Harnessing Competitive Interactions to Regulate Supramolecular "Micelle-Droplet-Fiber" Transition and Reversibility in Water

The supramolecular assembly of proteins into irreversible fibrils is often associated with diseases in which aberrant phase transitions occur. Due to the complexity of biological systems and their surrounding environments, the mechanism underlying phase separation-mediated supramolecular assembly is poorly understood, making the reversal of so-called irreversible fibrillization a significant challenge. Therefore, it is crucial to develop simple model systems that provide insights into the mechanistic process of monomers to phase-separated droplets and ordered supramolecular assemblies. Such models can help in investigating strategies to either reverse or modulate these states. Herein, we present a simple synthetic model system composed of three components, including a benzene-1,3,5-tricarboxamide-based supramolecular monomer, a surfactant, and water, to mimic the condensate pathway observed in biological systems. This highly dynamic system can undergo "micelle-droplet-fiber" transition over time and space with a concentration gradient field, regulated by competitive interactions. Importantly, manipulating these competitive interactions through guest molecules, temperature changes, and cosolvents can reverse ordered fibers into a disordered liquid or micellar state. Our model system provides new insights into the critical balance between various interactions among the three components that determine the pathway and reversibility of the process. Extending this "competitive interaction" approach from a simple model system to complex macromolecules, e.g., proteins, could open new avenues for biomedical applications, such as condensate-modifying therapeutics.