Redox Dyshomeostasis with Dual Stimuli‐Activatable Dihydroartemisinin Nanoparticles to Potentiate Ferroptotic Therapy of Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to conventional therapies, including chemo‐, radio‐, and immunotherapy. In this study, it is first determined that a combination of dihydroartemisinin (DHA) and RSL‐3 (a glutathione peroxidase 4 (GPX4) inhibitor) markedly induced ferroptosis of PDAC tumor cells. A mechanistic study revealed that DHA can react with iron ions to generate carbon radicals and deplete intracellular glutathione, thereby cumulatively triggering the lipid peroxidation of tumor cells with RSL‐3‐mediated GPX4 inhibition. A DHA‐conjugated amphiphilic copolymer is subsequently synthesized, and intracellular acidity and oxidation dual‐responsive DHA nanoparticles are further engineered for the tumor‐specific co‐delivery of DHA and RSL‐3. The resultant nanoparticles (PDBA@RSL‐3) efficiently induce ferroptosis of tumor cells in the Panc02 tumor‐bearing immune‐deficient mouse model, and elicit T‐cell‐based antitumor immunity in the immune‐competent mouse model. The combination of PDBA@RSL‐3 nanoparticles and programmed death ligand 1 blockade therapy efficiently inhibits PDAC tumor growth in the immune‐competent mouse models. This study may provide novel insights for treatment of PDAC with ferroptosis‐based immunotherapy.