A self-amplified ferroptosis nanoagent that inhibits the tumor upstream glutathione synthesis to reverse cancer chemoresistance.

Ferroptosis has recently become an attractive strategy to combat the chemoresistance of cancer cells, but the intracellular ferroptosis defense system greatly challenges the efficient ferroptosis induction. Herein, we report a ferrous metal-organic framework-based nanoagent (FMN) that inhibits the intracellular upstream glutathione synthesis and induces self-amplified ferroptosis of cancer cells, for reversing chemoresistance and boosting chemotherapy. The FMN is loaded with SLC7A11 siRNA (siSLC7A11) and chemotherapeutic doxorubicin (DOX), which shows enhanced tumor cell uptake and retention, thus ensuring the effective DOX delivery and tumor intracellular iron accumulation. Importantly, the FMN simultaneously catalyzes the iron-dependent Fenton reaction and triggers the siSLC7A11-mediated suppression of upstream glutathione synthesis for intracellularly self-amplified ferroptosis, which further inhibits P-glycoprotein activity for DOX retention, and regulates the expression of Bcl-2/Bax to reverse the apoptotic resistance state of tumor cells. The FMN-mediated ferroptosis is also demonstrated in ex vivo patient-derived tumor fragment platform. Consequently, FMN successfully reverses cancer chemoresistance and achieves a highly efficient in vivo therapeutic efficacy in MCF7/ADR tumor-bearing mice. Our study provides a self-amplified ferroptosis strategy via inhibiting intracellular upstream glutathione synthesis, which is effective to reverse cancer chemoresistance.