Bioorthogonal surface-enhanced Raman scattering flower-like nanoprobe with embedded standards for accurate cancer cell imaging

Developing precise and effective strategies for cancer identification and imaging is attractive due to their importance for early cancer detection, prognosis, and subsequent treatment. Herein, we reported a novel bioorthogonal surface-enhanced Raman scattering (SERS) nanoprobe for accurate cancer cell imaging. A novel coremolecule-shell nanoflower (Au@4-MBN@Au) with rich electromagnetic hot spots and enhanced Raman scattering was first synthesized by optimizing the embedded concentrations of 4-mercaptobenzonitrile (4-MBN). Then, Au@4-MBN@Au was further modified with FA-PEG-SH molecules to acquire the bioorthogonal SERS nanoprobe Au@4-MBN@Au-PEG-FA. The SERS nanoprobe illustrated a robust and stable nitrile stretching vibration Raman signal (2223 cm-1) in the cellular silent region, ensuring high sensitivity and ultra-accuracy SERS imaging of cancer cells. Furthermore, cell imaging results demonstrated Au@4-MBN@Au-PEG-FA could recognize FR-positive HeLa cells with high selectivity due to the high affinity between folate receptor and folic acid. More notably, Au@4-MBN@Au-PEG-FA has been applied to identify FR-positive Hela cells from co-cultured cancer cells with similar morphology by SERS imaging for the first time. With improved signal-to-background ratio, high selectivity, and excellent stability, we anticipate the SERS nanoprobe Au@4-MBN@Au-PEG-FA could be applied for FR-related cancer theranostics and clinical detection in the future.