Design Principles for Polyelectrolyte Complex Micelles: Insights from Thermodynamics and Structure

Polyelectrolyte complex micelles (PCMs) form from the self-assembly of oppositely charged block polyelectrolytes in aqueous solution, driven by a balance of electrostatic interactions and entropic effects that yield a dense core with a stabilizing corona. Experimental studies have demonstrated the importance of these systems in the targeted delivery of oligonucleotides. While prior work has highlighted how molecular architecture tunes PCM morphology, less is known about the fundamental thermodynamic driving forces that govern micelle formation, as well as their structural underpinnings. Here, we combine scattering techniques with isothermal titration calorimetry to quantify free energy contributions to PCM assembly. Our results reveal an entropic penalty from the corona-forming neutral block, which depends on the length of the charged blocks, but not the neutral block. We further show that the entropy of complexation could be related to polymer chain packing within the micelle, rather than corona chain conformation. Combined scattering and calorimetry data also suggest that the PCM core–corona interface may be more diffuse than expected. These findings provide new structural insights into the free energy landscape of charged polymer self-assembly.