In the last decade, surface-enhanced Raman spectroscopy (SERS) met increasing interest in the detection of chemical and biological agents due to its rapid performance and ultra-sensitive features. Being SERS a combination of Raman spectroscopy and nanotechnology, it includes the advantages of Raman spectroscopy, providing rapid spectra collection, small sample sizes, characteristic spectral fingerprints for specific analytes. In addition, SERS overcomes low sensitivity or fluorescence interference that represents two major drawbacks of traditional Raman spectroscopy. Nanoscale roughened metal surfaces tremendously enhance the weak Raman signal due to electromagnetic field enhancement generated by localized surface plasmon resonances. In this paper, we detected label-free SERS signals for arbitrarily configurations of dimers, trimers, etc., composed of gold nanoshells (AuNSs) and applied to the mapping of osteosarcoma intracellular components. The experimental results combined to a theoretical model computation of SERS signal of specific AuNSs configurations, based on open cavity plasmonics, give the possibility to quantify SERS enhancement for overcoming spectral fluctuations. The results show that the Raman signal is locally enhanced inside the cell by AuNSs uptake and correspondent geometrical configuration generating dimers are able to enhance locally electromagnetic fields. The SERS signals inside such regions permit the unequivocal identification of cancer-specific biochemical components such as hydroxyapatite, phenylalanine, and protein denaturation due to disulfide bonds breaking between cysteine links or proline.
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