Biomimetic gold nanocages for overcoming chemoresistance of osteosarcoma by ferroptosis and immunogenic cell death

Abstract

Chemoresistance remains a huge challenge for the treatment of osteosarcoma (OS). Multiple mechanisms are involved in chemoresistance of cisplatin. In our research, we found that Nrf2/xCT pathway contributes to the occurrence of chemoresistance of cisplatin in OS by enhancing the ability of antioxidative stress. Recently, oxidative stress defense and ferroptosis have attracted wildly attention in overcoming chemoresistance. Different from apoptosis, necroptosis, and autophagy, ferroptosis is a new programmed cell death pathway with the accumulation of reactive oxygen species (ROS). Synergistic treatment of ferroptosis and photothermal therapy (PTT) can perfectly overcome chemoresistance, and immunogenic cell death (ICD) induced by PTT can initiate effective anti-tumor immunity to suppress tumor growth and recurrence. Thus, we designed a cancer cell membrane coated gold nanocages loaded with RSL3 (C-R-AuNC) for the treatment of chemoresistance of OS. RSL3 induces ferroptotic cell death by the inhibition of glutathione peroxidase (GPX4). Gold nanocages coated with the cell membrane, as a nanocarrier, can achieve targeted drug delivery, controlled drug release, PTT, and induced ICD. In our researches, excellent outcomes for the treatment of chemoresistance of OS were achieved by C-R-AuNC, which is believed to serve as a promising strategy for clinic treatment of drug-resistant OS in future.