Bin Yang ^1,2,3 Guihu Luo ³ Tailei Nie ⁴ Zhenglan Ban ⁵ Quanxin Ning ⁵ Jialin Zhang ³ Xiangru Liu ⁶ Yanhua Lin ³ Xiaochun Xie ⁷ Qianyun Chen ³ Han Zhong ³ Ying Huang ³ Pan Liao ⁸ Yan Liu ⁵ Chenyang Guo ⁵ Chuanxu Cheng ^5,9* Er Wei Sun ^1,2,3*

• ¹ Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
• ² Institute of Clinical Immunology, Academy of Orthopedics, Guangzhou, China
• ³ Department of Rheumatology and Immunology, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan, China
• ⁴ Department of Pharmacy, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
• ⁵ National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, China
• ⁶ Xingtan Hospital Affiliated of Southern Medical University Shunde Hospital, Foshan, China
• ⁷ School of Medicine, South China University of Technology, Guangzhou, China
• ⁸ Department of Rheumatology and Immunology, Hunan University of Medicine General Hospital, HuaiHua, China
• ⁹ Columbia University, New York City, United States

Uricase replacement therapy is a powerful approach for managing hyperuricemia and/or gout. However, it presents significant challenges due to short blood circulation time, reduced catalytic activity, and excessive hydrogen peroxide (H₂O₂) production. To address these issues, we developed RBC@SeMSN@Uri, a red blood cell-coated biomimetic self-cascade bioreactor that combines uricase with a selenium-based nano-scavenger (SeMSN) to effectively degrade both uric acid (UA) and hydrogen peroxide (H₂O₂).The biomimetic bioreactor (RBC@SeMSN@Uri) with enhanced enzyme stability and reduced immunogenicity contained two different compartments that effectively degrades uric acid to allantoin while converts H₂O₂ into water, thus preventing oxidative damage and inflammation. As a consequence, RBC@SeMSN@Uri exhibited superior uric acid degradation and reduced H₂O₂-induced inflammatory responses compared to free uricase in vitro. It demonstrated prolonged circulation and significant therapeutic effects in acute and chronic hyperuricemia models, markedly lowering uric acid levels and mitigating kidney damage. Importantly, it effectively targeted inflamed joints and ameliorated joint swelling and inflammation in gouty arthritis models. Overall, the RBC-coated biomimetic self-cascade bioreactor for UA and H₂O₂ degradation presents a promising approach for safe and effective enzyme replacement therapy in the treatment of hyperuricemia and gout.