Photo‐Activated Oxidative Stress Amplifier: A Strategy for Targeting Glutathione Metabolism and Enhancing ROS‐Mediated Therapy in Triple‐Negative Breast Cancer Treatment

Abstract Amplifying oxidative stress within tumor cells can effectively inhibit the growth and metastasis of triple‐negative breast cancer (TNBC). Therefore, the development of innovative nanomedicines that can effectively disrupt the redox balance represents a promising yet challenging therapeutic strategy for TNBC. In this study, an oxidative stress amplifier, denoted as PBCH, comprising PdAg mesoporous nanozyme and a CaP mineralized layer, loaded with GSH inhibitor L‐buthionine sulfoximine (BSO), and further surface‐modified with hyaluronic acid that can target CD44, is introduced. In the acidic tumor microenvironment, Ca 2+ is initially released, thereby leading to mitochondrial dysfunction and eventually triggering apoptosis. Additionally, BSO suppresses the synthesis of intracellular reduced GSH and further amplifies the level of oxidative stress in cancer cells. Furthermore, PdAg nanozyme can be activated by near‐infrared light to induce photothermal and photodynamic effects, causing a burst of ROS and simultaneously promoting cell apoptosis via provoking immunogenic cell death. The high‐performance therapeutic effects of PBCH, based on the synergistic effect of aforementioned multiple oxidative damage and photothermal ablation, are validated in TNBC cells and animal models, declaring its potential as a safe and effective anti‐tumor agent. The proposed approach offers new perspectives for precise and efficient treatment of TNBC.