Transitioning through Phases: Routes to Fabricate Structured Polymer Nanoparticles

Conspectus: Polymer nanoparticles are pivotal to innovation across nanomedicine, catalysis, and materials engineering. In nanomedicine, they act as smart carriers for therapeutic agents capable of navigating complex biological barriers while enabling targeted, controlled release. In catalysis, surface-active polymer nanoparticles stabilize Pickering emulsions, advancing green chemical processes. Their precise engineering also underpins technologies, such as electronic inks and 3D-printed devices. These diverse applications demand nanoparticles with tunable properties, driving key questions: What governs their structure and stability? How do polymer physics, fluid dynamics, and mass transport interact in the design? How do physicochemical traits influence behavior in complex environments?Fabrication of polymer nanoparticles typically involves precipitation via solvent exchange during the controlled mixing. As a polymer solution meets a nonsolvent, it transitions from a homogeneous to a partially or fully insoluble state, leading to the aggregation of polymer chains into solid particles. Mixing time scales─from milliseconds to hours─critically shape particle size and distribution. Slower mixing produces particles with broad size distributions with the final sizes strongly influenced by the mixing rate. In contrast, rapid mixing, faster than precipitation, leads to diffusion-limited aggregation over ∼1 μm eddies, yielding uniform particle sizes. Flash NanoPrecipitation (FNP) exemplifies this by using turbulent mixing within milliseconds to produce nanoparticles with controlled sizes, morphologies, and surface chemistries. The scalability of FNP bridges lab-scale insights to industrial production, as seen in COVID-19 vaccine manufacturing (Warne, N. et al. Delivering 3 Billion Doses of Comirnaty in 2021. Nat. Biotechnol. 2023 2023, 41(2), 183−188. 10.1038/s41587-022-01643-1).In this Account, we discuss how phase transitions in multicomponent systems, guided by phase diagrams, drive nanoparticle formation. We examine the interplay of thermodynamics, kinetics, fluid mechanics, and polymer physics in the design of structured nanoparticles. Using Flory–Huggins theory, we show how polymer–solvent compatibility affects particle morphology during slow, quasi-equilibrium mixing. In contrast, FNP drives rapid Gibbs free energy minimization, where nucleation and growth dynamics control the final structure of precipitated nanoparticles. Through experiments and simulations, we explain how mixing and material properties shape nanoparticle architecture─and highlight challenges in translating principles from simple to complex systems.