Chlorination‐Driven BODIPY Fluorescent Probes for the Selective Monitoring of Myeloperoxidase Activity in Cells and Inflamed Mouse Models

Myeloperoxidase (MPO) generates hypochlorous acid (HOCl), a major oxidant in inflammatory biology and an increasingly recognized pathogenic mediator and therapeutic target in oxidative and inflammatory diseases. However, selective detection of MPO activity remains challenging because most HOCl-responsive fluorescent probes operate through nonspecific oxidative mechanisms, rendering them vulnerable to interference from competing reactive oxygen and nitrogen species. Here, we present an MPO-reporting fluorescent platform based on a meso-carboxamide-substituted 3,5-dimethyl BODIPY scaffold that exploits the electrophilic chlorinating reactivity of MPO-derived HOCl. The lead probe undergoes rapid chlorination at the 2,6-positions, generating highly emissive products with ca. 40 nm bathochromic shifts and overcoming the minimal spectral responses and fluorescence quenching that have limited earlier chlorination-based designs. The modular meso-carboxamide architecture further allows facile incorporation of targeting motifs without compromising probe performance. This platform enables quantitative MPO assays, cellular imaging of exogenous and endogenous MPO-derived HOCl, discrimination between cancer and normal cells based on redox differences, and noninvasive visualization of MPO-driven inflammation in a mouse model of atopic dermatitis. These results establish electrophilic chlorination as a viable design strategy for selective MPO-responsive fluorescent probes and provide a versatile tool for investigating MPO-associated inflammatory pathophysiology in biological and preclinical disease models.