Sensors that are able to detect and track single unlabelled biomolecules are an important tool both to understand biomolecular dynamics and interactions at nanoscale, and for medical diagnostics operating at their ultimate detection limits. Recently, exceptional sensitivity has been achieved using the strongly enhanced evanescent fields provided by optical microcavities and nano-sized plasmonic resonators. However, at high field intensities photodamage to the biological specimen becomes increasingly problematic. Here, we introduce an optical nanofibre based evanescent biosensor that operates at the fundamental precision limit introduced by quantisation of light. This allows a four order-of-magnitude reduction in optical intensity whilst maintaining state-of-the-art sensitivity. It enables quantum noise limited tracking of single biomolecules as small as 3.5 nm, and surface-molecule interactions to be monitored over extended periods. By achieving quantum noise limited precision, our approach provides a pathway towards quantum-enhanced single-molecule biosensors. IntroductionEvanescent optical biosensors that operate label-free and can resolve single molecules have applications ranging from clinical diagnostics 1 , to environmental monitoring 2, 3 and the detection and manipulation of viruses 4 , proteins and antibodies [5][6][7] . Further, they offer the prospect to provide new insights into motor molecule dynamics and biophysically important conformational changes as they occur in the natural state, unmodified by the presence of fluorescent markers or nanoparticle labels 5 . Recently, the reach of evanescent techniques has been extended to single proteins with Stokes radii of a few nanometers 1,6 by concentrating the optical field using resonant structures such as optical microcavities 2, 4, 5 and plasmonic resonators 1,6,7 . These advances illustrate a near-universal feature of precision opti- cal biosensors -that increased light intensities are required to detect smaller molecules or improve spatiotemporal resolution. This increases the photodamage experienced by the specimen, which can have broad consequences on viability 8 , function 9 , structure 10 and growth 11 . It is therefore desirable to develop alternative biosensing approaches that improve sensitivity without exposing the specimen to higher optical intensities.Here we demonstrate an optical nanofibre-based approach to evanescent detection and tracking of unlabelled biomolecules that utilises a combination of heterodyne interferometry and dark field illumination. This greatly suppresses technical noise due to background scatter, vibrations and laser fluctuations that has limited previous experiments 12,13 , allowing operation at the quantum noise limit to sensitivity introduced by the quantisation of light. The increased information that is extracted per scattered photon enables state-of-the-art sensitivity to be achieved with optical intensities four orders of magnitude lower than has been possible previously 1,6 . Using the biosensor, we detect nan...

We demonstrate a single-mode phononic waveguide that enables robust propagation of mechanical waves. The waveguide is a highly-stressed silicon nitride membrane that supports the propagation of out-of-plane modes. In direct analogy to rectangular microwave waveguides, there exists a band of frequencies over which only the fundamental mode is allowed to propagate, while multiple modes are supported at higher frequencies. We directly image the mode profiles using optical heterodyne vibration measurement, showing good agreement with theory. In the single-mode frequency band, we show low-loss propagation (∼ 1 dB/cm) for a ∼ 5 MHz mechanical wave. This design is well suited for phononic circuits interconnecting elements such as non-linear resonators or optomechanical devices for signal processing, sensing or quantum technologies.

The structural dynamics of macromolecules is important for most microbiological processes, from protein folding to the origins of neurodegenerative disorders. Noninvasive measurements of these dynamics are highly challenging. Recently, optical sensors have been shown to allow noninvasive time-resolved measurements of the dynamic polarizability of single-molecules. Here we introduce a method to efficiently predict the dynamic polarizability from the atomic configuration of a given macromolecule. This provides a means to connect the measured dynamic polarizability to the underlying structure of the molecule, and therefore to connect temporal measurements to structural dynamics. To illustrate the methodology we calculate the change in polarizability as a function of time based on conformations extracted from molecular dynamics simulations and using different conformations of motor proteins solved crystalographically. This allows us to quantify the magnitude of the changes in polarizablity due to thermal and functional motions.