Activity-Based Self-Enriched SERS Sensor for Blood Metabolite Monitoring

The monitoring of metabolites in biofluids provides critical clues for disease diagnosis and evaluation. Yet, the quantitative detection of metabolites remains challenging for surface-enhanced Raman spectroscopy (SERS) due to poor reproducibility in preparation and manipulation of SERS nanoprobes. Herein, we develop an activity-based, slippery liquid-infused porous surface SERS (abSLIPSERS) sensor for facile quantification of metabolites with unmodified naked metal nanoparticles (NPs) by integrating biocatalysis-boronate oxidation cascades with SLIPS-driven self-concentration and delivering. Upon mixing the target metabolite with a specific oxidase, a H₂O₂-sensitive phenylboronate probe, and the naked Au NPs, H₂O₂ produced from the biocatalytic reaction oxidizes the phenylboronate probe to phenol, resulting in a ratiometric SERS response. Meanwhile, the SLIPS enables the complete enrichment of molecules and NPs within an evaporating liquid droplet, delivering the probes to the SERS-active sites for Raman amplification. Compared with conventional SERS biosensors, abSLIPSERS avoids multistep synthesis and biofunctionalization of nanoprobes, which significantly simplifies the detection workflow and improves the reproducibility. The abSLIPSERS sensor also shows tunable dynamic range beyond 4 orders of magnitude and allows quantifying any other metabolites with specific enzymes. We demonstrate abSLIPSERS sensing of lactate, glucose, and choline in human serum for exploring energy metabolism in lung cancer. This study opens up a new opportunity for future point-of-care testing of circulating metabolites by SERS and will help to facilitate the translation of SERS bioanalysis to clinical settings.