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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. [ABSTRACT FROM AUTHOR]

The previous activatable probe toward one analyte can still produce imprecise signal as a result of the challenge cased by accurate identification in complex biological environment. As smarter molecules, dual-locked probes are able to respond to two different analyte with one or more output signals, which display significantly reduced background interference and increased spatial resolution. In this study, a smart cysteine/lipid droplets sequence-activated dual-locked fluorescent probe CN–NO 2 has been designed and synthesized for the detection of tumor tissues. The recognition group of CN–NO 2 removed after reacting with cysteine (Cys) and undergoing intramolecular rearrangement to generate complete fluorophores. This structure had a strong solvent effect; it could recognize lipid droplets (LDs) in cells, thus exhibiting fluorescence without secondary molecular adjustment. The fluorescence of CN–NO 2 was enhanced 1752-fold after double unlocking. Importantly, the unlocking process only takes 10 min. Furthermore, the fluorescence of CN–NO 2 was amplified remarkable and anchored at LDs after reacting with Cys in A549 cells. Therefore, CN–NO 2 clearly indicated the site of mouse xenograft tumor in vivo. Such sequence-activated dual-locked fluorescent probes are envisioned to execute more analysis and diagnostic tasks giving these unique characteristics. • The CN–NO 2 was enhanced 1752-fold after cysteine/lipid droplets double unlocking, and the unlocking process only takes 10 min. [ABSTRACT FROM AUTHOR]