Dysregulated Polarized Secretion of Small Extracellular Vesicles in the Retinal Pigment Epithelium: Mechanisms and Pathological Roles in Age-Related Macular Degeneration.

The pathogenesis of age-related macular degeneration (AMD) is intrinsically driven by retinal pigment epithelium (RPE) dysfunction. Under physiological conditions, the strictly polarized secretion of small extracellular vesicles (sEVs) by the RPE dictates outer retinal homeostasis. In response to oxidative and hypoxic stress, this secretory architecture is profoundly disrupted, transforming sEVs into mediators of drusen formation, inflammation, and neovascularization. This review systematically delineates the molecular machinery governing RPE-sEV trafficking, unveiling the distinct protein and miRNA cargo profiles segregated between the apical and basolateral domains. We highlight the unique secretory features of RPE and elucidate how AMD stressors disrupt this polarity via cytoskeletal collapse, secretory autophagy, and Rab GTPase dysregulation. Consequently, this altered sEV secretion abolishes apical neurotrophic support while deteriorating the basolateral microenvironment. Crucially, this establishes a vicious pathological loop where microenvironmental deterioration and sEV dysregulation are mutually causative. Recognizing dysregulated sEV polarity as a contributing factor to AMD, we propose that repairing RPE intracellular trafficking offers a fundamental strategy to restore secretory homeostasis and impede disease progression.