Polymerization-Induced Self-Assembly versus Nanoprecipitation: A Systematic Comparison of Block Copolymer Micelle Properties

Amphiphilic block copolymers (BCPs) can assemble into a wide range of kinetically (meta)stable, nonequilibrium nanostructures, yet how distinct assembly pathways determine micellar morphology and kinetic trapping remains poorly understood. Here, we present a systematic experimental–theoretical comparison of three fundamentally different aqueous assembly strategies, namely, nanoprecipitation via solvent exchange with N,N-dimethylformamide (DMF), solvent evaporation using acetone (ACE), and polymerization-induced self-assembly (PISA) of monomethoxy poly(ethylene glycol)₉₀-block-poly(diacetone acrylamide)_x (mPEG₉₀-b-p(DAAm)_x) with x = 30, 50, 100, and 200. An extensive physicochemical analysis combining transmission electron microscopy (TEM), dynamic light scattering (DLS), asymmetric flow field-flow fractionation (AF4), and detailed small-angle X-ray scattering (SAXS) profile fitting provides direct evidence for pathway-dependent micellar size, aggregation number, polyethylene glycol (PEG) packing density, and the coexistence of mixed spheroidal and worm-like morphologies. Whereas PISA produces exclusively spheroidal micelles, both nanoprecipitation routes yield persistent morphological phase coexistence across all block ratios. Direct comparison with self-consistent field (SCF) theory predictions of (near-)equilibrium micellar morphologies reveals that kinetic trapping is ubiquitous and most pronounced for PISA-derived particles. Notably, despite stronger kinetic trapping, PISA exhibits higher reproducibility than nanoprecipitation-based assemblies. These findings demonstrate that controlled kinetic trapping and assembly pathways can be rationally exploited to fine-tune micellar nanostructures for advanced applications such as drug delivery.