Abstract Background Uricase-based enzyme replacement therapies have emerged as an effective treatment for refractory gout and tumor lysis syndrome. However, their clinical adoption has been hindered by challenges such as instability, rapid clearance, and immune responses. While formulations such as PEGylated uricase have demonstrated clinical efficacy, they are limited by the development of anti-PEG antibodies, which reduces their therapeutic effectiveness. Thus, innovative drug delivery strategies are required to address these limitations and increase the effectiveness of uricase therapies. Area covered This review provides a comprehensive overview of uricase as a therapeutic enzyme and discusses both the approved formulations and recent advances in drug delivery systems (DDS) aimed at overcoming key challenges. It focuses on nanoparticle-based and polymer-conjugated systems designed to improve stability, extend enzyme half-life, and reduce immunogenicity. Additionally, this review explores the use of lipid-based carriers, polymeric nanoparticles, and inorganic frameworks to optimize enzyme delivery, offering insights into their potential to increase pharmacokinetics and minimize immune responses. Expert opinion Although uricase-based therapies show considerable promise for refractory gout and tumor lysis syndrome, challenges related to their stability, pharmacokinetics, and immunogenicity persist. Advanced DDS strategies offer viable solutions by stabilizing enzymes, prolonging circulation, and mitigating immune reactions. Achieving therapeutic efficacy requires balancing immune evasion and enzymatic activity to ensure long-term effectiveness. Further innovations in DDS are essential to develop safer and more reliable uricase therapies, expand their clinical use, and address unmet patient needs.