lncRNAs and miRNAs in Exosome-Mediated Macrophage Polarization: Implications for Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a progressive and multifactorial retinal disease that represents a leading cause of irreversible vision loss among the elderly. Increasing evidence suggests that exosomes, small extracellular vesicles that mediate intercellular communication, play a critical role in regulating immune and angiogenic signaling in the retina. These vesicles transport diverse molecular cargo, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Recent studies highlight the importance of exosome-mediated ncRNA signaling in macrophage polarization, a key immunological process involved in AMD progression. Exosomal miRNAs and lncRNAs released from retinal pigment epithelium (RPE) cells, endothelial cells, and immune cells can regulate macrophage phenotypes and alter inflammatory and angiogenic pathways within the retina. Dysregulated ncRNAs, including miR-21, miR-23a, miR-150, and the lncRNA NEAT1, have been implicated in promoting macrophage-driven inflammation, lipid dysregulation, and pathological neovascularization. Through these mechanisms, exosomal ncRNAs contribute to the transition from early retinal stress and drusen formation to advanced forms of AMD characterized by geographic atrophy or choroidal neovascularization. In addition to their mechanistic role in disease progression, exosomal ncRNAs show promise as minimally invasive biomarkers for early diagnosis and monitoring of AMD. Their stability in biological fluids, such as plasma, aqueous humor, and vitreous fluid, suggests their potential use in liquid biopsy approaches. Moreover, engineered exosomes carrying therapeutic ncRNAs represent a promising strategy for modulating macrophage polarization and restoring retinal immune homeostasis. This review integrates current knowledge on the exosome-ncRNA-macrophage axis in AMD, highlighting its role in retinal immune regulation, disease progression, and therapeutic development. Understanding this emerging signaling network may provide new opportunities to develop precision diagnostic tools and targeted therapies to prevent or slow retinal degeneration in AMD.