Chiral Ruthenium Nanozymes with Self‐Cascade Reaction Driven the NO Generation Induced Macrophage M1 Polarization Realizing the Lung Cancer “Cocktail Therapy”

Abstract Macrophages as the main cause of cancer immunosuppression, how to effectively induce macrophage M1 polarization remain the major challenge in lung cancer therapy. Herein, inspired by endogenous reactions, a strategy is proposed to coactivate macrophage M1 polarization by reactive oxygen species (ROS) and nitric oxide (NO) with self‐autocatalytic cascade reaction. To enhance the generation of NO and ROS, NO Precursor‐Arginine as capping agents for inducing synthesis two kinds of chiral ruthenium nanozyme (D/L‐Arginine@Ru). Under the properties of Ru nanozymes through synchronously mimicking the activity of oxidase and nitric oxide synthase (NOS), chiral Ru nanozyme can rapidly generate 1 O 2 and O 2 at first stage, and then catalyze Arginine to produce sufficient NO, thus enhance macrophage M1 polarization to reverse tumor immunosuppression. Moreover, combination the antitumor activity of 1 O 2 , NO, the chiral Ru nanozymes realize the “cocktail therapy” by inducing tumor cell apoptosis as well as ferroptosis. In addition, the chirality influences the bioactivity of Ru nanozymes that L‐Arginine@Ru shows the better therapeutic effect with stronger catalytic activity and natural homology. It is hoped the high performance of chiral Ru nanozyme with “cocktail therapy” is an effective therapeutic reagent and can provide a feasible treatment strategy for tumor catalytic therapy.