Plug-and-display labeling system for modular subunit vaccine development

The post-pandemic era demands vaccine platforms with rapid adaptability, personalization, and multivalency-requirements that conventional vaccine development paradigms struggle to fulfill. Modular subunit vaccines offer a transformative solution by enabling plug-and-display conjugation of antigen/adjuvant modules onto universal nanoscaffolds. However, their clinical translation relies on efficient anchoring technologies that must satisfy stringent criteria: bioorthogonality, fast reaction kinetics, quantitative controllability, and non-toxicity. In this critical and systematic review, we analyze existing antigen anchoring strategies, with a particular focus on coordination chemistry-based systems. These include polyhistidine-metal ion chelation and cobalt porphyrin coordination, which exhibit unique advantages for oriented, stable, and modular antigen display. We categorize existing strategies into three mechanistic classes: ( i ) non-covalent affinity tagging; ( ii ) biological covalent conjugation; and ( iii ) chemical covalent ligation. For each class, we examine in depth the underlying molecular recognition mechanisms, kinetic and thermodynamic profiles, and structure-activity relationships that govern vaccine immunogenicity. By comparing these strategies across key dimensions-compatibility, specificity, scalability, and translational potential, critical research gaps are identified and design guidelines for next-generation conjugation systems are proposed. Finally, we outline emerging frontiers, including AI-assisted conjugation system design, stimuli-responsive cleavable linkers, and in situ self-assembling vaccine platforms. This review aims to establish a theoretical framework for engineering plug-and-display modular nanovaccines and to promote interdisciplinary innovation at the intersection of coordination chemistry, supramolecular chemistry, and vaccinology.