Anti‐Apoptotic and Neurite‐Protective Nanomedicine Augments Embryonic Stem Cells‐Derived Retinal Ganglion Cell Transplantation in Glaucoma Recovery

ABSTRACT Retinal ganglion cell (RGC) degeneration represents a cardinal etiology of irreversible vision loss in glaucoma, where efficacious regenerative therapies remain scarce. RGC replacement therapy holds promise for visual function restoration, yet its therapeutic efficacy is constrained by the hostile glaucomatous microenvironment, dominated by oxidative stress that compromises transplanted RGC survival. Here, we report the design of multifunctional lithium‐epigallocatechin gallate nanoparticles (Li‐EGCG NPs) to synergistically enhance antioxidant capacity and neuroprotection. These NPs exhibit uniform spherical morphology, broad‐spectrum reactive oxygen species scavenging activity, and exceptional biocompatibility with embryonic stem cell‐derived RGCs (ESC‐RGCs). In vitro, Li‐EGCG NPs mitigate oxidative stress‐induced apoptosis, preserve neurite integrity, and maintain mitochondrial homeostasis in ESC‐RGCs. Transcriptomic analyses reveal activation of neuroprotective pathways, including apoptosis regulation, axon guidance, and mitochondrial function. In a retinal ischemia/reperfusion injury model, which serves as an acute pathological glaucomatous injury model, combinatorial Li‐EGCG NPs and ESC‐RGCs transplantation markedly improves ESC‐RGCs survival, preserves retinal architecture, and restores visual function beyond single‐modality therapy. This study establishes Li‐EGCG NPs as a robust nanomedicine platform for retinal neurodegenerative diseases, offering a promising strategy to augment cell‐based therapies.