Ferrous-Supply-Regeneration Nanoengineering for Cancer-Cell-Specific Ferroptosis in Combination with Imaging-Guided Photodynamic Therapy

Non-apoptotic ferroptosis is of clinical importance because it offers a solution to the inevitable biocarriers of traditional apoptotic therapeutic means. Inspired by industrial electro-Fenton technology featured with electrochemical iron cycling, we construct ferrous-supply-regeneration nanoengineering to intervene tumorous iron metabolism for enhanced ferroptosis. Fe³⁺ ion and naturally derived tannic acid (TA) spontaneously form a network-like corona onto sorafenib (SRF) nanocores. The formed SRF@Fe^IIITA nanoparticles can respond to a lysosomal acid environment with corona dissociation, permitting SRF release to inhibit GPX4 enzyme for ferroptosis initiation. TA is arranged to chemically reduce the liberated and the ferroptosis-generated Fe³⁺ to Fe²⁺, offering iron redox cycling to, thus, effectively produce lipid peroxide required in ferroptosis. Sustained Fe²⁺ supply leads to long-term cytotoxicity, which is identified to be specific to H₂O₂-overloaded cancer cells but minimal in normal cells. SRF@Fe^IIITA-mediated cell death proves to follow the ferroptosis pathway and strongly inhibits tumor proliferation. Moreover, SRF@Fe^IIITA provides a powerful platform capable of versatile integration between apoptosis and non-apoptosis means. Typically, photosensitizer-adsorbed SRF@Fe^IIITA demonstrates rapid tumor imaging owing to the acid-responsive fluorescence recovery. Together with ferroptosis, imaging-guided photodynamic therapy induces complete tumor elimination. This study offers ideas about how to advance anticancer ferroptosis through rational material design.