Gradient-Sequenced Thermoresponsive Peptoid Formed Colloidally Stable Simple Coacervate

<jats:p> Poly( <jats:italic toggle="yes">N</jats:italic> -methylglycine- <jats:italic toggle="yes">gradient</jats:italic> - <jats:italic toggle="yes">N</jats:italic> - <jats:italic toggle="yes">n</jats:italic> -butylglycine) formed stable, thermoresponsive coacervates in water, whereas a random copolymer with nearly identical composition and molecular weight remained insoluble near 0 °C, demonstrating that monomer sequence governs phase behavior. One-shot ring-opening copolymerization produced the copolypeptoid, which dissolved at low temperature and began to associate at 10–13 °C before completing coacervation near 30 °C. Light and X-ray scattering revealed hydrated, nearly homogeneous spherical particles with a diameter of 230 nm, a hydrodynamic radius of 116 nm, a radius of gyration of 89 nm, and a polydispersity index of 0.08. The particles possessed an ~1 nm interfacial layer, remained stable for at least six days in phosphate-buffered saline, and retained their size after tenfold dilution despite a near-neutral zeta potential, unlike poly( <jats:italic toggle="yes">N</jats:italic> -isopropylacrylamide) coacervates, which are partly stabilized by surface charge. Thus, sequence-generated interfacial organization stabilizes nonionic coacervates, providing a design principle for stimulus-responsive nanocompartments. </jats:p>