Self-Cycling Free Radical Generator from LDH-Based Nanohybrids for Ferroptosis-Enhanced Chemodynamic Therapy

Nonapoptotic ferroptosis has been a novel form of programmed cell death, which provides a new solution to enrich the anticancer treatment efficacy of traditional apoptotic therapeutic modality. Herein, a novel nanohybrid is designed by loading the PEG-encapsulated Artemisinin (denoted as A@P) on the ultrathin MgFe-LDH nanosheets (denoted as uLDHs) for improved chemodynamic therapy (CDT). The A@P/uLDHs cannot only realize the self-assembly between the Art and carrier but also be regarded as free radical generator. A comprehensive mechanistic study suggests that this unique A@P/uLDHs is able to in situ activate Art and self-cycling generate toxic C-centered free radical inside the cancer cells, without depending on abundant H₂ O₂ , accompanied with diminished cancerous antioxidation by depleting glutathione (GSH). The accumulation of ROS and depletion of GSH can further oxidize unsaturated fatty acid to generate lipid peroxide, whose overexpression can induce cell ferroptosis accompanied by cellular iron homeostasis turbulence. Both in vitro and in vivo results exhibit that A@P/uLDHs are an efficient nanoagent for highly efficient ferroptosis-enhanced CDT treatment. This work imparts the promising new visions about the ferroptosis-enhanced CDT via fine regulation of material design for improved cancer treatments.