Effective monitoring of the physiological progression of acute lung injury (ALI) in real time is crucial for early theranostics to reduce its high mortality. In particular, activatable fluorescence and photoacoustic molecule probes have attracted attention to assess ALI by detecting related indicators. However, the existing fluorophores often encounter issues of low retention in the lungs and slow clearance from the body, which compromise the probe’s actual capability for in situ imaging by intravenous injection in vivo. Herein, a novel near-infrared hemicyanines fluorophore (FJH) bearing a quaternary ammonium group was first developed by combining with the rational design and screening strategy. The properties of good hydrophilicity and blood circulation effectively enable FJH accumulation for lung imaging. Inspired by the high retention efficiency, the probe FJH-C that turns on fluorescence and photoacoustic signals in response to the ALI indicator (esterase) was subsequently synthesized. Notably, the probe FJH-C successfully achieved the selectivity and sensitivity toward esterase in vitro and in living cells. More importantly, FJH-C can be further used to assess lipopolysaccharides and silica-induced ALI through the desired fluo-photoacoustic signal. Therefore, this study not only shows the first activatable probe for real-time imaging of lung function but also highlights the fluorophore structure with high lung retention. It is believed that FJH and FJH-C can serve as an efficient platform to reveal the pathological progression of other lung diseases for early diagnosis and medical intervention.

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