From sequence to function: Peptide-nucleotide-based complex coacervates as protocell models

Complex coacervates formed through the liquid-liquid phase separation (LLPS) of peptides and nucleotide-based biomolecules have emerged as versatile model systems for understanding biomolecular self-assembly, compartmentalization, and emergent functionality. This review highlights recent advances in peptide-nucleotide-based complex coacervates, encompassing nucleotide motifs and nucleic acids in combination with peptides and polypeptides. We discuss the molecular features that drive phase separation, including multivalency, sequence, and charge distribution. We further examine how internal organization and responsiveness to external stimuli enable precise control over the physicochemical properties and functions of coacervate droplets. Their intrinsic capabilities, including compartmentalization, selective molecular sequestration, and catalysis, provide compelling opportunities for developing life-like assemblies with emergent biological functions. Finally, we highlight key conceptual gaps and future challenges that could guide the development of coacervates as functional materials at the interface of synthetic biology and chemistry.