Size Distributions of Gold Nanoparticles in Solution Measured by Single-Particle Mass Photometry

Specialized applications of nanoparticles often call for particular, well-characterized particle size distributions in solution, but this property can prove difficult to measure. High-throughput methods, such as dynamic light scattering, detect nanoparticles in solution with an efficiency that scales with diameter to the sixth power. This diminishes the accuracy of any determination that must span a range of particle sizes. The accurate classification of broadly distributed systems thus requires very large numbers of measurements. Mass-filtered particle-sensing techniques offer a better dynamic range but are labor-intensive and so have low throughput. Progress in many areas of nanotechnology requires a faster, lower-cost, and more accurate measure of particle size distributions, particularly for diameters smaller than 20 nm. Here, we present a tailored interferometric microscope system, combined with a high-speed image-processing strategy, optimized for real-time particle tracking that determines accurate size distributions in nominal 5, 10, and 15 nm colloidal gold nanoparticle systems by automatically sensing and classifying thousands of single particles sampled from solution at rates as high as 4000 particles per minute. We demonstrate this method by sensing the irreversible binding of gold nanoparticles to poly-d-lysine functionalized coverslips. Variations in the single-particle signal as a function of time and mass, calibrated by TEM, show clear evidence for the presence of diffusion-limited transport that most affects larger particles in solution.