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

摘要： Non-apoptotic ferroptosis is of clinical importance because it offers a solution to surmount the inevitable bio-carriers of traditional apoptotic therapeutic means. Inspired by industrial Electro-Fenton technology featured with electrochemical iron cycling, we construct a ferrous-supply-regeneration nanoengineering to intervene tumorous iron metabolism for enhanced ferroptosis. Fe3+ ion and naturally derived tannic acid (TA) spontaneously form network-like corona onto sorafenib (SRF) nanocore. The formed SRF@FeIIITA nanoparticles can respond to 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 thus to 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@FeIIITA-mediated cell death proves to follow ferroptosis pathway and strongly inhibits tumor proliferation. Moreover, SRF@FeIIITA provides a powerful platform capable of versatile integration between apoptosis and non-apoptosis means. Typically, photosensitizer-adsorbed SRF@FeIIITA 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.