Endogenous HClO-Gated Cascade MicroRNA Imaging for Precise Diagnosis of Atherosclerosis In Vivo

Precise imaging of atherosclerotic plaques using biomarkers could prompt the diagnosis and clinical management of atherosclerosis (AS)-driven cardiovascular diseases. MicroRNA-155 (miR-155) plays a critical role in AS development, with its expression notably upregulated in foam cells within plaques. However, miRNA imaging methods for atherosclerotic plaques face significant challenges, including low specificity, inefficient delivery, and poor cell selectivity. Herein, we develop an endogenous hypochlorous acid (HClO)-gated cascade signal amplification strategy for precise miR-155 imaging in living foam cells, enabling accurate in vivo and ex vivo detection of atherosclerotic plaques. This strategy utilizes a phosphorothioate (PT)-modified hairpin probe that is specifically deprotected by HClO and uncaged by miR-155, triggering a catalytic hairpin assembly (CHA) to amplify fluorescence signals. The PT-CHA probes are encapsulated in lipid nanoparticles (LNs), followed by conjugating with phosphatidylserine (PS)-binding peptide (PBP) for selectively targeting foam cells, enabling in vivo miR-155 imaging in atherosclerotic plaques. The fluorescence intensity of PT-CHA@LN-PBP in the aorta region shows clear differentiation among AS-bearing mice, miR-155^-/- mice, and healthy mice. Moreover, the fluorescence intensity strongly correlates with plaque area and AS progression and can discriminate plaque vulnerability risk with an area under the curve (AUC) of 0.94. Imaging of human aortic tissues further validates the probe's capacity to distinguish atherosclerotic plaques from normal endarterium. These findings establish PT-CHA@LN-PBP as a noninvasive, reliable diagnostic tool for precise assessment of AS.