Boost therapy of hepatocellular carcinoma by amplifying vicious cycle between mitochondrial oxidative stress and endoplasmic reticulum stress via biodegradable ultrasmall nanoparticles and old drug

Despite advances in early diagnosis and treatment of hepatocellular carcinoma (HCC), HCC shows a very high mortality and development of innovative drugs and treatment methods are highly desirable. Herein, we report an innovative therapy of HCC through the formation and amplification of vicious cycle between mitochondrial oxidative stress and ER stress by joint use of biodegradable ultrasmall Cu 2- x Se nanoparticles (CS NPs) and alcohol-abuse drug disulfiram (DSF). The CS NPs can alleviate the tumor hypoxia and generate reactive oxygen species (ROS) through their Fenton-like reaction with endogenous H 2 O 2 in tumor. Their released copper ions can react with DSF to in situ form active drug CuET to significantly suppress the growth of HCC and exhibit excellent anti-tumor effect. We reveal the novel anti-tumor mechanism of the formed CuET complex, which can immobilize nuclear protein localization protein 4 (NPL4) to inhibit the proteasome system to induce endoplasmic reticulum (ER) stress and increase the burden of Ca 2+ ions in mitochondria, leading to mitochondrial oxidative stress and the burst of ROS. The mitochondrial oxidative stress produces less ATP to induce the occurrence of autophagy, and the generated ROS further strengthens the ER stress. The formation of such vicious cycle between mitochondrial oxidative stress and ER stress significantly enhances the severe apoptosis of tumor cells and notable decrease in tumor size, which has been demonstrated in both subcutaneous and orthotopic HCC models. Our work provides insights into repurposing of metabolic nanoparticles and old drugs for new applications, demonstrates the great potential of this strategy in anti-tumor therapy. • Joint use of Cu2-xSe NPs and disulfiram can suppress HCC growth due to the in situ formation of anti-tumor drug CuET. • The CuET can cause and amplify a vicious cycle between ER stress and mitochondrial oxidative stress. • The ER stress increases the burden of Ca2+ in mitochondria, leading to mitochondrial oxidative stress and the burst of ROS. • The mitochondrial damage produces less ATP to induce autophagy, and the burst of ROS further strengthens the ER stress.