Copper-Based Targeted Nanocatalytic Therapeutics for Non-Small Cell Lung Cancer

Abstract Conventional treatments for non-small cell lung cancer (NSCLC) suffer from low remission rates, high drug resistance, and severe adverse effects. To leverage the therapeutic potential of reactive oxygen species (ROS), nanocatalytic medicine utilizes nanomaterials to generate ROS specifically within tumor sites, enabling efficient and targeted cancer treatment. In this study, hyaluronic acid (HA)-modified copper-N,N-dimethyl-N-phenylsulfonylbisamine (DMSA)-assembled nanoparticles (Cu-DMSA-HA NPs) are developed with tumor-targeting capability and efficiently catalyze ROS production via coordination chemistry. Targeted delivery is facilitated by HA surface modification through recognition of overexpressed cluster of differentiation 44 receptors on cancer cells, which enhances nanoparticle uptake. Once internalized, intracellular glutathione is depleted by the NPs, followed by a Fenton-like reaction that sustains ROS production. Both in vitro and in vivo studies demonstrate that this catalytic strategy effectively inhibits DNA replication, prevents cell cycle progression, downregulates glutathione peroxidase 4 expression, induces ferroptosis, and ultimately suppresses NSCLC progression. Overall, the readily prepared Cu-DMSA-HA NPs exhibit robust catalytic activity and tumor specificity, highlighting their strong potential for clinical translation in nanocatalytic cancer therapy.