pH-Tolerant Tripeptide Coacervates as Biomimetic Catalytic Microreactors

Intracellular liquid-liquid phase separation underpins the formation of biomolecular condensates that spatially organize and regulate biochemical reactions. Synthetic coacervates have emerged as promising analogues for constructing biomimetic microreactors; however, their practical utility is often limited by poor stability under harsh conditions, such as extreme pH and high ionic strength, which are relevant to both prebiotic environments and chemical processes. Here, we report a bioinspired strategy to construct tripeptide-based coacervates that exhibit exceptional tolerance across a broad range of pH and salt concentrations. By integrating aromatic residues and oligo(ethylene glycol) moieties into minimal peptide sequences, the resulting coacervates establish a dynamic yet robust microenvironment capable of partitioning diverse active species, including enzymes and both hydrophilic and hydrophobic substrates. This confined environment enables concentrating reactants and sustains catalytic activity under various conditions. As a result, these tripeptide coacervates function as versatile microreactors that enhance the efficiency of multiple chemical transformations, including bioorthogonal click reactions, nucleophilic aromatic substitution, and enzyme-mediated hydrolysis. This work demonstrates that short peptides can be rationally engineered to yield environmentally resilient and functionally versatile coacervate systems, providing a minimalistic platform for robust biomimetic catalysis with potential applications in prebiotic chemistry and synthetic biology.