Cascade Bilateral Regulation of Ferroptosis and Immune Activation Conducted by the Electron-Accepting-Inspired Glycopolymer-Based Nanoreactor

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