In a groundbreaking advancement poised to redefine the boundaries of molecular detection, researchers at South China University of Technology have unveiled a novel mechanism that significantly elevates the sensitivity and uniformity of single-molecule Raman spectroscopy. This breakthrough leverages the synergistic interaction between electromagnetic and chemical enhancement effects, brought together through an innovative Coulomb attraction-driven spontaneous “molecule-hotspot” pairing mechanism, enabling ultra-sensitive, rapid, and large-scale uniform detection of individual molecules.
Single-molecule Raman spectroscopy (SM-RS) represents a pinnacle of analytical precision, capable of providing detailed molecular insights that are typically obscured in bulk measurements due to ensemble averaging. Traditionally, achieving Raman signals with intensities comparable to those seen in fluorescence detection has long been an elusive goal, principally due to Raman scattering’s inherently weak cross-section. The team led by Professor Zhi-Yuan Li addresses this limitation by integrating advanced nanophotonic structures with two-dimensional (2D) semiconductor materials, thereby amplifying the Raman response to unprecedented levels.
Central to this innovation is the finely engineered SM-SERS (single-molecule surface-enhanced Raman spectroscopy) substrate, an intricate assembly that couples gold nanospheres with WS₂ monolayer flakes separated by a thin SiO₂ dielectric layer. The resulting system capitalizes on localized surface plasmon resonances within metallic nanogaps—regions where electromagnetic fields concentrate intensely at the nanoscale—to achieve electromagnetic enhancement (EME) factors reaching up to 10^11. Simultaneously, the WS₂ monolayers provide a complementary chemical enhancement effect (CME), estimated at 10^4 to 10^5, grounded in charge transfer interactions that further intensify Raman scattering at the molecule-substrate interface.
What sets this discovery apart is the elucidation of a Coulomb attraction-driven self-assembly process that ensures spatial precision between analyte molecules and plasmonic hotspots. Positively charged dye molecules such as Rhodamine B (RhB), Rhodamine 6G (R6G), and Crystal Violet (CV) are electrostatically drawn towards negatively charged gold nanoparticles. This spontaneous pairing, confirmed by zeta potential measurements, orchestrates the formation of optimized plasmonic nanogaps precisely where the molecules reside on WS₂ flakes. This self-aligning phenomenon not only maximizes signal enhancement but also dramatically improves the uniformity and reproducibility of single-molecule detection sites across large substrate areas.
The research tackles one of the perennial challenges in Raman spectroscopy: background fluorescence which often masks the weak Raman signals. By shifting the excitation wavelength to the near-infrared region (785 nm), the team effectively suppresses fluorescence interference encountered under visible light excitation. This strategic choice not only eliminates fluorescent noise but also amplifies the Raman signal intensity by approximately 100 times compared to conventional 532 nm laser excitation, delivering a significantly improved signal-to-noise ratio vital for reliable single-molecule detection.
Beyond fundamental scientific interest, the practical implications of this technique are substantial. The SM-SERS substrates demonstrate stable and reproducible detection capabilities over expansive macroscopic areas, with Raman mapping over 5 mm × 5 mm surfaces revealing a consistent distribution of active sites. At analyte concentrations as low as 10^-16 M, the sensors detect multiple active Raman hotspots even within small micro-scale regions, underscoring their remarkable sensitivity and uniform response. Such performance paves the way for applications demanding ultra-trace molecular detection with high throughput, including biosensing, environmental monitoring, and chemical analysis.
The integration of 2D WS₂ crystals plays a pivotal role not only in chemical enhancement but also in substrate stability and molecule affinity. The monolayer WS₂ provides a robust scaffold which binds analyte molecules tightly while maintaining compatibility with the metallic nanostructures responsible for electromagnetic enhancement. This dual-functionality ensures that the ‘hotspot’ plasmonic fields coincide spatially with molecular binding sites, essential for achieving consistent enhancement factors necessary for true single-molecule sensitivity.
Professor Zhi-Yuan Li’s team has meticulously optimized the interlayer architecture within the SM-SERS substrate. The presence of a precise 2 nm thick SiO₂ separation layer fine-tunes plasmonic interactions, balancing field enhancement with quenching effects that could otherwise limit sensitivity. This structural precision demonstrates an advanced understanding of nanoscale photonic engineering critical for maximizing the interplay between electromagnetic and chemical enhancements.
The Coulomb attraction-driven self-assembly mechanism discovered transcends earlier random adsorption models that suffered from low control over hotspot locations and analyte distribution. This electrostatic pairing ensures that each gold nanoparticle is strategically positioned atop analyte-bound WS₂ regions, fostering high-density and uniformly distributed hotspots. The mechanism’s inherent physical robustness translates into improved reproducibility and stability across multiple detection cycles, addressing a significant bottleneck in single-molecule Raman spectroscopic technologies.
Importantly, this work showcases universality by effectively detecting a spectrum of commonly studied Raman probe molecules—RhB, R6G, and CV—with detection sensitivities reaching femtomolar levels. The ultrafast detection speed, with acquisition times as brief as 50 milliseconds, further highlights the instrument’s capability for rapid real-time monitoring. Such attributes are crucial for dynamic studies of molecular interactions and transient phenomena at single-molecule resolution.
This research opens new avenues for the deployment of SM-RS in practical settings, where uniformity and scalability have historically limited commercial adoption. The large-area uniform distribution of active sites demonstrated through comprehensive Raman mapping reaffirms the substrate’s potential for high-throughput screening, a significant leap towards integrating single-molecule sensitivity into routine analytical workflows. The demonstrated stability and reproducibility raise confidence in the technique’s applicability for continuous monitoring and quantitative analysis.
Beyond the experimental achievements, this work contributes profound insights into the fundamental physics governing plasmon-molecule coupling and nanoscale charge interactions. By bridging electromagnetic and chemical enhancement regimes via a well-defined physical mechanism, it sets a precedent for future design strategies in nanoscale photonics and spectroscopy. These insights could stimulate innovations across related domains including surface chemistry, nanofabrication, and quantum optics.
Published in the July 2025 issue of Opto-Electronic Advances, this research underscores the collaborative potential of material science and photonics to transcend longstanding analytical challenges. The team’s holistic approach, combining meticulous materials engineering with advanced optical characterization and theoretical grounding, exemplifies the integrative efforts driving modern nanoscience.
Professor Zhi-Yuan Li’s leadership has been instrumental in this achievement. With nearly three decades of experience in micro-nano photonics, nonlinear optics, and quantum physics, his extensive body of work—highlighted by an H-index of 90 and over 34,000 citations—reflects a career dedicated to pushing the limits of optical science. His vision in orchestrating this synergy between 2D materials and plasmonic nanostructures heralds a new paradigm in molecular spectroscopy and sensing technologies.
This exciting development holds promise not only for academic research but also for transformative technological applications in fields as diverse as medical diagnostics, environmental surveillance, and chemical manufacturing. As the frontier of single-molecule detection continues to advance, innovations such as the Coulomb attraction-driven spontaneous molecule-hotspot pairing mechanism will be pivotal in shaping the future landscape of molecular analysis.
Subject of Research: Single-Molecule Raman Spectroscopy, Plasmonic Nanogaps, Chemical and Electromagnetic Enhancement, 2D Materials (WS₂), Nanophotonics
Article Title: Coulomb attraction driven spontaneous molecule-hotspot pairing, Enabling universal, fast, and large-scale uniform single-molecule Raman spectroscopy
News Publication Date: 16-Jul-2025
Web References: http://dx.doi.org/10.29026/oea.2025.240309
Image Credits: Lihong Hong, Haiyao Yang, Zhi-Yuan Li
Keywords: Single-Molecule Detection, Surface-Enhanced Raman Spectroscopy, Plasmonic Nanogaps, WS₂ Monolayers, Electromagnetic Enhancement, Chemical Enhancement, Coulomb Attraction, Nanophotonics, Near-Infrared Excitation, Fluorescence Suppression, Molecular Sensing, 2D Materials
