Multifunctional Biomimetic Hollow Nanoparticles with Inhibiting Thioredoxin Reductase Activity for Cancer Therapy

Cell redox homeostasis plays an important role in mediating cellular reactions and regulating biological responses. Up to now, numerous methods based on disrupting cellular redox homeostasis have been developed for cancer therapy, but the treatment efficacy remains a challenges. Thioredoxin reductase (TrxR) is highly overexpressed in cancer cells, promoting malignant tumor survival. Inhibiting TrxR activity presents a promising approach to perturbing cellular redox homeostasis for cancer chemotherapy. Herein, we reported a novel strategy utilizing multifunctional biomimetic hollow nanoparticles (IrSe2) that effectively inhibit TrxR activity, exhibit high reactive oxygen species (ROS) generation capacity, and catalyze a cascade of intracellular biochemical reactions for the treatment of breast cancer. In this system, IrSe2 nanoparticles could inhibit TrxR activity and deplete glutathione (GSH), thereby disrupting the antioxidant defense system and further improving intracellular ROS levels. Furthermore, IrSe2 nanoparticles are simultaneously featured with peroxidase- and oxidase-like activities, generating increased ROS. Both in vitro and in vivo experimental results reveal that the anticancer activity of IrSe2 is mediated by its nanozyme activity and inhibition of both TrxR and GSH activity, leading to apoptosis. This work not only paves a new way for designing high-performance nanozymes and nanocatalysts for practical applications but also underscores the potential of combining TrxR and GSH inhibition to disrupt cellular redox homeostasis and enhance ROS release as a promising strategy for breast cancer therapy.