Biomolecular condensates and their pathologies: A colloidal, interfacial, and transport perspective

Abstract

Biomolecular condensates are micron-scale, membraneless compartments that concentrate proteins and nucleic acids by liquid-liquid phase separation (LLPS). Condensates play critical roles in transcription, mRNA metabolism, stress responses, and signaling across the cell, with their dysregulation increasingly correlated with several pathologies spanning neurodegeneration, cancer, cardiometabolic disease, and viral infections. The emergent biology of condensates can be cohesively viewed through the framework of colloidal, interfacial, and transport phenomena. Here we review the condensate literature through this joint lens, treating each condensate as a biological colloid whose behavior is captured by four measurable physical quantities: a Flory--Huggins interaction parameter that determines whether the dense phase forms at all, a partition coefficient that dictates the degree of client molecule accumulation, a viscoelastic relaxation time that sets whether the dense phase responds as a liquid or a solid, and an interfacial tension that governs droplet shape and interfacial dynamics. Each quantity is traced to its physical origin, its measured range in biological condensates, and the techniques that quantify it, for both three-dimensional droplets and two-dimensional membrane-tethered condensates. Interpreting disease as the displacement of these physical quantities from their functional ranges, we reorganize condensate pathologies into a small set of physical failure modes --- saturation concentration dysregulation, aberrant aging and liquid-to-solid transitions, disrupted partitioning, interfacial aggregation, and pathogen hijacking --- and show how the same parameters become design variables for condensate-targeted drugs and engineered coacervate delivery vehicles. The review concludes with open questions at the interface of condensate biology and colloidal and interfacial science.