FeDSNP‐Pa Nanoassemblies: A Triple‐Action Therapeutic Strategy Targeting Oxidative Stress, Inflammation, and Pyroptosis for Retinal Ganglion Cell Protection in Glaucoma

Abstract Glaucoma is an irreversible blinding eye disease characterized by the death of retinal ganglion cells (RGC). Excessive reactive oxygen species (ROS) generation and inflammatory responses are significant contributors to RGC death. However, effective clinical treatments for glaucoma remain limited. Developing a method to eliminate ROS, suppress inflammation and inhibit pyroptosis can provide new insights into glaucoma therapy. In this study, a metallated nanosized polymer loaded with sodium pyruvate (Pa) for drug delivery (FeDSNP‐Pa) is designed and prepared. First, in high‐ROS environment, this polymeric enzyme mimic (PEM) catalyzes the conversion of excess hydrogen peroxide into oxygen and water, while upregulating the expression of antioxidant proteins superoxide dismutase (SOD) and catalase (CAT). This process alleviates hypoxic microenvironments and eliminates ROS. Second, this PEM complex mitigates intracellular inflammatory responses by inhibiting the TNF‐α/NF‐κB pathway. Furthermore, FeDSNP‐Pa releases PA in high‐ROS environments, which inhibits the NLRP3/Caspase‐1/GSDMD signaling pathway. In summary, this work demonstrates that FeDSNP‐Pa significantly protects RGCs from damage induced by elevated intraocular pressure by inhibiting oxidative stress, inflammatory responses and pyroptosis. Thus, FeDSNP‐Pa may offer a novel therapeutic option for glaucoma patients.