Live cell-plasmonic synergistic "sieving-enrichment" enables signal amplification and tunable molecular gating for...

Developing biochemical sensors that emulate the dynamic selectivity, high specificity and matrix tolerance of living systems is a long-standing goal in analytical science. While significant progress has been made with both functionalized nanomaterials and engineered whole-cell sensors, these approaches often remain limited by static, pre-defined recognition and slow, indirect signal readouts, respectively. Here, we introduce a live cell-plasmonic synergistic sensing system integrating the "sieving-enrichment" capability of native, un-engineered living cells with the direct molecular fingerprinting of SERS to overcome these limitations. In this system, plasmonic nanoparticles are internalized to exploit intracellular transport and enrichment pathways, enabling amplified and high-fidelity SERS signals within confined intracellular spaces to obtain direct molecular recognition. The cell membrane functions as a bio-sieve, providing adaptive matrix tolerance by excluding external interferents, while enabling tunable molecular gating through differential analyte permeability or simply modulation of the cell's metabolic state. This deep bio-integration even enables discrimination between structural analogues as well as different binding states of the same biomarker. This versatile system achieves pretreatment-free, matrix-tolerant quantitative analysis from environmental analysis to biomedical diagnostics. This work establishes a generalizable sensing paradigm whose molecular specificity can be readily realized on-demand by selecting cell lines with distinct transport or metabolic machinery.