Enrichment-Free Detection of Trace Exosomes Enabled by Liquid Crystal Optics

Detection of stem cell exosomes advances our understanding of stem cell biology and offers new pathways for disease treatment and diagnosis. However, the clinical translation is significantly hindered by low yields and the need for time-consuming enrichment. Here, we propose "direct exosome detection (DED)", an efficient, cost-effective, label-free, and highly specific liquid crystal (LC)-based optical platform that detects trace exosomes in complex media without pre-enrichment. By harnessing the optical amplification effect of LC, the specific binding of exosomes to hexadecyltrimethylammonium bromide (CTAB)-absorbed aptamers triggers a stretch-to-hairpin-like conformational transition of aptamers, causing a planar-to-vertical alignment and, correspondingly, a bright-to-dark optical signal transition in the LC. Molecular dynamics (MD) simulations validate that LC orientational orders and the collective optical responses respond to subtle biochemical binding events and their interaction energies at the LC-aqueous interface, consistent with the experimental results. This DED platform enables ultra-high sensitivity with a detection limit of 9.18 × 10³ particles/mL, with an <i>R</i>² value of 0.9976 for the detection of mesenchymal stem cell (MSC) exosomes, while offering significantly faster detection time within 10 min. The LC-based DED platform also demonstrates robust performance in exosome drug screening and high selectivity in complex clinical samples, including prostate cancer‑derived exosomes. Finally, a smartphone‑integrated portable DED (S-DED) prototype validates the approach for point‑of‑care testing. LC-based DED offers a simple, reliable, and highly sensitive paradigm for trace exosome detection and early disease diagnosis.