Injectable Hydrogel-Encapsulating Pickering Emulsion for Overcoming Lenvatinib-Resistant Hepatocellular Carcinoma via Cuproptosis Induction and Stemness Inhibition

Lenvatinib resistance (LenR) presents a significant challenge in hepatocellular carcinoma (HCC) treatment, leading to high cancer-related mortality rates globally. Unlike traditional chemotherapy resistance mechanisms, LenR in HCC is primarily driven by increased cancer cell stemness. Disulfiram, (DSF), functioning as a Cu ionophore, can coordinate with Cu²⁺ to overcome LenR in HCC by inhibiting cancer cell stemness and cuproptosis. However, DSF faces challenges due to its poor water solubility, while copper ions present issues related to systemic toxicity during widespread use. To address this, DSF and CuO nanoparticles (NPs) were co-encapsulated to form an oil-in-water Pickering emulsion (DSF@CuO), effectively elevating DSF and copper ion concentrations within the tumor microenvironment (TME). DSF@CuO was then combined with sodium alginate (SA) to form a DSF@CuO-SA solution, which gelatinizes in situ with Ca²⁺ in the TME to form a DSF@CuO Gel, enhancing Pickering emulsion stability and sustaining DSF and copper ion release. A DSF@CuO Gel exhibits enhanced stability and therapeutic efficacy compared to conventional administration methods. It effectively induces mitochondrial dysfunction and cuproptosis in LenR HCC cells by downregulating DLAT, LIAS, and CDKN2A, while upregulating FDX1. Furthermore, it suppresses cancer stemness pathways through activation of the JNK/p38 MAPK pathway and inhibition of the NF-κB and NOTCH signaling pathways. These findings suggest that DSF@CuO Gels are a promising therapeutic strategy for treating LenR HCC. In vivo and in vitro LenR HCC models demonstrated significant therapeutic efficacy. In conclusion, this novel approach underscores DSF@CuO Gel's potential to overcome LenR in HCC, offering a novel approach to address this clinical challenge.