Keqian Du, Yiming Guo, Junjie Zhou, Yaping Liu, Lin Jiang, Dawei Hua, Di Zhang, Yuqi Zhang, Zijian Deng, Xingyu Zheng, Jianping Guo, Jing Ni, Yingjie Li, Shichao Sun, Zhiming Lin, Jianlin Huang, Lin-Ping Wu
Hyperuricemia and its complications, including gouty arthritis and hyperuricemic nephropathy, are driven by elevated serum urate levels and crystal deposition. While exogenous uricase offers therapeutic potential, its utility is limited by rapid clearance and immunogenicity. Here we show a malic acid-derived lipid nanoparticle platform with antioxidant and low-immunogenicity properties for delivering circular RNA encoding secretory uricase to treat hyperuricemia and its complications. Leveraging the safety and anti-inflammatory and antioxidant properties of malic acid, a combinatorial library of ionizable lipids is developed. After systematic screening and optimization, LMA2-C10 LNPs are selected to deliver circRNA for its high transfection efficiency, low-immunogenicity, and antioxidant activity. In male animal models, the system achieves sustained urate reduction, attenuation of tissue inflammation and fibrosis, alleviation of arthritic pain, and preservation of renal function. This integrated strategy simultaneously addresses hepatic urate catabolism, peripheral crystal clearance, and long-lasting pharmacological activity, presenting an alternative strategy to resolve the core challenges in hyperuricemia management.