Endogenous Iron(II) Self-Enriched Fenton Nanocatalyst via FTH1 Activity Inhibition and Iron(III) Reduction for Amplified Cancer 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).