The thermodynamic state map of biomolecular condensates

Abstract

Biomolecular condensates spatiotemporally regulate cellular biochemistry through liquid-liquid phase separation. In this Perspective, we refine the Condensate Code as a testable thermodynamic state map that integrates continuous cellular inputs, intrinsic molecular grammar and boundary conditions to govern measurable material states. Building on stickers-and-spacers and related grammar frameworks, we highlight a continuum from electrostatic coacervates to viscoelastic networks. We define active anti-grammar as an operational umbrella for localized repulsive or hydration-promoting effects that can counterbalance excessive cohesion when embedded in, modified within or recruited to dense phases. This view predicts measurable changes in partitioning, FRAP recovery, viscosity, aging and fibril-nucleation kinetics. Disruption of the code can drive pathogenic liquid-to-solid transitions and spatial uncoupling with organelle mechanotoxicity. We therefore conceptualize physical therapeutics as programmable macromolecular modulators that test whether localized anti-cohesive effects can remodel pathological material states while monitoring targeting, partitioning, oligomeric intermediates and safety.