroy cellular antioxidant defense system respectively. The excellent antitumor efficacy in 4T1 tumor-bearing mice of PCCNs is achieved through disrupting ROS homeostasis-involved therapy under the guidance of photothermal/photoacoustic imaging. Conclusion: Our study provides a proof of concept of all-in-one nanozymes to eliminate tumors via disrupting ROS homeostasis.

Automated summary

Reactive oxygen species (ROS) play important roles in the cell cycle, and disrupting ROS homeostasis in the tumor microenvironment is recognized as an ideal antitumor strategy. The study developed a novel theranostic nanoagent based on PEG@Cu2-xS@Ce6 nanozymes (PCCNs) and demonstrated their effectiveness in generating ROS, inducing photodynamic therapy (PDT) and photothermal therapy (PTT), and depleting glutathione (GSH). The PCCNs showed promising antitumor efficacy in vitro and in vivo by disrupting ROS homeostasis and enhancing therapy under the guidance of photothermal/photoacoustic imaging.