Ultrasound-enhanced exosome secretion and antibody-free SERS profiling for Alzheimer's disease via iPSC-derived cortical organoids.

Exosomes offer a promising vehicle for noninvasive diagnosis of neurodegenerative diseases by carrying multiple biomarkers across the blood-brain barrier. However, traditional exosome analysis often misses subtle genotype-specific variations because of weak signals from a few exosomes, reliance on markers, and limited understanding of disease signatures. Here, we present a sound way to understand Alzheimer's disease through label-free surface-enhanced Raman scattering (SERS) profiling of cortical organoid-derived exosomes. Initially, we enhanced exosomal SERS signal levels by optimizing ultrasound parameters to increase exosome secretion from cortical organoids. Using this strategy, we distinguished apolipoprotein E genotype-dependent differences in intact exosomal fingerprints. Transcriptome analysis confirmed that ultrasound stimulation increased exosome secretion and up-regulated exosome-related genes functionally linked to Alzheimer's pathology. Ultrasound-based stimulation and label-free exosome profiling reveal genotype-specific pathologies, providing a precision-diagnostic framework for Alzheimer's disease.