Systematic Analysis of Plasma‐Derived Extracellular Vesicle‐Enriched Samples in Age‐Related Macular Degeneration Reveals Oxidative Stress Linked to Altered Lipid and Protein Profiles

Vision impairment caused by age‐related macular degeneration (AMD) is a global health priority. Retinal pathology is driven by ageing and exacerbated by genetic and environmental risk factors. Peripheral blood circulation is increasingly recognised as a contributor to disease initiation and progression, and a source of biomarkers to support earlier diagnosis and personalised treatment strategies. Here, we performed an analysis of plasma‐derived extracellular vesicle (EV)‐enriched samples from 30 AMD and 30 controls. Proteomics identified significantly altered proteins in AMD, the majority of which were downregulated with a strong interaction network involving complement proteins and endopeptidase inhibitors. Importantly, many of the altered proteins are known AMD biomarker candidates and act in pathways affecting AMD: oxidative stress response, immune function and proteolysis dysregulation. Lipidomics revealed an increase in total sphingomyelin to ceramide ratio in AMD, indicating lipid metabolism defects. Raman spectroscopy complemented these findings by demonstrating protein and lipid oxidative modifications, alongside compositional abnormalities in AMD samples. Thus, AMD plasma EV‐enriched samples carry a systemic signature of complement and coagulation dysregulation, impaired redox homeostasis, and altered sphingolipid metabolism, reflecting established mechanisms of AMD retinal pathology. These AMD‐associated biochemical profiles form a promising source for developing new diagnostics and mechanistic insights for precision medicine.