Coacervate‐Droplet Cased Synthetic Cells Regulated By Activated Carboxylic Acids (ACAs)

Abstract Regulating the formation and dissolution of active complex coacervate droplets with chemical reactions offers a powerful synthetic cell model. Such active droplets are also helpful in understanding the non‐equilibrium nature of membrane‐less organelles. Like many membrane‐less organelles, these droplets rely on high‐chemical potential reagents, like ATP, to maintain their transient nature. This study explores Activated Carboxylic Acids (ACAs) as a high‐chemical potential fuel to modulate the lifetime of peptide‐based coacervates through transient pH changes. We demonstrate that nitroacetic acid, a commonly used ACA, can effectively induce the formation and dissolution of coacervates by transiently altering the solution′s pH. The system, comprising the zwitterionic peptide Ac‐FRGRGD‐OH and polyanions, forms coacervates upon protonation at low pH and dissolves as the pH returns to neutral. Our findings indicate that the lifetime of these synthetic cells can be fine‐tuned by varying the amount of ACA added, and the system can be refueled multiple times without significant interference from by‐products. This ACA‐driven reaction cycle is versatile, accommodating various coacervate compositions and enabling the uptake of diverse compounds, making it a valuable model for compartmentalization. The study underscores the potential of ACA‐fueled coacervates as a platform for investigating biomolecular condensates and developing synthetic life systems.