Bioinspired catalytic nanogel as an inflammatory cascade-targeted therapeutic for rheumatoid arthritis.

The inflammatory cascade is a key driver of chronic inflammation in rheumatoid arthritis (RA) and facilitates the migration of circulating immune cells into the inflamed joints. Recent studies have unveiled the complexity of this cascade, which involves intricate interactions between immune cells, neutrophil extracellular traps (NETs), reactive oxygen species (ROS), and inflammatory cytokines. Given the central role of the inflammatory cascade in RA pathogenesis, targeting it represents a highly promising therapeutic strategy. However, research specifically focused on modulating the inflammatory cascade remains limited. In this study, we introduce a novel bioinspired catalytic nanogel designed to target the inflammatory cascade for the immunotherapy of RA. Nanogel coated with cationic polymer enables the targeted penetration into cartilage as well as the capture of NETs via charge-trapping effects. The captured NETs are further degraded by DNase I-conjugating nanogel. To fundamentally reduce ROS that can induce NETs generation, nanogels exhibit intrinsic catalase, superoxide dismutase, and hydroxyl radical activities, effectively inhibiting oxidative stress responses. Of note, the enhanced therapeutic effects are observed in mouse RA model including targeted and long-term accumulation of cascade nanogel in the inflamed joints, efficient NETs scavenging, alleviated intra-articular inflammation, and reduced bone destruction. Also, transcriptome analysis indicates that nanogel treatment markedly downregulates NETs formation signaling pathway, upregulates anti-inflammatory pathways and finally reduces neutrophil infiltration-caused autoimmune damage. These results make the bioinspired catalytic nanogel system an ideal inflammatory cascades-targeting therapy for the systemic autoimmune disease.