Self-Activated Cascade-Responsive Sorafenib and USP22 shRNA Co-Delivery System for Synergetic Hepatocellular Carcinoma Therapy

Resistance to sorafenib severely hinders its effectiveness against hepatocellular carcinoma (HCC). Cancer stemness is closely connected with resistance to sorafenib. Methods for reversing the cancer stemness remains one of the largest concerns in research and the lack of such methods obstructs current HCC therapeutics. Ubiquitin-specific protease 22 (USP22) is reported to play a pivotal role in HCC stemness and multidrug resistance (MDR). Herein, a galactose-decorated lipopolyplex (Gal-SLP) is developed as an HCC-targeting self-activated cascade-responsive nanoplatform to co-delivery sorafenib and USP22 shRNA (shUSP22) for synergetic HCC therapy. Sorafenib, entrapped in the Gal-SLPs, induced a reactive oxygen species (ROS) cascade and triggered rapid shUSP22 release. Thus, Gal-SLPs dramatically suppressed the expression of USP22. The downregulation of USP22 suppresses multidrug resistance-associated protein 1 (MRP1) to induce intracellular sorafenib accumulation and hampers glycolysis of HCC cells. As a result, Gal-SLPs efficiently inhibit the viability, proliferation, and colony formation of HCC cells. A sorafenib-insensitive patient-derived xenograft (PDX) model is established and adopted to evaluate in vivo antitumor effect of Gal-SLPs. Gal-SLPs exhibit potent antitumor efficiency and biosafety. Therefore, Gal-SLPs are expected to have great potential in the clinical treatment of HCC.

Automated summary

Resistance to sorafenib in hepatocellular carcinoma is closely linked to cancer stemness, with the lack of effective methods to reverse this stemness being a major obstacle in current HCC therapeutics. The development of Gal-SLPs, which target HCC and co-deliver sorafenib and shUSP22, shows promising results in suppressing USP22 expression, inhibiting multidrug resistance, and efficiently inhibiting HCC cell viability and proliferation. In vivo studies using a sorafenib-insensitive patient-derived xenograft model demonstrate potent antitumor effects and biosafety of Gal-SLPs, suggesting their potential in clinical HCC treatment.