Biomimetic Cascade Nanozyme Catalytic System for the Treatment of Lymph Node Metastasis in Gastric Cancer

Abstract Lymphatic metastasis of gastric cancer is a challenging issue in clinical practice. Recently, copper single‐atom nanozymes (SAZ) have gained tremendous attention due to its superior peroxidase (POD) activity that has good nonocatalytic tumor therapy (NCT) capabilities, and photothermal properties. Therefore, using a high‐expressing P‐selectin platelet membrane (PM) to encapsulate SAZ and cisplatin is proposed, forming PSC nanoparticles. Due to their exquisite nanoscale size and the unique structure of lymphatic vessels, PSC can highly target cancer cells in invasive primary tumors and metastatic lymph nodes that both highly express CD44. It is noteworthy that cisplatin can simultaneously perform chemotherapy and generate H₂O₂ under the action of NADPH oxidases (NOXs) that further enhance the catalytic activity of SAZ and increase intracellular reactive oxygen species (ROS) production. Both in vitro and vivo experiments have demonstrated the superior targeting and elimination capability of the PCS system in primary and metastatic tumor cells. In addition, transcriptomic analysis reveals that PSC + NIR induced apoptosis in MFC cells. This marks the first proposal of combining single‐atom nanozymes and chemotherapy drugs for dual‐targeting in gastric cancer and lymphatic metastasis, providing new insights into a challenging clinical issue in the treatment of gastric cancer lymphatic metastasis.