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Not AvaStimuli-responsive polypeptides offer unique advantages for biomedical applications due to their biocompatibility, degradability, and structural tunability. In this study, we report the synthesis of innovative redox-responsive polypeptide-based diblock copolymers consisting of functional disulfide-containing homocysteine derivatives and hydrophobic γ-benzyl-l-glutamate segments via sequential ring-opening polymerizations. The polymerization kinetics revealed that the polymerizations were well-controlled with living characteristics, resulting in diblock copolymers PHcy-b-PBLG with narrow molecular weight distributions. The resulting functional-hydrophobic diblock copolymers were further converted to a variety of pendant chains via thiol–disulfide exchange reactions, yielding amphiphilic polymers with tunable surface charges. These disulfide-linked materials readily self-assembled into nanoparticles in aqueous environments with hydrophobic PBLG forming the core and redox-sensitive PHcy forming the shell. The redox-responsive nanoparticles displayed a narrow size distribution, excellent colloidal stability, and excellent biocompatibility. The disulfide bonds within the polymer backbone confer redox sensitivity, allowing potential cleavage in reducing environments. Owing to their tunable surface functionality, redox-responsiveness, and biocompatibility, this platform provides a versatile route to engineer responsive nanostructures for biomedical applications, for example, positively charged nanoparticles toward nucleic acid delivery.ilable 

Not AvaDisulfide-containing synthetic polypeptides hold significant promise as biodegradable and biocompatible carriers for controlled drug and gene delivery, enabling triggered therapeutic release with reduced cytotoxicity. However, disulfide incorporation remains challenging, whether through direct polymerization of disulfide-containing monomers or postpolymerization modification. In this work, we present an innovative and simple strategy to incorporate disulfide bonds into polypeptides using ring-opening polymerization of the N-carboxyanhydride of homocysteine, a thiol-containing amino acid. The polymerization was well-controlled, yielding repeating units up to 100 with narrow dispersity. The pendant side chains were readily converted into various GSH-responsive moieties, including anionic, neutral, zwitterionic, and cationic groups, as well as therapeutic agents toward a wide range of biomedical applications. The drug-loaded amphiphilic polymer-drug conjugates displayed triggered release of intact drug and potent anticancer activities. Furthermore, cationic polyhomocysteine derivatives effectively delivered siRNA, eGFP mRNA, and more complex CRISPR components with extremely low cytotoxicity and excellent transfection efficiency.ilable