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Existing methods for the optical detection of single molecules require the molecules to absorb light to produce fluorescence 1 or direct absorption signals 2 , 3 , 4 . This limits the range of species that can be detected, because most molecules are purely refractive. Metal nanoparticles 5 , 6 or dielectric resonators 7 , 8 , 9 can be used to detect non-absorbing molecules because local changes in the refractive index produce a resonance shift. However, current approaches only detect single molecules when the resonance shift is amplified by a highly polarizable label 8 , 10 , 11 or by a localized precipitation reaction on the surface of a nanoparticle 12 . Without such amplification, single-molecule events can only be identified in a statistical way 13 . Here, we report the plasmonic detection of single molecules in real time without the need for labelling or amplification. Our sensor consists of a single gold nanorod coated with biotin receptors, and the binding of single proteins is detected by monitoring the plasmon resonance of the nanorod with a sensitive photothermal assay 14 . The sensitivity of our device is ∼700 times higher than state-of-the-art plasmon sensors 15 and is intrinsically limited by spectral diffusion of the surface plasmon resonance. Gold nanorods coated with biotin can be used to detect single proteins in real time by monitoring the surface plasmon resonance of the nanorod with a photothermal assay.

Liquid–liquid phase separation (LLPS) of biopolymers has recently been shown to play a central role in the formation of membraneless organelles with a multitude of biological functions 1 – 3 . The interplay between LLPS and macromolecular condensation is part of continuing studies 4 , 5 . Synthetic supramolecular polymers are the non-covalent equivalent of macromolecules but they are not reported to undergo LLPS yet. Here we show that continuously growing fibrils, obtained from supramolecular polymerizations of synthetic components, are responsible for phase separation into highly anisotropic aqueous liquid droplets (tactoids) by means of an entropy-driven pathway. The crowding environment, regulated by dextran concentration, affects not only the kinetics of supramolecular polymerizations but also the properties of LLPS, including phase-separation kinetics, morphology, internal order, fluidity and mechanical properties of the final tactoids. In addition, substrate–liquid and liquid–liquid interfaces proved capable of accelerating LLPS of supramolecular polymers, allowing the generation of a myriad of three-dimensional-ordered structures, including highly ordered arrays of micrometre-long tactoids at surfaces. The generality and many possibilities of supramolecular polymerizations to control emerging morphologies are demonstrated with several supramolecular polymers, opening up a new field of matter ranging from highly structured aqueous solutions by means of stabilized LLPS to nanoscopic soft matter. Spontaneous liquid–liquid phase-separation behaviour of high-aspect-ratio fibrils, obtained from supramolecular polymerizations of synthetic components, forms tactoids by means of an entropy-driven pathway.

The photophysical properties of single-molecule emitters are altered by nanophotonic structures such as single plasmonic nanoparticles. The intensity and spectral properties of plasmon-coupled emitters have been studied extensively, but little is known about the effect of plasmon coupling on emission polarization. Here, we examine how particle-emitter coupling modifies the polarization of single fluorophores in both experiment and simulation. We quantify degree of linear polarization using Stokes polarimetry with a polarization-sensitive camera and quantify the Stokes parameters with a single-shot acquisition without requiring additional optics in the detection path. We then perform polarization-resolved measurements of plasmon-coupled fluorescence from single-molecule emitters using an approach based on DNA-PAINT. We quantify the effect of the setup and associated noise sources on the measured Stokes parameters. We then quantify the angle of linear polarization (AoLP) and the degree of linear polarization (DoLP) for thousands of single molecules. We compare our results to a numerical model that propagates the plasmon-coupled single-molecule emission through the optical setup to yield the polarized point spread function in the camera plane. Simulations and experiments are in good agreement and shed new light on the polarization of antenna-coupled fluorophores, while it establishes single-shot polarimetry as a promising and straightforward method to quantify polarization properties at the single-molecule level.

Individual dye molecules coupled to a plasmonic nanoantenna have been established as a versatile foundation for single‐molecule studies. Crucial parameters such as fluorescence intensity enhancement, spectral properties, and emission patterns sensitively depend on the exact position of the dye molecule relative to the antenna and its hot spots. Knowledge about the binding location is therefore of paramount interest, however, it is highly challenging to obtain. We present a comprehensive approach based on correlative microspectroscopy of the optical properties of single fluorophores that transiently bind to gold nanocones using the DNA‐PAINT method. These 3D nanoantennas offer independently tunable in‐ and out‐of‐plane plasmon resonances with strong electric field enhancements at the tip apex and the nanocone base. We exploit site‐specific deformations of the point spread function in a high‐throughput approach as a means to correlate the position of the fluorophores on the nanoantenna surface to previously inaccessible parameters, investigating location‐specific binding probability, mode‐dependent spectral reshaping, and location‐resolved fluorescence enhancement factors. Our approach provides unprecedented multimodal quantification by correlating spatial and spectral information to open new avenues in fundamental studies of light–matter interactions and applications like biosensing. The fluorescence intensity as well as the spectral shape of the emission of single dye molecules strongly depend on the molecules’ exact position relative to plasmonic nanoparticles in hybrid systems. By point‐spread function modification analysis, the vertical binding location of single fluorophores on gold nanocones is obtained and correlated to both spectral features and particle‐size dependent binding rates.

Digital storage in five dimensions In the cause of cramming more and more data onto optical storage devices, materials scientists have sought to add extra dimensions to recording media, literally. Now a group from Melbourne's Swinburne University of Technology has developed a five-dimensional optical recording technique with the potential to increase storage capacities by several orders of magnitude. The extra dimensions are the wavelength and polarization of light, which integrated with the familiar three spatial dimensions creates true five-dimensional recording within one volume. The result is a theoretical 1.6 terabytes capacity for a DVD-sized disk. The new system makes use of surface plasmon resonance (SPR)-mediated photothermal reshaping of a substrate of gold nanorods immersed in a polymer layer. Crosstalk-free readout is via two-photon luminescence. Immediate applications can be found in security patterning and multiplexed optical storage. By exploiting not only the three spatial dimensions but also other ways to record information, it is theoretically possible to store much more onto an optical device such as a DVD than has hitherto been possible. Here, a five-dimensional optical recording technique using polarization of light and its wavelength as the two additional dimensions, is demonstrated. The method consists of using a substrate of gold nanorods immersed in polymer. Multiplexed optical recording provides an unparalleled approach to increasing the information density beyond 10 12 bits per cm 3 (1 Tbit cm -3 ) by storing multiple, individually addressable patterns within the same recording volume. Although wavelength 1 , 2 , 3 , polarization 4 , 5 , 6 , 7 , 8 and spatial dimensions 9 , 10 , 11 , 12 , 13 have all been exploited for multiplexing, these approaches have never been integrated into a single technique that could ultimately increase the information capacity by orders of magnitude. The major hurdle is the lack of a suitable recording medium that is extremely selective in the domains of wavelength and polarization and in the three spatial domains, so as to provide orthogonality in all five dimensions. Here we show true five-dimensional optical recording by exploiting the unique properties of the longitudinal surface plasmon resonance (SPR) of gold nanorods. The longitudinal SPR exhibits an excellent wavelength and polarization sensitivity, whereas the distinct energy threshold required for the photothermal recording mechanism provides the axial selectivity. The recordings were detected using longitudinal SPR-mediated two-photon luminescence, which we demonstrate to possess an enhanced wavelength and angular selectivity compared to conventional linear detection mechanisms. Combined with the high cross-section of two-photon luminescence, this enabled non-destructive, crosstalk-free readout. This technique can be immediately applied to optical patterning, encryption and data storage, where higher data densities are pursued.

Biosensing at the single-molecule level provides digital signals that enable the direct counting of individual molecular binding events. Single-molecule sensing provides digital signals, opening avenues toward kinetic fingerprinting while conferring higher tolerance to mechanical and temperature drift. Currently, single-molecule sensing is predominantly based on fluorescence probes. However, their weak signal poses challenges and necessitates the use of a research-grade microscope with a large footprint and high price. Here, we overcome these challenges and present a low-cost and compact microscopy platform for single-molecule biosensing. We quantify the performance of the platform where the use of a low numerical aperture lens results in a 10-fold reduced collection efficiency and a 6-fold increased background. Despite this, the strong digital signals provided by single-molecule plasmon-enhanced fluorescence are easily resolved, resulting in a limit of detection of 11 pM and a response time of 2 minutes. In addition, we demonstrate that the strong enhanced signals enable single-molecule detection of nucleic acid in diluted serum. Lastly, we integrate an automated pump and microfluidics to demonstrate continuous monitoring biosensing of a cancer marker on this miniaturized platform, thereby paving the way toward broad adoption of single-molecule devices for diagnostics.

This perspective discusses the future role of all-optical label-free single-molecule sensing. After summarizing the core working principles of the different detection modalities we discuss future research directions in terms of technology development and applications. In terms of future technologies we address research directions in the areas of multi-parametric and interaction free sensors, integration and miniaturization, and advanced data analysis. We further describe potential applications towards probing of protein interactions, DNA and protein sequencing, and molecular diagnostics.

Cancer remains a leading cause of mortality and morbidity worldwide. Consequently, the scientific community continues to pursue improvements in diagnostic methods and subsequent treatments. To enhance treatment efficacy and reduce the probability of adverse outcomes, reliable and sensitive diagnostic methods are essential. A potential solution may lie in the synergy between nanotechnology and optical biosensors, as they can provide exceptional sensitivity in the detection of disease biomarkers. This review focuses on fluorescent DNA probes assembled onto metal nanoparticles for cancer‐related applications. These hybrid biosensors exhibit remarkable and versatile optical properties enabling to enhance signal emission by orders of magnitude. In these configurations, metallic particles function as optical antennas for fluorescent dyes, significantly increasing their photon emission rates. This review presents a novel perspective on recent advancements in cancer diagnostics and treatment utilizing hybrid biosensors. Current methodologies for cancer diagnostics are examined, toward elucidating their advantages and limitations. The subject matter is critically evaluated, and fundamental concepts are explored to assess the most promising avenues for clinical applications. These biosensors may potentially integrate into medical practice and healthcare in the near future, both for the diagnosis and prognosis of cancer, as well as for precision (P4) medicine. Cancer is a leading cause of mortality, prompting advancements in diagnostics and therapy. The potential of hybrid nanobiosensors, specifically fluorescent DNA probes on metal nanoparticles, to improve cancer disease management is highlighted. Owing to the plasmonic properties of metal nanoparticles, these biosensors feature improved signaling emission through fluorescence enhancement, offering new insights into cancer diagnostics/therapy.

Purpose Timely detection of multidimensional frailty is important to prevent further negative outcomes. Perspectives of general practitioners (GPs) or informal caregivers might serve as a first, global screener to identify older people in need of a more extended assessment. Therefore, we aimed to investigate whether proxy assessments are associated with older people’s self-reported environmental, physical, psychological, social and overall frailty. Methods A cross-sectional study was conducted on 78 community-dwelling people aged 60 years and over, their GPs ( n  = 57) and informal caregivers ( n  = 50). Self-reported frailty was assessed with the Comprehensive Frailty Assessment Instrument. GPs and informal caregivers rated each frailty domain and overall frailty on a scale of 0 (not frail at all) to 10 (severely frail). Associations between proxy scores and self-reported frailty were examined by correlation analyses. Results Significant low to moderate associations were found between (1) self-reported physical frailty and physical frailty scores given by the GPs ( r  = 0.366, p  ≤ 0.01) and informal caregivers ( r  = 0.305, p  ≤ 0.05), and (2) self-reported psychological frailty and psychological frailty scores given by the GPs ( r  = 0.230, p  ≤ 0.05) and informal caregivers ( r  = 0.254, p  ≤ 0.05). No significant associations were found between proxy scores and self-reported environmental, social and overall frailty. Conclusions Global proxy scores as short, subjective screeners for detecting frailty cannot completely replace self-reported frailty. Nonetheless, low to moderate correlations were found for physical and psychological frailty ratings, suggesting that proxy scores might be of value as a first sign of something being wrong for these domains.