Cascade\nBilateral\nRegulation of Ferroptosis and Immune\nActivation Conducted by the Electron-Accepting-Inspired Glycopolymer-Based\nNanoreactor

The immunosuppressive tumor environment,\ncharacterized\nby elevated\nredox levels, significantly impairs the effectiveness of oxidation\nand the immune response. Here, an electron-accepting-inspired glycopolymer-based\nnanoreactor (chitosan-grafted nitrobenzene nanoparticles) CNP employing\nhypoxia-activated group nitrobenzene was constructed to realize cascade\nbilateral regulation of ferroptosis and immune activation by intervening\nantioxidant systems. The as-prepared CNP could consume nicotinamide\nadenine dinucleotide phosphate (NADPH) in the hypoxia-response process,\nallowing it to be involved in the recycling of glutathione (GSH) and\nthioredoxin (Trx). This ultimately affects redox homeostasis, leading\nto reduced GSH levels, increased reactive oxygen species (ROS), and\ninhibition of (glutathione peroxidase 4) Gpx4. By taking advantage\nof the sensitivity difference between tumor cells and dendritic cells\n(DCs) to the ferroptosis inducer erastin (Er) based on varying xCT\nexpression levels, we developed Er-loaded nanoparticles CNP/Er. These\nnanoparticles not only enhance ferroptosis in 4T1 cells through Gpx4\ninhibition by CNP but also promote DC maturation by utilizing CNP’s\nhypoxia-responsive mechanism to increase ROS levels. The CNP/Er was\nbelieved to be an ideal candidate for bilateral regulation of ferroptosis\nand immune activation in one nanoreactor.