Degradable iron-rich mesoporous dopamine as a dual-glutathione depletion nanoplatform for photothermal-enhanced ferroptosis and chemodynamic therapy

Glutathione (GSH) is a crucial factor in limiting the effects of chemodynamic therapy (CDT) and ferroptosis, an iron-based cell death pathway. Based on this, we constructed iron-rich mesoporous dopamine ( [email protected] ) nanovehicles with a dual-GSH depletion function by combining MPDA and Fe. Poly (ethylene glycol) (PEG) was further modified to provide desirable stability ( [email protected] ) and glucose oxidase (GOx) was grafted onto [email protected] ( [email protected] ) to address the limitation of hydrogen peroxide (H 2 O 2 ). After the nanoparticles reached the tumor site, the weakly acidic microenvironment promoted the release of Fe. Then Fe II reacted with H 2 O 2 to generate hydroxyl radical ( OH) and Fe III . The generated Fe III was reduced to Fe II by GSH, which circularly participated in the Fenton reaction and continuously produced tumor inhibitory free radicals . Meanwhile, GOx consumed glucose to provide H 2 O 2 for the reaction. MPDA had also been reported to deplete GSH. Therefore, dual consumption of GSH led to the destruction of intracellular redox balance and inhibition of glutathione-dependent peroxidase 4 (GPX4) expression, resulting in an increase in lipid peroxides (LPO) and further induction of ferroptosis. Additionally, MPDA-mediated photothermal therapy (PTT) raised the temperature of tumor area and produced photothermal-enhanced cascade effects. Hence, the synergistic strategy that combined dual-GSH depletion-induced ferroptosis, enhanced CDT and photothermal cascade enhancement based on [email protected] could provide more directions for designing nanomedicines for cancer treatment.