Effect of Polymer Structure on the Thermodynamics of Polyelectrolyte Complex Micelle Formation

Polyelectrolyte complex micelles (PCMs) are nanoparticles that form through the associative phase separation between hydrophilic neutral–charged block copolymers and oppositely charged polyelectrolytes, resulting in a dense, charged core surrounded by a stabilizing neutral corona. Among other applications, these constructs have been studied as nonviral vectors for therapeutic nucleic acid delivery for a variety of potential clinical indications. Although prior research has focused on tailoring PCM morphology and size by modifying block polyelectrolyte characteristics, thermodynamic considerations have received comparatively little attention in the design of PCMs. In this study, we explore the dependencies of PCM complexation thermodynamics, particularly the entropy of complexation, on polyelectrolyte block length and PCM structure. We employ scattering (DLS, SAXS, MALS) to characterize PCM structure, while using isothermal titration calorimetry to provide quantitative thermodynamic data. Compared to complexation between homopolymers, we observe that PCM formation involving block polyelectrolytes introduces an entropic cost related to the neutral corona-forming block. This penalty depends on the sizes of the charged blocks but is relatively insensitive to the neutral block size. Scattering results show that PCM complexation entropy is not correlated with indicators of corona chain conformation, such as brush height and corona surface chain density. Rather, for PCMs composed of polymers with equal charged block lengths, complexation entropy is correlated with monomer density within the core and corona. Our findings also suggest a negligible free polymer concentration in PCM formulations with net neutral charge. These insights advance the rational design of block copolymers for encapsulating a wide array of therapeutically relevant cargos and deepen our understanding of the factors governing PCM formation.