Blu-Ray-Based Quantification of CD98+ Extracellular Vesicles for Early Detection of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a major global health burden, with an increasing incidence driven by metabolic syndrome-related cases. Early detection is critical; however, current diagnostic tools, including ultrasonography and alpha-fetoprotein (AFP), lack adequate sensitivity and specificity, particularly for non-viral HCC. In this "discovery-stage" study, we identified CD98, a transmembrane oncoprotein, as a robust biomarker highly expressed across all HCC stages, independent of etiological factors. CD98 is enriched on extracellular vesicles (EVs) released by HCC cells and can be accurately quantified using Blu-ray-based ExoCounter technology. In plasma samples from patients with early-stage (stage I/II) non-viral HCC (n = 136) and healthy controls (n = 50), CD98+ EV levels were significantly elevated (p < 0.001) and demonstrated strong diagnostic performance (AUC = 0.743; sensitivity 64%, specificity 86%). Importantly, CD98+ EV levels detected small tumors (≤3 cm) with 59% sensitivity, outperforming AFP (33%). These findings highlight circulating CD98+ EVs as a promising, noninvasive biomarker for early non-viral HCC detection, providing a clinically applicable platform that integrates EV quantification with a novel anti-CD98 monoclonal antibody for precision oncology.