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 (
MPDA@Fe) nanovehicles with a dual-GSH depletion function by combining
MPDA and Fe. Poly (
ethylene glycol) (PEG) was further modified to provide desirable stability (PM@Fe) and
glucose oxidase (GOx) was grafted onto PM@Fe (GPM@Fe) to address the limitation of
hydrogen peroxide (H2O2). After the nanoparticles reached the
tumor site, the weakly acidic microenvironment promoted the release of Fe. Then FeII reacted with H2O2 to generate
hydroxyl radical (
OH) and FeIII. The generated FeIII was reduced to FeII by GSH, which circularly participated in the Fenton reaction and continuously produced
tumor inhibitory
free radicals. Meanwhile, GOx consumed
glucose to provide H2O2 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
MPDA@Fe could provide more directions for designing nanomedicines for
cancer treatment.