Dilute but Dense – Reversible Crosslinking Enables Water‐Rich (Bio)polymer Condensates

Liquid-liquid phase separation (LLPS) of polymers underlies the formation of biomolecular condensates and offers a versatile route to functional soft materials. Traditionally, LLPS is attributed to changes in solvent quality or associative coacervation, but here a purely entropic connectivity-driven mechanism is demonstrated: reversible crosslinking. Using coarse-grained simulations of a minimal bead-spring model in good solvent, it is shown that transient, pairwise crosslinks alone can drive phase separation at ultralow polymer densities, yielding highly swollen, water-rich condensates. The phase behavior exhibits closed-loop coexistence and re-entrant percolation. This is captured quantitatively by a mean-field Semenov-Rubinstein theory with a single fit parameter, the effective repulsion parameter. Notably, phase boundaries are largely robust to rearrangements of crosslinkable domains along the sequence; only highly blocky sequences appreciably reduce the phase separation region and can even convert condensates into micelles or connected micelle networks. These results establish an entropy-enabled mechanism for mesoscale organization and suggest routes to programmable, membraneless materials in synthetic and RNA-protein contexts.