Mild periodate oxidation-based sialic acid-targeted background-free SERS imaging in cells and tissues

• Specific SERS profiling of sialic acid on cell and tissue samples. • Selective labeling of sialic acid is achieved by its mild oxidation by periodate. • The labeled Raman reporter has a background-free signal in Raman cellular silent region at 2130 cm −1 . • This strategy is expected to facilitate early diagnosis and therapeutic monitoring of cancer in the clinic. The detection of sialic acid (SA) on the membranes of cancer cells is a significant indicator for the early diagnosis of cancer and the determination of its stage. Therefore, its precise profiling is crucial for clinical diagnosis and treatment, but some challenges remain. In this study, we developed a surface-enhanced Raman scattering (SERS) imaging method without background interference; this method could efficiently analyze SA expression in cancer cells and clinically differentiate the relevant cancer tissues with different metastatic levels. Molecular traps targeting SA were constructed based on the selective periodate oxidation under specific mild conditions and the rapid in-situ gold nanoparticle growth strategy on the cell surface. They achieved specific SERS imaging of SA with the benefit of background-free Raman tags. This method was quick, simple, and noninvasive and could enable early cancer diagnosis, staging, and effective treatment monitoring.