Multimetal‐Doped Nanoenzymes Reprogram Macrophages for Immunotherapy of Gouty Arthritis

The deposition of monosodium urate crystals triggers joint inflammation, which serves as a critical factor in gouty arthritis development. However, current monotherapy is unable to simultaneously reduce uric acid and suppress inflammation. We identified through bioinformatics and clinical sample analysis that oxidative stress-related indicators were significantly elevated in patients with gouty arthritis. In light of this clinical finding, we developed a polydopamine-based nanozyme with high superoxide dismutase and catalase activities via bimetallic ion coordination, which was subsequently loaded with uricase, rapamycin, and hyaluronic acid. In the gouty arthritis model, hyaluronic acid could target the CD44 receptor on the surface of macrophages, enhancing nanoprobe accumulation at the joint. The nanoprobe exhibited excellent biocompatibility and eliminated significantly monosodium urate crystals through multienzyme cascade reactions, while simultaneously addressing the accumulation of byproducts such as hydrogen peroxide, thereby markedly alleviating joint swelling and pain. In addition, the levels of Interleukin-1 beta and Interleukin-6 were significantly reduced, and the NF-κB signaling pathway was effectively suppressed. The phenotypic of macrophages was transformed from pro-inflammatory M1 to anti-inflammatory M2 phenotype. Meanwhile, rapamycin effectively suppressed the immunogenicity of uricase and enhanced its therapeutic efficacy in vivo.