ROS-scavenging hydrogen nanotherapy simultaneously targets inflammation and pain in rheumatoid arthritis

Relieving pain while treating rheumatoid arthritis (RA) is a pressing clinical need to improve satisfaction of patients, which has not received the due attention and solution. Herein, we propose a strategy to kill two birds with one stone, for which we emphasize synergetic therapeutic outcome of analgesia and inhibiting RA progression through introducing hydrogen nanogenerator to scavenge reactive oxygen species (ROS) at lesion locations. This system exhibited efficient ROS scavenging and reducing apoptosis of C17.2 cells. In a complete Freund's Adjuvant-induced RA mouse model, this controlled hydrogen release behavior significantly downregulated pro-inflammatory mediators, protecting chondrocytes from apoptosis and preventing cartilage degradation. Furthermore, hydrogen therapy could effectively restrain the release of inflammatory factors and central sensitization by alleviating mitochondrial dysfunction in peripheral neurons and inhibit NF-κB pathway. Targeting ROS, this approach represents a significant advancement in RA management, offering superior efficacy against nociplastic pain compared to conventional analgesic therapies, providing a novel treatment mode of synergistic anti-inflammatory therapy and pain management. © 2025 The Authors.