Enzyme-Instructed Self-Assembly for Cellular Supramolecular Chemistry

Enzyme-instructed self-assembly (EISA) uses endogenous enzymatic activity to convert soluble precursors into self-assembling species, enabling the spatiotemporal formation of supramolecular nanostructures directly within cellular environments. Unlike other supramolecular strategies triggered by pH, redox, or light, EISA leverages the inherent spatial localization and dynamic kinetics of enzymes to achieve precise, context-dependent control over where and when assembly occurs. While previous reviews have summarized EISA's mechanisms and biomedical applications, this perspective positions EISA as a conceptual framework for supramolecular chemical biology-emphasizing its role in mimicking higher-order protein assemblies and in bridging molecular design with cellular function. We discuss how EISA enables programmable conformational and morphological switching, the creation of growth factor-mimicking assemblies, and the in situ formation of artificial supramolecular architectures inside or around cells. By highlighting EISA as a catalytic strategy for constructing functional supramolecular systems in vivo, this perspective outlines a new direction for integrating enzymatic control with nanoscale self-organization in cellular supramolecular chemistry, generalizing EISA beyond alkaline phosphatases to programmable multi-enzyme networks, and thereby advancing adaptive biomaterials, programmable therapeutics, and synthetic cellular machines.