Physicochemical principles of RNA-mediated crowding

Molecular crowding in cells is not solely a consequence of excluded volume but emerges from interaction networks shaped by RNA and proteins. Here we examine the physicochemical principles underlying RNA-mediated crowding, focusing on how sequence-driven multivalency, structural topology, and network connectivity govern molecular organization. Repeats, secondary structures, and higher-order motifs such as G-quadruplexes act as interaction modules that promote percolation and phase separation, while RNA length and concentration tune phase boundaries. These RNA-encoded features promote multivalent RNA-RNA and RNA-protein interactions that shape condensate assembly, dynamics, and organization across scales. In this framework, crowding emerges as an RNA-centered, interaction-driven property linking molecular features to mesoscale organization in both physiological and pathological contexts.