Ion-DrivenCyclic Hotspot Modulation for Tunable SERSDetection of Alpha-Fetoprotein

Abstract Accurate detection of alpha-fetoprotein (AFP) is vital for early cancer diagnosis, yet traditional immunoassays suffer from limited sensitivity. Although surface-enhanced Raman scattering (SERS) is a formidable analytical tool, existing platforms often encounter a performance saturation bottleneck upon reaching equilibrium, lacking a controllable regulation mechanism capable of guiding the stepwise intensification of hotspots for continuous gain throughout the analytical process. This work proposes a metal-ion-mediated cyclic amplification strategy. Inspired by coordination chemistry, aluminum ions (Al3+) serve as highly specific “molecular glues” that coordinate with the surface ligands of His/4-MBA-functionalized gold nanoparticles (His/4-MBA@Au NPs) to trigger their controlled aggregation. By iteratively introducing these Al3+ ions and functionalized Au NPs onto a solid-phase immunocomplex, we achieved a stepwise, programmable densification of 3D SERS hotspots. Unlike conventional “single-trigger” modes, this multicycle process allows for the evolutionary growth of assay performance, where hotspot tunability is realized by adjusting the number of cycles: initial stages (Cycle 1) provide a broad dynamic range, while highly densified hotspot architectures (Cycle 5) deliver superior ultratrace sensitivity. Consequently, the limit of detection (LOD) for the target AFP improved progressively from 8.6 pg·mL–1 in Cycle 1 down to an ultimate 0.043 pg·mL–1 in Cycle 5. This strategy exhibits excellent anti-interference capability in human serum, offering a versatile blueprint for ultratrace biomarker detection.