Coacervate droplets as a liquefier for the solid-to-liquid transition of RNA aggregates

Abstract Biomolecular condensates are functionally gated by their material properties. While RNA is a primary structural scaffold, its sequence-specific interactions can aberrantly drive condensates into dysfunctional solid aggregates. Yet, actively reversing this solidification to restore function remains a fundamental challenge, impeding progress in synthetic biology and therapeutics interventions. Here, we establish that complex coacervates can be engineered as liquefiers to actively remodel solid RNA-peptide aggregates into functional liquid droplets. Integrating systematic experiments with all-atom simulations, we decode a multiscale mechanism: coacervate infiltration at the micrometer scale mediates molecular buffering at the nanometer scale, which fluidizes the crosslinked network to drive macroscopic liquefaction. This capability is governed by a design rule, where coacervates formed by small-molecular anions exhibit optimal efficacy. We deploy this principle to functionally rescue silenced RNA within a model of pathologically solidified ribonucleoprotein assemblies. Our work provides a general framework for the active, compositional control of biomolecular phase behavior, with direct implications for managing pathological aggregation and engineering functional condensates in synthetic and living systems.