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, Jiaguo Huang
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. Acute kidney injury (AKI) frequently arises as a complication of hepatic ischemia reperfusion injury (HIRI), yet simultaneous optical imaging of both remains challenging. Here, the authors develop a unimolecular cascaded activatable reporter with dual responses and pharmacokinetic conversion for non-invasive multiplex chemiluminescence imaging and fluorescent urinalysis of HIRI and associated AKI.