Boosting the sub-cellular biomolecular cancer signals by self-functionalized tag-free nano sensor

Surface Enhanced Raman Scattering (SERS)-based sub-cellular cancer diagnosis can simultaneously obtain multiple biomolecular signals crucial in diagnostic platform for a heterogeneous disease like cancer. But, SERS-probes being typically tagged with chemical functionalization demonstrate limitations due to adverse biocompatibility, ineffective cellular internalization, SERS-signal quenching and spectral contamination. Although, tag-free SERS-probes overcome these limitations; complexity in spectral interpretation and detection insensitivity make it disadvantageous. In this study, we have exploited the inherent charges of cellular biomolecules and introduced self-functionalized complementary charged, tag-free SERS nano probes for biomolecule-specific investigation. Extremely small nano probes (sub 10 nm), synthesized with multiphoton ionization were functionalized with charge by physical synthesis without any ligands or chemical processes. The probes demonstrated significant SERS (EF~10⁶) with analyte molecules (4ATP & 4MBA). Multifold signal boost was achieved for the signals of cellular components - amplification of ~7 fold for DNA, ~16 fold for proteins and ~24 fold for lipids with the commentary charged nano probes as compared to the neutral nano probes. The signal boost was attributed to the efficient delivery of extremely small, complementary charged probes to the cellular biomolecules of interest enabling simultaneous detection of sub-cellular biomolecules such as DNA, proteins and lipids and with high reproducibility. Cancer classification and investigation of drug resistance in cancer with single cell sensitivity was demonstrated. Such biomolecule-specific investigation of cancer from intact cells will open pathways for comprehensive cancer diagnosis.