Creating Compartmentalized Pockets for Length-Tunable Short Peptide Growth

Living systems achieve precise control over macromolecular synthesis within the confined pockets of enzymes. Reproducing such spatial regulation in artificial systems remains a significant challenge in molecular engineering. Although artificial nanoconfinement has been explored to regulate polymerization, tunable and length-specific peptide growth has yet to be realized. Here, we present a highly stable metal-organic framework (MOF) as an artificial oligomerization platform that enables confined N-carboxyanhydride (NCA) ring-opening polymerization (ROP) with dynamically tunable short peptide growth. Reaction kinetics and NMR analyses reveal a confined oligomerization process within one-dimensional channels segmented by Zr₆ clusters. Compared with unconfined solution NCA polymerization showing nearly no chain-length selectivity in short-chain growth, these regularly repeating subcompartments provide defined reaction pockets that achieve pronounced chain-length selectivity and remarkably high peptide loading while maintaining framework integrity. The short peptide chain length can be dynamically tuned by monomer size and reaction kinetics, converting confinement from a template limitation into an active design principle. Moreover, pre-coordination of amino acids at Zr₆ clusters modifies the pocket microenvironment, accelerating NCA-ROP by over 30-fold. Selecting suitable monomers further enables the formation of A-(B)_n sequence peptides. This work establishes a robust MOF-based platform inspired by natural biosynthetic machinery, advances understanding of confined oligomerization and polymerization, and provides a versatile platform for creating functional peptide-MOF materials with potential application in biomimetic catalysis.