Molecularly imprinted plasmonic nanosensors: A reagent-free platform for ultrasensitive, real-time drug detection in complex biofluids

The development of rapid, sensitive, and selective sensors for drug detection in biological fluids remains a critical challenge in clinical and forensic analysis. While localized surface plasmon resonance (LSPR) offers a powerful label-free detection mechanism, its selectivity in complex matrices typically relies on biological receptors that lack stability and are costly. To address this limitation, we developed a novel plasmonic sensing platform integrating gold nanoparticles (AuNPs) with molecularly imprinted polymers (MIPs) to create robust synthetic receptors termed AuNP@MIP nanosensors and demonstrated its application for amphetamine detection. The AuNP@MIP composites were synthesized via solid-phase polymerization, and the effect of AuNP core size (5-100 nm) on sensor performance was systematically optimized. Comprehensive characterization using dynamic light scattering (DLS) and transmission electron microscopy (TEM) confirmed the composite morphology and homogeneity. The optimized LSPR sensor exhibited exceptional sensitivity and selectivity for amphetamine, achieving detection limits of 0.24 nM in buffer, 0.36 nM in urine, and 0.50 nM in plasma, with a linear range of 0.3-1.0 nM across all matrices, confirmed by triplicate measurements. No response was observed for paracetamol, while selectivity against structural analogues (methamphetamine and phenethylamine) showed negligible cross-reactivity (<0.2% for methamphetamine and <0.4% for phenethylamine). The AuNP@MIP platform combines the high sensitivity of plasmonic transduction with the tailor-made selectivity and robustness of MIPs, enabling rapid, real-time analysis directly in complex matrices without extensive sample preparation. This work establishes a versatile and powerful strategy for on-site drug monitoring, paving the way for next-generation, reagent-free biosensors.