EndogenousIron(II) Self-Enriched Fenton Nanocatalystvia FTH1 Activity Inhibition and Iron(III) Reduction for AmplifiedCancer Ferroptosis Therapy

Due to the increased expression of iron storage proteins in cancer cells, utilizing the endogenous iron-catalyzed Fenton reaction for cancer ferroptosis therapy has recently emerged as a prominent research focus. However, endogenous iron primarily exists within ferroxidase FTH1 in the Fe (III)-bound state, hindering the effective catalysis of the Fenton reaction. Herein, an endogenous iron(II) self-enriched Fenton nanocatalyst (BAI@cLANCs) is fabricated by encapsulating the FTH1 inhibitor baicalin (BAI) in cross-linked lipoic acid nanocarriers (cLANCs) to amplify endogenous ferroptosis. Once internalized, BAI@cLANCs are disrupted by glutathione (GSH) in tumor cells to release BAI, which inhibits FTH1 activity and hinders Fe²⁺ oxidation. Meanwhile, cLANCs degrade into dihydrolipoic acid (DHLA), which reduces Fe³⁺ to Fe²⁺, synergically enriching endogenous Fe²⁺. Simultaneously, both BAI and DHLA stimulate H₂O₂ production and facilitate the Fenton reaction to produce abundant ^·OH, thereby triggering lipid peroxidation and inducing tumor ferroptosis. Moreover, the reduction of Fe³⁺ to Fe²⁺ depletes GSH, facilitating ^·OH production and inactivating glutathione peroxidase-4, ultimately amplifying tumor ferroptosis. Overall, this work highlights the potential of an endogenous iron(II) self-enriched Fenton nanocatalyst for cancer ferroptosis therapy, providing a paradigm for amplifying endogenous ferroptosis by inhibiting FTH1 activity and reducing iron(III) to enrich endogenous iron(II).