Iron-Chelating and ROS-Scavenging Polymers with Thioketal and Thioether Bonds Delivering Ferroptosis Inhibitor Lip-1 Provide a Triple Therapeutic Strategy for Retina Ganglion Cells in Acute Glaucoma.

Abstract

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.