Synergistic hydroxyl radical formation, system XC- inhibition and heat shock protein crosslinking tango in ferrotherapy: A prove-of-concept study of sword and shield theory

Ferroptosis provide new insights into designing nanomedicines for enhanced cancer therapy; however, its antitumor efficacy is relatively low, mainly due to self-protective mechanism of cancer cells, e.g., heat shock protein (HSP) overexpression. Since HSPs can be modified/inhibited by lipid peroxidation (LPO) ending products, we construct a nanoplatform, namely MPDA@Fe3O4-Era, to amplify intracellular reactive oxygen species (ROS) and LPO for synergistic ferrotherapy. Upon tumor acidic microenvironment and local near-infrared stimuli, this nanoplatform releases Fe3O4 and reacts with intracellular hydrogen peroxide (H2O2) to promote Fenton reaction, and yields significant intracellular ROS (specifically hydroxyl radical, (OH)-O-center dot) and LPO. In turn, LPO ending products crosslink HSPs to destroy self-preservation pathways of cancer cells to enhance anticancer effect. Meanwhile, the released erastin inhibits system X-(C) over bar signal pathway to depletes glutathione. Fe3O4 loading further provides magnetic resonance imaging T2-weighted signal to guide anti-tumor treatment. Together, this nanoplatform not only provides (OH)-O-center dot (as a sword to attack tumor cells), but also inhibits system X-(C) over bar signal pathway and crosslinks HSP (break down the shield of tumor cells) to maximize synergistic ferro-therapeutic effect. MPDA@Fe3O4-Era plus laser irradiation possessed highly efficient tumor suppression with magnified the levels of (OH)-O-center dot and inactive glutathione peroxidase 4 (GPX4), which can promote the development of precise cooperative cancer therapy.

Automated summary

Ferroptosis provides insights into designing nanomedicines for cancer therapy. However, its efficacy is limited due to cancer cells' self-protective mechanisms. A nanoplatform, MPDA@Fe3O4-Era, is constructed to amplify reactive oxygen species (ROS) and lipid peroxidation (LPO) for enhanced ferrotherapy.