Autonomous Nanoparticle Synthesis Guided by <i>In Situ</i> Multiscale Structural Characterization

Autonomous synthesis platforms promise rapid exploration of vast parameter spaces; yet, integrating <i>in situ</i> structural characterization in closed-loop synthesis optimization remains challenging. We demonstrate a realization of such a closed-loop platform coupled with a droplet-flow microreactor, <i>in situ</i> X-ray scattering methods (SAXS/WAXS), and Gaussian process optimization to synthesize citrate-reduced Au nanoparticles with targeted characteristics. The system efficiently explored ∼19,000 synthesis recipes through 365 experiments, achieving precise control over size (4-60 nm) and polydispersity (σ < 0.11) across large citrate/gold ratios, exceeding traditional synthesis boundaries (1-10). Beyond confirming classical Turkevich-Frens trends, partial-dependence analysis revealed strong nonlinear coupling among precursor, citrate, and pH effects. Combining quantitative SAXS/WAXS analysis with electron microscopy characterization, we uncovered that crystallite size (<i>d</i>_c) and particle size (<i>d</i>) follow <i>d</i>_c = 0.18<i>d</i> + β, where synthesis chemistry controls the intercept β while maintaining a universal slope. This parallel-band structure enables independent tuning of crystallite domain size at fixed particle diameter through a combination of chloride, gold precursor, citrate, and pH contributions (cross-validated Spearman ρ = 0.7 ± 0.1). High-resolution electron microscopy shows multiple lattice-fringe orientations within single particles, directly confirming polycrystalline domains and the ability to tune <i>d</i>_c at the fixed <i>d</i>. The platform's validation includes indistinguishable static versus flowing measurements, stable droplet transport at 100 °C, and <5% run-to-run variation, establishing a robust framework for mapping and controlling multiscale nanoparticle structure across expansive chemical spaces. The developed closed-loop platform can be applied to a borad range of nanosyntheis processes.