Eugene Shakhnovich

Biomolecular condensates are functional assemblies, which can enrich intrinsically disordered proteins (IDPs) and/or RNAs at concentrations that are orders of magnitude higher than the bulk. In their native functional state, these structures can exist in multiple physical states including liquid-droplet phase, hydrogels, and solid assemblies. On the other hand, an aberrant transition between these physical states can result in loss-of-function or a gain-of-toxic-function. A prime example of such an aberrant transition is droplet aging—a phenomenon where some condensates may progressively transition into less dynamic material states at biologically relevant timescales. In this essay, we review structural and viscoelastic roots of aberrant liquid–solid transitions. Also, we highlight the different checkpoints and experimentally tunable handles, both active (ATP-dependent enzymes, post-translational modifications) and passive (colocalization of RNA molecules), that could alter the material state of assemblies.