Iron-Chelating and ROS-Scavenging Polymers with Thioketal and Thioether Bonds Delivering Ferroptosis Inhibitor Lip-1...

Glaucoma is an irreversible blinding eye disease characterized by retinal ganglion cell (RGC) death with emerging evidence highlighting ferroptosis as a crucial mechanism. Herein, two iron-chelating and reactive oxygen species (ROS)-scavenging polymers with thioketal and thioester bonds delivering Lip-1 are designed and self-assembled into NPs^Lip-1, which pose a triple threat to RGC of Acute Glaucoma via ROS scavenging, iron ion chelation, and potent ferroptosis inhibition. Upon immediate cellular uptake of NPs^Lip1 by RGCs, the elevated intracellular ROS triggers the cleavage of thioether bonds and the oxidation of thioester bonds, resulting in ROS consumption and simultaneous release of Lip-1 and exposure of polymer chains with pendant 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) groups. On the one hand, the NOTA groups can chelate with iron ions, thereby inhibiting ferroptosis in RGCs. On the other hand, the released Lip-1 can inhibit ferroptosis by upregulating glutathione peroxidase 4 (GPX4). Together, NPs^Lip-1 with a triple threat markedly reduced ferroptosis and oxidative stress, significantly enhancing the survival of R28 cells. Further, NPs^Lip-1 effectively inhibits the RGC ferroptosis and preserves the visual function. Overall, the findings indicated NPs^Lip-1 provides substantial protection for RGCs via suppressing oxidative stress and ferroptosis, representing a promising therapeutic avenue for glaucoma.