Label-Free Single Exosome Detection Using Frequency-Locked Microtoroid Optical Resonators

Recently exosomes have attracted interest due to their potential as cancer biomarkers. We report the real-time, label-free sensing of single exosomes in serum using microtoroid optical resonators. We use this approach to assay the progression of tumors implanted in mice by specifically detecting low concentrations of tumor-derived exosomes. Our approach measures the adsorption of individual exosomes onto a functionalized silica microtoroid by tracking changes in resonant frequency of the microtoroid. When exosomes land on the microtoroid, they perturb its refractive index in the evanescent field and thus shift its resonance frequency. Through digital frequency locking, we are able to rapidly track these shifts with accuracies of better than 10 attometers (one part in 1011). Samples taken from tumor-implanted mice from later weeks generated larger frequency shifts than those from earlier weeks. Analysis of these shifts shows a distribution of unitary steps, with the maximum step having a height of ∼1.2 fm, corresponding to an exosome size of 44 ± 4.8 nm. Our results demonstrate the development of a minimally invasive tumor “biopsy” that eliminates the need to find and access a tumor.