Engineering stimuli-responsive functionalized polypeptides: synthesis, properties, and biomedical applications

Stimuli-responsive polypeptides have emerged as a versatile class of biomimetic materials with considerable potential in biomedical applications. This review highlights recent advances in their synthesis, design, and properties, with particular emphasis on the ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs) as a primary route to well-defined polypeptides. Strategies involving both pre-polymerization and post-polymerization modifications are discussed for the incorporation of diverse functional and stimuli-responsive moieties. The development of polypeptide-polymer hybrids is further presented as an effective approach to combine the hierarchical structural features of polypeptides with the tunability of synthetic polymers. Furthermore, key stimuli-responsive behaviors, including thermos-, pH-, photo-, and redox-responsiveness, are examined in relation to their influence on self-assembly and solution properties. Collectively, these insights establish critical structure-property relationships that guide the rational design of next-generation smart materials for applications in drug delivery, tissue engineering, and related biomedical applications.