Cancer-Erythrocyte Membrane-Mimicking FeO Nanoparticles and DHJS for Ferroptosis/Immunotherapy Synergism in Tumors.

Ferroptosis is characterized by iron accumulation and lipid peroxidation. However, a clinical dose of FeO nanoparticles could not cause effective ferroptosis in tumors, and the mechanism is yet to be completely understood. In this study, using RNA-seq data, we found that tumor cells could feedback-activate the antioxidant system by upregulating Nrf-2 expression, thus avoiding ferroptosis caused by FeO nanoparticles. We also found that DHJS (a probe for ROS generation) can antagonize Nrf-2 expression when it synergizes with FeO nanoparticles, thus inducing ferroptosis in tumor cells. Considering these findings, we created a biomimetic hybrid cell membrane camouflaged by PLGA-loaded FeO and DHJS to treat osteosarcoma. The hybrid cell membrane endowed the core nanoparticle with the extension of blood circulation life and enhanced homologous targeting ability. In addition, DHJS and FeO in nanoparticles prompted synergistically lethal ferroptosis in cancer cells and induced macrophage M1 polarization as well as the infiltration of CD8(+) T cells and dendritic cells in tumors. In summary, this study provides novel mechanistic insights and practical strategies for ferroptosis induction of FeO nanoparticles. Meanwhile, the synthesized biomimetic nanoparticles exhibited synergistic ferroptosis/immunotherapy against osteosarcoma.