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Unimolecular near-infrared chemiluminescent reporter for cascaded multiplex imaging of ischemia-reperfusion injury in the liver-kidney axis

Bankang Ruan, Weiliang Deng, Jingjing Che, Shujuan Yi, Jie Liu, Weiping Xu, Yuyan Jiang, Ya Zhou, Pan Xie, Huhai Zhang, Hongwen Zhao and Jiaguo Huang ()
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Bankang Ruan: Sun Yat-sen University
Weiliang Deng: Sun Yat-sen University
Jingjing Che: Sun Yat-sen University
Shujuan Yi: Sun Yat-sen University
Jie Liu: University of Chinese Academy of Sciences
Weiping Xu: University of Chinese Academy of Sciences
Yuyan Jiang: Stanford University School of Medicine
Ya Zhou: Sun Yat-sen University
Pan Xie: Army Medical University
Huhai Zhang: Army Medical University
Hongwen Zhao: Army Medical University
Jiaguo Huang: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Acute kidney injury (AKI) frequently arises as a complication of hepatic ischemia-reperfusion injury (HIRI), yet simultaneous optical imaging of both remains challenging due to the lack of unimolecular dual-responsive probes. Herein, we report a library of hemicyanine-based chemiluminophores (HCLs) with tunable emission to second near-infrared window (725 − 1025 nm) achieved by integrating bicyclic dioxetane onto hemicyanine skeletons to develop multiple-responsive chemiluminescent probes. HCL1 and HCL5 respectively emitting at 725 nm and 1025 nm are selected to construct a cascaded activatable reporter CAR for crosstalk-free duplex chemiluminescence imaging of interlinked biomarkers. Following systemic injection to male mice, CAR preferentially accumulates in the liver and reports HIRI-associated superoxide anion (O2•−), which initiates self-fragmentation and liberates the secondary reporter KIR into kidneys to report AKI-associated N-acetyl-β-D-glucosaminidase (NAG). Such mechanism allows CAR to serve as a reservoir for gradual release of AKI reporters, providing a significantly prolonged imaging window compared to co-administering separate probes. CAR further permits remote detection of HIRI-induced AKI via urinalysis. This study not only offers a powerful tool for simultaneous detection of HIRI and HIRI-induced AKI, but also highlights a unimolecular probe design for ultrasensitive detection of deeply-seated intercorrelated diseases.

Date: 2025
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DOI: 10.1038/s41467-025-62348-y

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