Aug 2026· Biosensors & bioelectronics· Vol 313, pp.
119147
· 0 citations· 41 references
Medicine
TL;DR
A novel, enzyme-free surface-enhanced Raman scattering (SERS) platform based on a "dual-hotspot amplification" strategy that enhances detection sensitivity but also provides a useful design concept for the ultrasensitive analysis of carbohydrate-derived biomarkers.
Abstract
The precise detection of CA19-9 is paramount for early cancer diagnosis and clinical monitoring. However, traditional immunoassays are often hampered by their heavy reliance on matched antibody pairs and the insufficient sensitivity of enzymatic amplification systems. To address these limitations, we report a novel, enzyme-free surface-enhanced Raman scattering (SERS) platform based on a "dual-hotspot amplification" strategy. The core innovation lies in exploiting the dual-connectivity of phenylboronic acid (PBA) to achieve precise hotspot modulation via a multi-cycle assembly. By utilizing D-glucose as a reversible molecular bridge, this strategy successfully breaks the traditional "one-to-one" linear binding limit of PBA. It facilitates a synergistic transition from heterogeneous binding, which anchors nanoprobes to a BSA@CPBA macromolecular scaffold, to homogeneous binding that drives continuous inter-particle cross-linking. This cycle-dependent assembly transforms individual immune recognition events into a highly coupled 3D dendritic plasmonic network, resulting in progressive accumulation of plasmonic hotspots and amplified macroscopic SERS signals. Under optimized conditions, the proposed sensor achieves an exceptionally low limit of detection of 6.2 × 10-5 U/mL and a wide linear dynamic range spanning five orders of magnitude (10-4 to 10 U/mL). Furthermore, the platform demonstrates outstanding specificity and excellent reproducibility (RSD = 8.34%). Practical utility was validated in human serum samples with near-ideal recovery rates (98.67%-103.87%) and excellent agreement with clinical chemiluminescence immunoassays. This modular and cost-effective approach not only enhances detection sensitivity but also provides a useful design concept for the ultrasensitive analysis of carbohydrate-derived biomarkers.
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.
Meiqi Bao, Ling Zhang, Hongcai Liu et al.· Analytical Chemistry· 0 citations
A cascade-driven dual-signal attenuation strategy that holds great promise for high‑performance electrochemical biosensing in complex biological samples.
Ge Song, Jiaqing Wang, Xianrui Jiang et al.· Analytical and Bioanalytical...· 0 citations
Early and multiplex detection of Alzheimer’s disease (AD) biomarkers is essential for timely diagnosis and accurate disease staging; however, conventional immunoassays lack the sensitivity and multi-channel capability required to quantify extremely low-abundance proteins in complex biological matrices. In this work, we present a novel triple-target electrochemiluminescence (ECL) biosensor based on magnetic metal–organic frameworks (MMOFs) integrated with quantum-dot (QD)–mediated resonance energy transfer (RET) for the simultaneous detection of three clinically significant AD biomarkers: Amyloid Precursor Protein (APP), Clusterin, and Glial Fibrillary Acidic Protein (GFAP). The MMOF platform provides a high-surface-area, magnetically responsive scaffold that enables efficient immobilization of primary antibodies, while MoS₂ QDs, carbon quantum dots (CQDs), and CdSe/ZnS QDs act as spectrally distinct RET acceptors, facilitating clean and interference-free multiplexed ECL readout from a single TCPO-triggered excitation event. Under optimized analytical conditions, the biosensor displayed strong, concentration-dependent ECL responses across a wide dynamic range (40 ng/mL down to 0.0004 ng/mL). The calculated limits of detection demonstrated excellent sensitivity, achieving 0.67 pg/mL for APP, 0.92 pg/mL for Clusterin, and 0.54 pg/mL for GFAP, confirming the platform’s capability to quantify trace-level biomarkers far below their physiological concentrations. This remarkable performance arises from the highly efficient CRET mechanism between TCPO high-energy intermediates and the QD emitters, further enhanced by the synergistic dual co-reactant system (H₂O₂/APS).
Figure 1
Muhammad Faizan, Chi-Hsien Liu· ECS Meeting Abstracts· 0 citations
The precise quantification of adenosine triphosphate (ATP) at physiologically critical femtomolar levels in complex biological fluids remains a formidable challenge, constrained by irreconcilable demands for extreme sensitivity, specificity, and operational robustness. Conventional integrated platforms, such as LC-SERS, often suffer from functional fragmentation, in which separation and detection operate sequentially without synergy, thereby limiting overall performance. Stand-alone amplification strategies, meanwhile, are intrinsically hampered by matrix interference. Herein, we introduce a versatile biosensing paradigm that overcomes these limitations through the synergistic integration of two orthogonal amplification mechanisms within a unified microfluidic platform. Our dual-signal amplification microfluidic platform (2Amp-MFP) integrates online micro high-performance liquid chromatography (μHPLC) for target pre-enrichment and interference removal with a nanozyme-catalyzed SERS aptasensor (NC-SERS aptasensor) for ATP recognition and catalytic signal generation. The upstream amino-silica monolith (ASM) provides phosphate-dependent retention, allowing adenosine diphosphate (ADP), adenosine monophosphate (AMP), and matrix components to be removed during loading and washing, while triphosphate species are retained and subsequently eluted with a Mg2+-containing mobile phase. In the downstream aptasensor, ATP is selectively recognized, triggering the displacement of a fraction of the aptamer-conjugated Au@Pt nanozymes from the sensor interface. After washing, the Au@Pt@Aptamer NPs remaining hybridized on the monolith catalyze the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) to generate Raman-active reporter oxTMB, yielding a SERS intensity that decreases with increasing ATP concentration. Under optimized conditions, the 2Amp-MFP achieved a limit of detection (LOD) of 63 fM for ATP and enabled specific quantification of spiked ATP in human serum and urine samples. This synergistic dual-signal amplification strategy provides a promising platform for trace ATP analysis in complex biological matrices.
The critical need for accessible disease monitoring underscores the urgency of developing advanced point-of-care testing (POCT). We present a DNA-regulated catalytic-plasmonic colocalization-based synergy coupling mechanism that resolved the spatiotemporal disjunction commonly present in conventional SERS-catalysis systems through programmed spatial confinement. Rolling circle amplification-derived DNA nanocages were employed as programmable spatial regulators to precisely position Au@Pt nanozymes within plasmonic hotspots via base pair encoded hybridization, thereby enforcing spatial and temporal consistency between catalytic generation of Raman-active species and electromagnetic field enhancement. This strategy integrated coordinated interface, pore, and interlayer confinement, enabling cross-scale signal amplification from molecular to microscale levels. As a result, it yielded exceptional SERS enhancement (an approximate 41-fold versus controls), sensitivity (102 exosomes µL-1), and reproducibility (6.5% RSD). To translate this mechanism into practical application, a portable dual-modal detection platform with potential point-of-care applicability was developed that preserved catalytic-plasmonic colocalization during both colorimetric screening and SERS quantification. The device achieved radical miniaturization (95% volume, 91% weight reduction) and cost-efficiency (90% reduction vs. commercial systems). By coupling programmable nanomaterial design with customizable device engineering, we established a robust paradigm for next-generation POCT, providing a promising platform for biomedical detection, environmental surveillance, and food safety monitoring.
Yeru Wang, Rongke Gao, Zihao Wang et al.· Advances in Materials· 0 citations
This programmable dual-aptamer amplified luminescent proximity homogeneous assay (AlphaLISA) provides a rapid, homogeneous, and highly adaptable strategy for tumor-derived sEVs analysis, offering promising potential for noninvasive cancer diagnostics.