Ultrasensitive determination of surface proteins on tumor-derived small extracellular vesicles for breast cancer identification based on lanthanide-activated signal amplification strategy

Small extracellular vesicles (sEVs) carrying multiple tumor-associated proteins inherited from parental cells play crucial roles in noninvasive breast cancer (BC) diagnosis. However, it is challenging to assess the subtle varia-tions of surface proteins on sEV membranes due to the highly heterogeneous BC. Therefore, a simple and ultrasensitive assay based on lanthanide (Ln3+)-activated luminescence signal amplification was developed to detect multiple surface proteins on BC-derived sEVs. Multiple protein biomarkers on sEVs can be well identified with high sensitivity and specificity through dissolution-amplified luminescence of the NaEuF4 nanoparticle-based nanoprobe. We employ linear discriminant analysis to successfully discriminate triple negative BC cell (MDA-MB-231 cell) derived sEVs from other breast cell lines (MCF-7, SK-BR-3, BT474 and MCF-10A cell). Furthermore, the strategy enables high accuracy for districting the progression stages of BC patients and healthy donors. The simple and sensitive signal amplification strategy exhibits great potential for early clinic diagnosis by precise protein profiling of sEVs.