A Cyclodiaryliodonium NOX Inhibitor for the Treatment of Pancreatic Cancer via Enzyme‐Activatable Targeted Delivery by Sulfated Glycosaminoglycan Derivatives

Abstract Pancreatic cancer renders a principal cause of cancer mortalities with a dismal prognosis, lacking sufficiently safe and effective therapeutics. Here, diversified cyclodiaryliodonium (CDAI) NADPH oxidase (NOX) inhibitors are rationally designed with tens of nanomolar optimal growth inhibition, and CD44‐targeted delivery is implemented using synthesized sulfated glycosaminoglycan derivatives. The self‐assembled nanoparticle‐drug conjugate (NDC) enables hyaluronidase‐activatable controlled release and facilitates cellular trafficking. NOX inhibition reprograms the metabolic phenotype by simultaneously impairing mitochondrial respiration and glycolysis. Moreover, the NDC selectively diminishes non‐mitochondrial reactive oxygen species (ROS) but significantly elevates cytotoxic ROS through mitochondrial membrane depolarization. Transcriptomic profiling reveals perturbed p53, NF‐ κ B, and GnRH signaling pathways interconnected with NOX inhibition. After being validated in patient‐derived pancreatic cancer cells, the anticancer efficacy is further verified in xenograft mice bearing heterotopic and orthotopic pancreatic tumors, with extended survival and ameliorated systemic toxicity. It is envisaged that the translation of cyclodiaryliodonium inhibitors with an optimized molecular design can be expedited by enzyme‐activatable targeted delivery with improved pharmacokinetic profiles and preserved efficacy.