A Ferroptosis-Inducing and Leukemic Cell- Targeting Drug Nanocarrier Formed by Redox-Responsive Cysteine Polymer for Acute Myeloid Leukemia Therapy

Ferroptosis is an alternative strategy to overcome chemo-resistance, but effective therapeutic approaches to induce ferroptosis for acute myeloid leukemia (AML) treatment are limited. Here, we developed glutathione (GSH)-responsive cysteine polymer-based ferroptosis-inducing nanomedicine (GCFN) as an efficient ferroptosis inducer and chemo-therapeutic drug nanocarrier for AML treatment. GCFN depleted intracellular GSH and inhibited glutathione peroxidase 4, a GSH-dependent hydro-peroxidase, to cause lipid peroxidation and ferroptosis in AML cells. Furthermore, GCFN-loaded paclitaxel (PTX@GCFN) targeted AML cells and spared normal hematopoietic cells to limit the myeloablation side effects caused by paclitaxel. PTX@GCFN treatment extended the survival of AML mice by specifically releasing paclitaxel and simultaneously inducing ferroptosis in AML cells with restricted myeloablation and tissue damage side effects. Overall, the dual-functional GCFN acts as an effective ferroptosis inducer and a chemotherapeutic drug carrier for AML treatment.

Automated summary

The study developed GSH-responsive cysteine polymer-based ferroptosis-inducing nanomedicine (GCFN) as an effective therapy for acute myeloid leukemia (AML). GCFN depleted intracellular GSH and inhibited glutathione peroxidase 4 to induce ferroptosis in AML cells. PTX@GCFN targeted AML cells and reduced myeloablation side effects caused by paclitaxel, leading to extended survival of AML mice with simultaneous ferroptosis induction.