Self-assembled nanoplatform-mediated co-delivery of brusatol to sensitize sorafenib for hepatocellular carcinoma treatment

Sorafenib (Sor), recognized as a frontline multi-kinase inhibitor, constitutes the primary targeted therapy for hepatocellular carcinoma (HCC). Despite its potential, many HCC patients exhibit reduced responsiveness to Sor, thereby undermining its therapeutic efficacy. Recent studies highlight the importance of nuclear factor erythroid-2-related factor 2 (Nrf2) activation in HCC, which contributes to Sor resistance. Brusatol (Bru), a plant-derived Nrf2 inhibitor, counteracts this resistance but faces challenges due to its poor solubility in aqueous media. In this study, we developed a glutathione (GSH)-responsive nanoplatform that effectively dispersed in water for the co-delivery of Bru and Sor (B/S NP). This approach enhanced Bru's therapeutic efficacy and increased Sor sensitivity in HCC. Our nanoplatform significantly reduced Nrf2 expression, thereby increasing Sor sensitivity both <i>in vitro</i> and <i>in vivo</i>, while presenting a favorable biosafety profile. These findings suggest that the nanoplatform-mediated co-delivery of Bru and Sor offers an innovative approach to enhance Sor's effectiveness in HCC treatment.