Lipid Messengers: Mechanisms and Clinical Applications of Exosomal Lipids in Neurodegenerative Diseases.

Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, represent an escalating global health burden owing to their complex pathophysiology and limited therapeutic options. Exosomes, nanoscale extracellular vesicles (30-150 nm) capable of crossing the blood-brain barrier (BBB), have emerged as critical mediators of intercellular communication in the central nervous system. While research has predominantly focused on exosomal proteins and nucleic acids, the functional significance of exosomal lipids in neurodegeneration is increasingly recognized. This review outlines the biological characteristics of exosome lipids. Then, we focus on three core mechanisms: how lipid imbalance drives neuronal damage (including membrane dysfunction, lipid peroxidation, and mitochondrial energy crisis), how the lipid-mediated inflammatory network regulates microglial activation and BBB integrity, and how the lipid microenvironment affects the folding, aggregation, and cross-cell transmission of pathological proteins. Critically, these mechanisms form a mutually reinforcing vicious cycle, jointly driving the progression of the disease. Based on this framework, we have summarized the specific alterations of exosomal lipids in diseases such as Alzheimer's disease and Parkinson's disease. The clinical potential of exosomal lipids as liquid biopsy biomarkers and drug delivery carriers is discussed, alongside current challenges including technical standardization, heterogeneity analysis, and quantitative accuracy. A comprehensive understanding of exosomal lipid dynamics is essential for developing novel diagnostic and therapeutic strategies for neurodegenerative diseases.