Monocyte‐Differentiation‐Activated Fluorescent “Scout” Probe for Precise in Vivo Detection of Vulnerable Plaque

Abstract Precise identification of vulnerable plaque (VAP) is essential for the prevention of acute cardiovascular diseases, yet current molecular probes are hampered by poor VAP lesion penetration and high background. Here, the innate tropism of circulating inflammatory monocytes for VAP, and their differentiation‐driven expression of legumain (Lgmn) in response to the VAP microenvironment is exploited. A monocyte differentiation‐activated fluorescent (MDAF) probe is conceived that hitchhikes monocytes to precisely migrate to VAP and is activated by Lgmn during monocyte differentiation. This activation triggers in situ self‐assembly, resulting in spatiotemporally controlled aggregation‐induced emission (AIE) fluorescence signals, and turning the monocyte itself into an on‐site “scout” that reports plaque instability. In Apoe ^−/− mice bearing both vulnerable and stable plaques, the MDAF produces a striking OFF/ON fluorescence switch confined to vulnerable lesions, yielding a markedly improved signal‐to‐noise ratio (SNR). By integrating fluorescence emission computed tomography (FLECT), MDAF probe surpasses the depth limitations of conventional fluorescence imaging. Therefore, the AIE signal of the MDAF probe is more than just a “fluorescent read‐out,” and it also acts as a crucial safety switch that transforms the monocyte into a ratiometric immune scout for plaque instability. This innovative strategy offers a translatable approach for the precision diagnosis of VAP.