Ru‐Ph Nanozyme‐Based Hydrogels for Tumor Chemodynamic Therapy by Enhancing Enzyme Catalytic Efficiency Through Multiple Pathways

Abstract The discovery of nanozymes has opened new possibilities for tumor therapy. However, their reliance on the tumor microenvironment and limited catalytic efficiency hinder broader applications. In this study, ruthenium‐phenanthroline nanoparticles (Ru‐Phs) are synthesized by combining ruthenium with phenanthroline and subsequently coloaded with the proton pump inhibitor (PPI) pantoprazole into sodium alginate (ALG) to form a Ru‐Phs‐PPI‐ALG hydrogel for in situ tumor therapy. This hydrogel demonstrates excellent chemodynamic properties, forming a gel within tumor tissues and gradually releasing Ru‐Phs, which generates highly toxic reactive oxygen species (ROS) via peroxidase‐like (POD‐like) activity. The inclusion of PPI reduced the intracellular pH of tumor cells, accelerating the Fenton reaction and ROS accumulation. Additionally, the high photothermal conversion efficiency of Ru‐Phs‐PPI‐ALG enables heat generation under near‐infrared (NIR) irradiation, which not only disrupts tumor cell structures but also further enhances the POD‐like catalytic activity of Ru‐Phs. The hydrogel effectively killed 4T1 cells in vitro, and transcriptomic analysis confirms its potent chemodynamic efficacy. In vivo experiments demonstrate significant tumor ablation and excellent biocompatibility. This multipathway strategy to increase enzyme activity and improve chemodynamic effects provides a promising approach for advancing nanozyme applications in tumor therapy.