Acid-activated mitochondria-targeting nanoprodrug for reactive oxygen species (ROS)-tolerant cancer therapy via antioxidant defense inhibition

The intracellular balance of reactive oxygen species (ROS) is crucial for cancer cell survival and tumor development, with mitochondria playing a key role in maintaining this balance through antioxidant defenses. Despite the efficacy of ROS-modulating strategies in many tumors, certain ROS-tolerant malignancies, such as HepG2 cells, pose significant therapeutic challenges due to their robust antioxidant systems and unique redox microenvironments. In this work, we have developed a self-amplifying nanoprodrug (nCACT) designed to target ROS-tolerant tumor cells. nCACT is constructed from a prodrug conjugate that combines a glutathione (GSH)-depleting chemotherapeutic agent, a mitochondria-targeting moiety, and a ROS-stimulated amplifying linker. The nCACT leverages the enhanced permeability and retention effect for tumor accumulation and cellular uptake, followed by acid-activated drug release and mitochondrial targeting. By disrupting ROS defense mechanisms and inducing mitochondrial dysfunction, nCACT effectively elevates ROS levels and depletes GSH, suppressing cancer cell growth. Our findings demonstrate that nCACT represents a novel and powerful strategy for overcoming ROS resistance in cancer therapy, offering a promising avenue for treating ROS-tolerant malignancies.