A circRNA-based uricase replacement therapy for sustained treatment of hyperuricemia

Abstract

Hyperuricemia, a major risk factor for gout and kidney disease, arises from the evolutionary loss of human uricase and remains a significant medical challenge due to its high prevalence. However, limited therapeutic options are available for refractory hyperuricemia that typically require long-term treatment. Here we developed a circRNA-based uricase replacement strategy and evaluated its efficacy in uricase-knockout mice as a model for severe hyperuricemia. Lipid nanoparticle-mediated delivery of circRNA enabled efficient in vivo expression of an engineered human-like uricase, which rapidly reduced serum urate levels after a single injection and maintained the urate-lowering effect for up to 10 days. Repeated administration led to sustained urate reduction for 10 weeks, mitigated renal injury, and exhibited favorable biosafety. These findings highlight the therapeutic potential of circRNA-based uricase replacement for the long-term treatment of hyperuricemia and its associated complications.