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

ABSTRACT 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.