Chiral molecule sensing is vital for drug development and biomedical applications. However, single-molecule chiroptic detection remains challenging with traditional techniques like single-molecule Raman and fluorescence spectroscopy, and nanopore sensing, which struggle to discriminate enantiomers. Nanophotonics offers a promising solution using superchiral fields and plasmon-coupled circular dichroism (PCCD), characterized by single-particle circular differential scattering (CDS) spectroscopy. While synergy of enhancement mechanisms improves sensing to a few biomolecules, limited control over gap size and biomolecule orientation results in small CDS enhancement and a chiral sensing limit above single molecules. Extreme nanophotonic constructs like Au NPOMs with sub-nm gaps offer huge local electric field enhancement, enabling single-molecule strong coupling, active quantum plasmonics, and optomechanics. Easily fabricated via drop-casting, these NPOMs provide single-particle nanocavities with out-of-plane electric field dipoles, serving as a sensitive platform for single chiral molecules where quantum tunneling might affect chiroptic responsivity. This study investigates whether this quantum tunneling effect, typically detrimental due to reduced local E-field, impacts the optical chirality of the tunneling structure.

Previous research has explored various nanophotonic approaches to enhance chiral sensing. Nanoparticles, nanorods, and nanochains have been investigated, but they suffer from limitations in sensitivity and control over the interaction with chiral molecules. The use of superchiral fields and plasmon-coupled circular dichroism (PCCD) has shown some promise, but the sensitivity remains limited. Studies on nanoparticle-on-mirror (NPOM) structures have demonstrated significant local field enhancement, but their application to chiral sensing at the single-molecule level has not been fully explored. This study builds upon these previous efforts by combining the advantages of NPOM structures with the unique properties of helical oligoamide sequences to achieve unprecedented sensitivity in chiral sensing.

The researchers synthesized helical oligoamide sequences (OSs) with controlled P or M-helicity, which can duplex into enantiomers of double helices (DHs) via π-π interactions. These DHs exhibit distinctive absorption and circular dichroism (CD) in the UV region. A self-assembled monolayer (SAM) of these helices was formed on Au films, and Au NPs were drop-cast on top to create the NPOM/OS system. The ultrathin spacer of the SAM (<2 nm) resulted in intense electric field confinement in the nanogap. Circular differential scattering (CDS) spectroscopy was used to measure the chiroptic response of the NPOM/OS system. The researchers used a customized dark-field microscope to acquire CDS spectra with both right and left circularly polarized light. The CDS intensity was statistically analyzed over multiple individual NPs. Finite element method (FEM) simulations were performed to model the system and compare with the experimental results. The packing density of DHs in the SAM film was measured using quartz crystal microbalance. Temperature-induced dissociation of OS DHs was used to further reduce the gap size and study the quantum tunneling regime. A quantum-corrected model (QCM) was used to simulate the scattering spectra in both classical and quantum regimes. The researchers introduced a term to account for the additional contribution of Coulomb interactions between chiral OS and tunneling electrons to the overall chiral light-matter interaction. The mode volume of the NPOM was calculated using the Purcell formula. The synthesis of OSs involved standard organic chemistry techniques, including column chromatography and NMR spectroscopy. Detailed characterization of OSs is provided in Supplementary Information.

The NPOM/OS system exhibited a giant CDS enhancement (up to -6 × 10⁶), significantly larger than other nanophotonic structures. The strong Coulomb interactions between the chiral supramolecules and tunneling electrons compensated for the decrease in local E-field caused by tunneling, leading to a dramatic increase in CDS enhancement in the quantum regime. The system could detect a minimum of four molecules per single Au particle, allowing for the detection of enantiomeric excess within a monolayer. The racemic mixture, achiral as an entity, was locally resolved as enantiomer excess (ee) in the single Au NPOM gap due to population fluctuations. The experimental CDS spectra showed good agreement with FEM simulations. As the gap size decreased, the plasmon resonances first redshifted and then blueshifted due to quantum tunneling. The quantum-corrected model accurately predicted the scattering spectra in the quantum regime. The additional contribution of Coulomb interactions between chiral OS and tunneling electrons enhanced the CDS intensity even below the quantum tunneling limit. The alignment of the molecular dipole to the plasmonic dipole further increased the CDS enhancement. The NPOM system demonstrated superior chiral sensing capabilities compared to other nanophotonic structures in terms of mode volume, g-factor, and detection limit. The study revealed the full picture of light-chiral matter interaction at different scales.

The high sensitivity of the NPOM/OS system is attributed to the giant Coulombic interactions of electron tunneling and the PCCD mechanism. This system offers advantages over other chiral nanophotonic structures due to its facile fabrication, small mode volume, intense local electric field, and large g-factor. The unique design enables access to the quantum plasmonic regime, revealing additional CDS enhancement from the quantum tunneling effect. The study provides a comprehensive understanding of chiral light-matter interactions. The design principles and measurement techniques presented can serve as a guideline for developing advanced nanosensors for enantiomer discrimination, biomedical diagnosis, and drug quality control.

This research successfully demonstrated a novel chiral sensing platform based on a tunable supramolecular plasmonic system. The combination of helical oligoamide sequences and nanoparticle-on-mirror resonators achieved unprecedented single-molecule sensitivity. The observed enhancement in chiral sensitivity in the quantum tunneling regime highlights the importance of Coulomb interactions between chiral molecules and tunneling electrons. This work offers significant advancements in chiral sensing with implications for various applications, including biomedical diagnostics and drug development. Future research could explore different chiral molecules and NPOM designs to further optimize the system's performance and expand its applicability.

The study focused on a specific type of chiral molecule (helical oligoamide sequences). The generalizability of the findings to other types of chiral molecules needs further investigation. The fabrication method relies on self-assembly, which can lead to variations in the nanogap size and orientation of molecules. The simulations were based on certain assumptions and approximations, which might affect the accuracy of the results. A more detailed investigation into the influence of the substrate effects on CDS intensity is needed.