Biological Templates for Gold Nanocluster Assembly: Design and Biomedical Applications

ABSTRACT Gold nanoclusters (AuNCs) are ultrasmall (<2 nm) aggregates of gold atoms that exhibit discrete electronic states, size‐dependent photoluminescence, and exceptional biocompatibility, making them ideal candidates for theranostic applications. Their tunable surface chemistry enables targeted delivery, while strong near‐infrared emission and environmental responsiveness allow for sensitive detection and deep‐tissue imaging. Recent advances have revealed that controlled assembly of AuNCs into higher‐order architectures—guided by biological scaffolds such as nucleic acids, peptides, and proteins—can markedly enhance their optical and electronic properties through aggregation‐induced emission (AIE) and stabilization of surface ligands. This review summarizes recent progress in the design and biomedical applications of AuNC assemblies generated using biomolecules as structure‐directing scaffolds. Covalent and noncovalent interactions with biomolecules enable the formation of well‐defined one‐, two‐, and three‐dimensional structures with tunable morphologies and sizes. These assemblies display distinctive photophysical behaviors that have been exploited for biosensing, bioimaging, and therapeutic applications in both cellular and in vivo models. Compared with individual AuNCs, assembled systems offer improved uptake, prolonged circulation, and efficient clearance, while protecting labile cargos such as nucleic acids and proteins. Moreover, their ordered and defined architectures can be engineered for controlled drug release and synergistic photo‐ or radiotherapeutic effects. Despite these advances, fundamental understanding of how structural organization governs photophysical responses remains limited. Elucidating parameters such as intercluster spacing and loading density will be essential for optimizing performance. Overall, biologically guided AuNC assemblies represent a powerful platform for multifunctional biosensing and therapy, bridging nanoscale design with biological function.