g-C3N4 Nanosheets as a Ferroptosis-Targeted Nanoprobe: Mitigating Iron Overload and Restoring Male Fertility via Nrf2 Pathway Activation.

Ferroptosis induced by iron overload has been recognized as a critical factor in germ cell damage and subsequent male infertility. However, current ferroptosis inhibitors are often constrained by systemic side effects and limited targeting. Herein, we developed graphitic carbon nitride (g-C3N4) nanosheets as a multisite iron chelation strategy to inhibit iron overload-induced ferroptosis and prevent male reproductive dysfunction. Characterized by excellent stability and intrinsic fluorescence, the g-C3N4 nanosheets enable specific iron ion (Fe3+ and Fe2+) sequestration, exhibiting iron-responsive fluorescence quenching with remarkable selectivity and sensitivity. Both in vitro and in vivo studies confirmed that iron overload induces significant germ cell damage, whereas g-C3N4 nanosheets treatment targeted ferroptosis via the Nrf2 pathway, thereby preserving male reproductive function. Moreover, g-C3N4 exhibited excellent biosafety, with minimal cytotoxicity in vitro and no adverse effects in vivo. These findings highlight the potential of g-C3N4 nanosheets as a promising therapeutic platform for the treatment of ferroptosis-related diseases.