Abstract
Effective delivery of nucleic acid therapeutics and small-molecule drugs requires materials that can protect therapeutic cargo during transport while enabling release after cellular entry. Conventional cationic carriers often suffer from high cytotoxicity, limited degradability, and insufficient control over intracellular activation. To address these limitations, this dissertation develops programmable polypeptide platforms in which backbone structure, side chain chemistry, and redox responsiveness can be systematically tuned. A polyhomocysteine (PHcy)-based platform was constructed through the synthesis of disulfide-functional N-carboxyanhydride monomers and controlled ring-opening polymerization. The resulting polypeptides provide a biodegradable backbone and side chain handles for post-polymerization modification. By installing cationic groups through redox-responsive disulfide linkages, PHcy was converted into a carrier for mRNA delivery. These carriers formed stable mRNA complexes, showed reduced cytotoxicity compared with conventional cationic polymers, and enabled delivery of EGFP mRNA and Cas9-mRNA/gRNA cargos. Block copolypeptide variants were prepared to examine how self-assembly influences RNA binding, cytocompatibility, and transfection. The same redox-responsive design was extended to small-molecule drug delivery using polymer-DM1 conjugates. These conjugates self-assembled into nanoparticles, released DM1 under reducing conditions, and produced dose-dependent cytotoxicity in cancer cell models. Redox-active polylysine derivatives bearing carbonyl-containing side chains were synthesized as polymer electrode materials. These materials showed reversible redox behavior and stable cycling performance, demonstrating that polypeptide backbones can also serve as degradable scaffolds for charge-storage applications. These studies establish polypeptides as modular materials whose function can be directed through monomer design, polymer architecture, and side chain modification.