Visualizing Molecular Architectures of Cellular Condensates: Hints of Complex Coacervation Scenarios

In the last decade, liquid-liquid phase separation has emerged as a fundamental principle in the organization of crowded cellular environments into functionally distinct membraneless compartments. It is now established that biomolecules can condense into various physical phases, traditionally defined for simple polymer systems, and more recently elucidated by techniques employed in life sciences. We review pioneering cryoelectron tomography studies that have begun to unravel a wide spectrum of molecular architectures, ranging from amorphous to crystalline assemblies, that underlie cellular condensates. These observations bring into question current interpretations of microscopic phase behavior. Furthermore, by examining emerging concepts of non-classical phase separation pathways in small-molecule crystallization, we draw parallels with biomolecular condensation that highlight aspects not yet fully explored. In particular, transient and meta-stable intermediates that might be challenging to capture experimentally inside cells could be probed through computational simulations and enable a multi-scale understanding of the subcellular organization governed by distinct phases.