FXF-OMe Is a Stable Tripeptide Motif for Ultra-Short Peptide Coacervates That Establishes Structure-Property-Function...

Ultra-short peptide coacervates (USPCs), formed via liquid-liquid phase separation (LLPS) of peptides containing five or fewer amino acids, offer a minimal platform for microreactors and for probing structure-property relationships governing LLPS and liquid-to-solid transitions (LSTs). USPCs form uniquely hydrophobic liquid interiors compared to larger peptide-based and complex coacervates, enabling aqueous reactivity with hydrophobic substrates. As a result, USPCs have emerged as promising candidates for next-generation microreactors with the potential to surpass nanoparticle-based systems in modularity, scalability, and biocompatibility. Existing USPCs face two major challenges: poor stability against LSTs, which irreversibly eliminate the liquid microenvironment, and a lack of well-developed structure-property relationships that would enable rational materials design. Here, we establish FXF-OMe as a minimal motif, inspired by previously reported sticker-spacer USPC motifs, that dramatically enhances resistance to LSTs while enabling investigation of structure-property relationships. Using this platform, we identify hydrophobic effects as the dominant determinant of coacervate material properties over specific peptide-peptide interactions. We further demonstrate that improved stability and tunability enable selective dye partitioning, enhanced reaction yields, and kinetic control in sulfur photo-oxidation reactions. Collectively, these results position FXF-OMe as a foundation for de novo USPC design and establish USPCs as tunable, stable platforms for precision microreactor applications.