Neutrophil‐Mimetic, ROS Responsive, and Oxygen Generating Nanovesicles for Targeted Interventions of Refractory Rheumatoid Arthritis

Abstract Rheumatoid arthritis (RA) is the most prevalent inflammatory joint disease worldwide, leading to irreversible disability and even mortality. Unfortunately, current treatment regimens fail to cure RA due to low therapeutic responses and off‐target side effects. Herein, a neutrophil membrane‐cloaked, natural anti‐arthritic agent leonurine (Leo), and catalase (CAT) co‐loaded nanoliposomal system (Leo@CAT@NM‐Lipo) is constructed to remodel the hostile microenvironment for RA remission. Due to the inflammation tropism inherited from neutrophils, Leo@CAT@NM‐Lipo can target and accumulate in the inflamed joint cavity where high‐level ROS can be catalyzed into oxygen by CAT to simultaneously accelerate the drug release and alleviate hypoxia at the lesion site. Besides, the neutrophil membrane camouflaging also enhances the anti‐inflammatory potentials of Leo@CAT@NM‐Lipo by robustly absorbing pro‐arthritogenic cytokines and chemokines. Consequently, Leo@CAT@NM‐Lipo successfully alleviated paw swelling, reduced arthritis score, mitigated bone and cartilage damage, and reversed multiple organ dysfunctions in adjuvant‐induced arthritis rats (AIA) rats by synergistic effects of macrophage polarization, inflammation resolution, ROS scavenging, and hypoxia relief. Furthermore, Leo@CAT@NM‐Lipo manifested excellent biocompatibility both at the cellular and animal levels. Taken together, the study provided a neutrophil‐mimetic and ROS responsive nanoplatform for targeted RA therapy and represented a promising paradigm for the treatment of a variety of inflammation‐dominated diseases.