Vishwakarma and colleagues demonstrate that small extracellular vesicles derived from lineage-tailored human retinal ganglion-like cells restore mitochondrial and metabolic homeostasis in glaucomatous neurodegeneration. These vesicles reprogram retinal bioenergetics and promote mitochondrial homeostasis to enhance neuroprotection, offering a promising translational strategy for glaucoma and other optic neurodegenerative disorders.