1 Optical Bio-Microsystems Laboratory, Department of Mechanical and Industrial Engineering, Concordia University, Montreal, QC H3G 1M8, Canada.

Cancer diagnosis requires alternative techniques that allow for early, non-invasive, or minimally invasive identification. Traditional methods, like tissue biopsies, are highly invasive and can be traumatic for patients. Liquid biopsy, a less invasive option, detects cancer biomarkers in body fluids such as blood and urine. However, early-stage cancer often presents low biomarker levels, making sensitivity a challenge for integrating liquid biopsy into early diagnosis. Recent studies revealed that extracellular vesicles (EVs) secreted by cells are apt markers for liquid biopsy. Detecting extracellular vesicles (EVs) for liquid biopsy faces challenges like low sensitivity, EV subtype heterogeneity, and difficulty isolating pure populations. Label-free methods, such as plasmonic biosensors and Raman spectroscopy, offer potential solutions by enabling direct analysis without markers, improving accuracy, and reducing complexity. This review paper discusses current challenges in EV-based liquid biopsy for cancer diagnosis and prognosis. It addresses the effective use of microfluidics and nano-plasmonic approaches to address these challenges. Enhancing label-free EV detection in liquid biopsy could revolutionize early cancer diagnosis by offering non-invasive, cost-effective, and rapid testing. This could improve patient outcomes through personalized treatment and ease the burden on healthcare systems.