In‐Sequence High‐Specificity Dual‐Reporter Unlocking of Fluorescent Probe Enables the Precise Identification of Atherosclerotic Plaques

Abstract The formation of atherosclerotic plaques is the root cause of various cardiovascular diseases (CVDs). Effective CVD interventions thus call for precise identification of the plaques to aid clinical assessment, diagnosis, and treatment of such diseases. In this study, we introduce a dual‐target sequentially activated fluorescence reporting system, termed i n‐ s equence h igh‐sp e cificity dual‐ r eporter un lock ing (iSHERLOCK), to precisely identify the atherosclerotic plaques in vivo and ex vivo. ISHERLOCK was achieved by creating a three‐in‐one fluorescent probe that permits highly specific and sensitive detection of lipid droplets and hypochlorous acid via “off‐on” and ratiometric readouts, respectively. Based on this format, the upregulated lipid accumulation and oxidative stress—the two hallmarks of atherosclerosis (AS)—were specifically measured in the atherosclerotic plaques, breaking through the barrier of precise tissue biopsy of AS and thus aiding effective CVD stewardship.