ROS-responsive oridonin and dihydroartemisinin hetero-polymeric prodrug NPs for potentiating ferroptosis in gastric cancer by disrupting redox balance

Gastric cancer presents a significant global health concern, with conventional therapies often limited in effectiveness. The abnormal redox balance in gastric cancer cells may represent a breakthrough in the treatment of gastric cancer. In this study, we report for the first time the development of reactive oxygen species (ROS)sensitive hetero-polymeric prodrug nanoparticles (NPs) designed for the co-delivery of the Chinese herbal extract oridonin (ORI) and dihydroartemisinin (DHA) in combination therapy for gastric cancer. This strategy aims to disrupt the intracellular redox balance and ultimately induce ferroptosis in gastric cancer cells. The ROSresponsive ORI and DHA polymeric prodrug were synthesised by conjugating ORI or DHA to poly(ethylene glycol)-block-poly(L-lysine) (PEG-b-PLL) via a ROS-sensitive linker thioketal (TK). The resulting polymeric pro- drugs self-assemble in water to form NPs OD-M. After internalization by gastric cancer cells, OD-M released ORI and DHA in response to high ROS conditions within cancer cells. The released ORI reacts with GSH to induce GSH depletion while DHA amplifies intracellular ROS levels, ultimately inducing ferroptosis in gastric cancer cells. Experimental results demonstrate that OD-M acts as both a GSH scavenger and ROS generator, effectively disrupting intracellular redox balance, inducing ferroptosis, and exhibiting effective anticancer efficacy in vitro and in vivo, offering a departure from traditional methods.