Structure-Tailoring Cerium Nanozymes with Self-Cascade ROS Scavenging Catalysis Modulate the Microbiota-Gut-Joint Axis for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is closely associated with intestinal microbiota dysbiosis, highlighting the therapeutic potential of targeting the microbiota-gut-joint axis. Current interventions often overlook the cascade nature of reactive oxygen species (ROS) generation in driving intestinal and systemic inflammation. Herein, a valence-engineered CeO(X)-based nanozyme with self-cascade catalytic activity is developed, mimicking sequential oxidase-superoxide dismutase-peroxidase functions to enable continuous ROS scavenging while minimizing oxygen generation. By precisely tuning Ce(3+)/Ce(4+) ratios from 0.27 to 0.93 through Au deposition (0.23 wt.%→5.2 wt.%), Dual functionality is achieved: 1) enhanced oxygen vacancy generation (71.4%) for efficient ROS scavenging via superoxide anion→hydrogen peroxide→hydroxide ion conversion, and 2) suppressed oxygen production to maintain the anaerobic microenvironment essential for gut microbiota. Encapsulating the nanozyme with sodium alginate (SA) to form Au/CeO(X)(0.93)@SA ensures resistance to gastric acid upon oral administration. In RA model rats, this strategy restored gut microbial balance, normalized short-chain fatty acid profiles, and significantly attenuated joint inflammation and cartilage degradation. The therapeutic efficacy is further evidenced by reduced systemic pro-inflammatory cytokine levels and improved intestinal barrier integrity. This study established a design paradigm for gut microenvironment-adapted nanozymes, offering a dual-action strategy for early RA intervention through synchronized ROS elimination and microbiota homeostasis restoration.