Prodrug-inspired therapeutics: Albuminized ceria nanozymes for osteoarthritis treatment

Osteoarthritis (OA) represents a highly prevalent degenerative joint disorder primarily driven by chronic inflammation and oxidative stress within the hypoxic microenvironment. Although the oral prodrug sulindac (SUL) is commonly used to manage OA, its therapeutic efficacy must rely on in vivo reduction into its active form, sulindac sulfide (SSUL), to mitigate inflammation. Inspired by "repurposing old drugs" and leveraging the redox properties of nanoceria, we developed albuminized ceria nanozymes loaded with SUL (BSA-SSUL-Ce) via self-assembly, where the valence state transformation drives SUL to SSUL. Notably, BSA-SSUL-Ce was selectively internalized by inflammatory macrophages, enabling precise delivery to inflammatory sites. Compared with prodrug SUL, the SOD enzymatic properties of BSA-SSUL-Ce conferred themselves with reducibility, facilitating attenuation of inflammatory signals by SSUL. Following, these nanocomposites exerted catalase activity, scavenging reactive oxygen species in situ and converting them into oxygen, thereby inhibiting hypoxia-inducible factor-1α. In a rat model of chronic OA, intra-articular injection of BSA-SSUL-Ce achieved synergistic therapeutic effects and good biocompatibility. Moreover, the preventive effect of BSA-SSUL-Ce in acute liver injury inflammatory models further expands its potential scenarios. This platform represents a promising therapeutic and preventive candidate for treating acute and chronic inflammatory diseases.