Ionophore-Based SERS Nanosensors for Selective Electrolyte Detection and Intracellular Mapping

Quantitative detection of electrolyte ions in complex biological environments requires nanosensors with high sensitivity, reproducibility, and selectivity. We report an ionophore-based nanoscale surface-enhanced Raman spectroscopy (SERS) platform that integrates Au/Ag nanoparticles with chromoionophore I (CHI) for ratiometric ion detection. The plasmonic nanostructures provide a stable and biocompatible interface for assembling ionophores, ion exchangers, and indicator molecules, yielding reproducible SERS responses with relative standard deviations below 6.6%. The nanosensors exhibited limits of detection of 0.01 mM for Na⁺ and Ca²⁺ and 0.1 mM for K⁺, with excellent selectivity against competing cations. 2-Naphthalenethiol (2-NT) was further cofunctionalized with the SERS-based ion-selective nanosensors as an internal standard, allowing precise normalization of the CHI signal. These nanosensors achieved sensitive detection of Na⁺ in human blood serum without matrix interference and further enabled in situ mapping of intracellular Na⁺ dynamics in live HT-29 cells. Moreover, pixel-wise conversion of SERS intensity ratios demonstrated a strong potential for quantitative intracellular ion mapping. This work establishes a versatile nanosensor platform for electrolyte ion quantification in biological samples, opening opportunities for the multiplexed SERS detection of small inorganic species in biofluids and living systems.