A controlled metal-free synthetic methodology toward well-defined thermoresponsive polypeptides by decreasing the reaction temperature to 0 degrees C has been developed. Good control over the molecular weight in the polymerization of a trithiocarbonate-functionalized N-carboxyanhydride (MES-L-Glu-NCA) monomer was obtained using n-hexylamine as the initiator at 0 degrees C. It yielded homopolypeptide macrotransfer agent (PMESLG) with narrow molecular weight distribution (PDI< 1.3) and controllable chain length. Detailed H-1 NMR and MALDI-TOF-MS analysis clearly confirmed that frequently occurring side-reactions was absent at 0 degrees C, and the polymerization was controlled. The resultant PMESLG was applied to mediate the reversible addition-fragmentation chain transfer (RAFT) polymerization of oligo-ethylene-glycol acrylate (OEGA) for the metal-free synthesis of thermoresponsive polypeptides. These thermoresponsive polypeptides have wellcontrolled molecular weight, adopted regular a-helical conformation, and exhibited a lower critical solution temperature between 23 degrees C and 55 degrees C. To the best of our knowledge, there are very few reports about the synthesis of well-defined thermoresponsive graft polypeptides via NCA polymerization and RAFT. Consequently, this provides a new strategy for the synthesis of promising intelligent material for future biomedical applications. (C) 2016 Wiley Periodicals, Inc.