Expanding the Design Space of Covalent Peptide Assemblies: From Amino Acid Modularity to kinetic control

Peptide assembly has emerged as a versatile platform for constructing functional biomaterials through the cooperative noncovalent interactions. However, the inherent dynamic nature of interactions often results in limited structural stability, poor environmental robustness, and unpredictable assembly pathways. To overcome these limitations, covalent peptide assembly has recently emerged by integrating robust covalent networks with non-covalent self-assembly, providing enhanced structural stability while preserving sequence-encoded physicochemical and functional properties. Nevertheless, rational design principles for covalent peptide assemblies remain largely unexplored, making precise control over structure and function challenging. Herein, amino acid modularity and kinetic control as complementary design framework are introduced for programming covalent peptide assemblies. We first established sequence-structure-property relationships by systematically substituting single amino acids, generating modular peptide library with diverse physicochemical and biological functions. Building on the sequence-based strategy, we next introduce light-modulated kinetic control to regulate assembly pathways without altering molecular composition, enabling precise control over hierarchical morphology. Furthermore, extending kinetic regulation to the degree of covalent locking enables programming of the internal network state, allowing selective stabilization of distinct structural states with tunable degradation, cargo release, structural dynamics, and biological functions. Overall, this work establishes covalent peptide assembly as a versatile molecular tool in which molecular sequence and assembly kinetics can be systematically encoded to create customized architectures with tailored structural and functional properties.

Reference
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[2] Yun-Mi Hur, Kido Kwon, Kyoung-Ik Min, Adv. Compos. Hybrid Mater., 2026, 9, 134.