Hepatitis viral infections are the most common cause of hepatitis liver disease, which eventually leads to cancer and fibrosis if undetected early. Therefore, early detection would allow for pre-ventive and therapeutic actions. Here, a Raman spectroscopy-based biosensor was developed using plasmonic molybdenum trioxide quantum dots-based substrates functionalized with a proteoglycan (Syndecan-1) as a novel bioreceptor for target hepatitis E virus (HEV). The innova-tive bio-detection system achieved a detection limit of 1.05 fg/mL for tested HEV antigen (ORF2), indicating superb clinically relevant sensitivity and performance. The designed biosensing system incorporating a glycan motif as a bioreceptor instead of the conventional antibodies or aptamers, presents new insights for the ultrasensitive detection of HEV and other infectious viruses.