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Single-molecule detection is one of the fundamental challenges of modern biology. Such experiments often use labels that can be expensive, difficult to produce, and for small analytes, might perturb the molecular events being studied. Analyte size plays an important role in determining detectability. Here we use laser-frequency locking in the context of sensing to improve the signal-to-noise ratio of microtoroid optical resonators to the extent that single nanoparticles 2.5 nm in radius, and 15.5 kDa molecules are detected in aqueous solution, thereby bringing these detectors to the size limits needed for detecting the key macromolecules of the cell. Our results, covering several orders of magnitude of particle radius (100 nm to 2 nm), agree with the ‘reactive’model prediction for the frequency shift of the resonator upon particle binding. This confirms that the main contribution of the frequency shift for the resonator upon …