ROS-Responsive Prodrug Containing Dihydroartemisinin and Cinnamaldehyde for the Potential Treatment of Nonalcoholic Steatohepatitis.

The treatment of nonalcoholic steatohepatitis (NASH) has long been challenging due to its complex and heterogeneous pathogenesis. The NASH disease process is rooted in dysregulation caused by oxidative stress, where the overproduction of reactive oxygen species (ROS) exacerbates disease progression. To address these issues, we developed a ROS-sensitive prodrug containing dihydroartemisinin (DHA) and cinnamaldehyde (CA). By application of a thin-film hydration method, the synthetic prodrug was encapsulated with TPGS and Soluplus to prepare nanomicelles (DHA-CA@NMs). Furthermore, the formed nanomicelles allowed for targeted delivery to inflammatory sites with high ROS production. In NASH tissue, the elevated ROS cleaved the ROS-sensitive linker in the DHA-CA prodrugs to release DHA and CA, then exerting anti-inflammatory effects and ameliorating the inflammatory microenvironment. The results from experiments indicated that DHA-CA@NMs achieved amelioration of hepatic inflammation through the suppression of macrophage polarization, preventing oxidative stress, counteracting ferroptosis, and suppressing NF-κB pathway activation. Furthermore, in vivo studies confirmed that DHA-CA@NMs exhibited excellent biosafety and therapeutic efficacy against the mice with methionine- and choline-deficient (MCD) diet-induced NASH. These findings suggest the potential of the DHA-CA@NMs nanotherapeutic system for treating NASH.