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 Ce³⁺/Ce⁴⁺ 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.