Tuning adsorption and morphology in poly(glutamic acid) via controlled acidic partial deprotection

Abstract Synthetic polypeptides prepared from N ‐carboxyanhydride (NCA) monomers are important platforms for environmental and medical applications due to their biomimetic structures which can beleveraged to deliver tunable properties. During synthesis, amino acid side chains are generally protected to prevent undesired side reactions. Following polymerization, full deprotection is typically pursued to expose the largest number of functional groups, with the expectation that greater functional group availability enhances intermolecular interactions and overall performance. While the extent of deprotection is known to impact polypeptide properties, the specific effects of partial deprotection on polypeptide functionality have not received significant attention. Here, we demonstrate that controlled acidic partial deprotection offers a straightforward and reproducible means for adjusting amphiphilicity and assembly in benzyl‐protected poly(glutamic acid) and poly(glutamic acid‐ block ‐tyrosine) polypeptides. Over time, partial acidic deprotection can generate distinct morphologies which either match or outperform fully deprotected analogs. For the poly(glutamic acid) homopolymer, partial deprotection produces a population of ~130 nm assemblies that present more accessible surface area, leading to adsorption that matches that of fully deprotected poly(glutamic acid). These outcomes are repeatable across reactions and reproducible across 100 mg to 3 g scales, indicating that the behavior reflects inherent polymer structuring rather than anomalous effects. In the copolypeptide poly(glutamic acid‐ block ‐tyrosine), maximal drug adsorption similarly occurs at partial deprotection, correlating with the presence of small ~70 nm nanoassemblies which outperform more deprotected samples. These effects appear pH‐dependent, with assemblies forming only when glutamic acid is deprotonated. When protonated, nanoassembly formation is suppressed, and adsorption generally correlates with particle size distribution which is influenced by the degree of deprotection and the resulting balance between hydrophobic association and chain hydration. Together, these results introduce deprotection as a functional design parameter for tuning polypeptide morphology and adsorption, extending the strategies available for controlling structure–property relationships in NCA‐derived polypeptide materials. © 2026 The Author(s). Polymer International published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.