Application-Driven Modular Design of Gold Nanoclusters for In Vivo Fluorescence Imaging.

Atomically precise gold nanoclusters (AuNCs) combine ultrasmall size (<3 nm), large Stokes shifts, high photostability, favorable biocompatibility, efficient renal clearance, and tunable second near-infrared emission, which enables deep‑tissue imaging with minimal background interference. These attributes offer distinct advantages over conventional fluorescent probes in terms of biosafety, tissue penetration, and signal‑to‑background ratio, making AuNCs highly promising candidates for in vivo fluorescence imaging. Existing reviews have systematically cataloged synthetic methods and imaging applications, but rarely establish direct correlations between structural design and specific imaging demands. This review adopts an application‑driven reverse design logic. Starting from the physiological constraints and imaging requirements of representative diseases, we translate these demands into modular structural configurations of the metallic core, surface chemistry, and assembly structure. By analyzing representative in vivo scenarios, we extract universal design principles and discuss the coupling effects and trade‑offs among the three modules. This framework offers theoretical insights and actionable strategies for developing high‑performance AuNC probes tailored to complex biological environments, with the aim of bridging the gap between material‑oriented research and clinical translation.