Adaptive Condensates via Bidirectional Phase Transition Responsive to Physiological Cues

Abstract

Biomolecular condensates are membraneless organelles formed via liquid–liquid phase separation (LLPS) that organize biochemical reactions in the absence of a bounding membrane. Their dynamic phase behavior — including transitions through kinetically trapped intermediates and aging processes such as liquidto-solid transitions — is increasingly recognized as central to their biological function. Efforts to reconstitute such systems in vitro through artificial condensates, such as coacervates, have provided valuable platforms to dissect and engineer their behavior. Nevertheless, a comprehensive understanding of the mechanisms governing these phase transitions remains essential for mapping the full lifecycle of condensates and for stabilizing them in functionally desirable states. Herein, we report single-component, small-molecule-based condensates that exhibit bidirectional phase transitions. These condensates adopt a solid-like state with intermediate material properties between liquid-like condensates and solid aggregates, enabling adaptive transitions in response to physiological cues such as pH and redox state. Such bidirectional phase behavior allows the condensates to be dynamically tuned and functionally activated at targeted biointerfaces. To gain mechanistic insight, we systematically characterize the phase transition process across multiple length scales, integrating direct visualization of mesoscale morphology and dynamics, nanoscale structural characterization of condensate organization, and molecular-level computational modeling to elucidate the underlying interactions and transition pathways.