Dual stimuli‐responsive polypeptide prepared by thiol‐ene click reaction of poly(<scp>l</scp>‐cysteine) and <i>N</i>, <i>N</i>‐dimethylaminoethyl acrylate

<jats:title>Abstract</jats:title><jats:p>Stimuli‐responsive polymers that can undergo conformational changes with external triggers have enabled themselves as smart materials for various utilizations, among which biodegradability is of particular importance to be engineered for biomedical application. In this study, a thermo and pH dual responsive polypeptide (<jats:italic>N</jats:italic>, <jats:italic>N</jats:italic>‐dimethylaminoethyl acrylate‐modified poly(<jats:sc>l</jats:sc>‐cysteine)) (PLC‐<jats:italic>g</jats:italic>‐DMAEA) was prepared by the combination of <jats:italic>N</jats:italic>‐carboxyanhydride ring‐open polymerization and thiol‐ene click chemistry. The biodegradable poly(<jats:sc>l</jats:sc>‐cysteine) (PLC) with pendant thiol groups provided an easily clickable backbone for postmodification, which was demonstrated by reacting with a well‐known monomer of <jats:italic>N</jats:italic>, <jats:italic>N</jats:italic>‐dimethylaminoethyl acrylate (DMAEA) to achieve both temperature and pH responsiveness. The irreversible thermo‐response of PLC‐<jats:italic>g</jats:italic>‐DMAEA could be attributed to the ordered β‐sheets formed upon heating, leading to the trapped side groups with poor water accessibility. Moreover, this copolymer precipitated at pH ranging from 7.5 to 9.7, but protonation of tertiary amine groups (pH < 7.5) and salt forming of masked thiol groups (pH > 9.7) rendered it soluble in water. Our results revealed that a ready available vinyl monomer could be easily clicked onto the biodegradable PLC and its stimuli responsiveness would be reserved. Moreover, the primary and secondary structures of PLC might influence the conformation, thus leading to the unique responsive behavior of the resulted copolymer.</jats:p>