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@Fe(3)O(4)-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 Fe(3)O(4) and reacts with intracellular hydrogen peroxide (H(2)O(2)) to promote Fenton reaction, and yields significant intracellular ROS (specifically hydroxyl radical, (•)OH) 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)(−) signal pathway to depletes glutathione. Fe(3)O(4) loading further provides magnetic resonance imaging T2-weighted signal to guide anti-tumor treatment. Together, this nanoplatform not only provides (•)OH (as a “sword” to attack tumor cells), but also inhibits system X(C)(−) signal pathway and crosslinks HSP (break down the “shield” of tumor cells) to maximize synergistic ferro-therapeutic effect. MPDA@Fe(3)O(4)-Era plus laser irradiation possessed highly efficient tumor suppression with magnified the levels of (•)OH and inactive glutathione peroxidase 4 (GPX4), which can promote the development of precise cooperative cancer therapy.