An “AND” Molecular Logic Gate as a Super‐Enhancers for De Novo Designing Activatable Probe and Its Application in Atherosclerosis Imaging

Abstract Developing activatable fluorescent probes with superlative fluorescence enhancement factor (F/F₀) to improve the signal‐to‐noise (S/N) ratio is still an urgent issue. “AND” molecular logic gates are emerging as a useful tool for enhanced probes selectivity and accuracy. Here, an “AND” logic gate is developed as super‐enhancers for designing activatable probes with huge F/F₀ and S/N ratio. It utilizes lipid‐droplets (LDs) as controllable background input and sets the target analyte as variable input. The fluorescence is tremendously quenching due to double locking, thus an extreme F/F₀ ratio of target analyte is obtained. Importantly, this probe can transfer to LDs after a response occurs. The target analyte can be directly visualized through the spatial location without a control group. Accordingly, a peroxynitrite (ONOO⁻) activatable probe (CNP2‐B) is de novo designed. The F/F₀ of CNP2‐B achieves 2600 after reacting with ONOO⁻. Furthermore, CNP2‐B can transfer from mitochondria to lipid droplets after being activated. The higher selectivity and S/N ratio of CNP2‐B are obtained than commercial probe 3'‐(p‐hydroxyphenyl) fluorescein (HPFin vitro and in vivo. Therefore, the atherosclerotic plaques at mouse models are delineated clearly after administration with in situ CNP2‐B probe gel. Such input controllable “AND” logic gate is envisioned to execute more imaging tasks.