Weizhong Ding, Ming Jia, Shankun Yao, Zhipeng Liu, Fengwu Xu, Mingfeng Li, Chenqi Wang, Weijiang He, Yuncong Chen, Zijian Guo
Cyanine dyes are highly valued as imaging agents in molecular imaging and disease diagnosis. However, their slow hepatobiliary clearance often raises concerns about their potential chronic toxicity. As such, developing general strategies to construct renal-clearable activatable probes based on cyanine dyes holds great promise. Herein, we developed a novel cyanine imaging platform that exhibited high renal clearance efficiency, enabling real-time disease monitoring based on urine fluorescence readouts. Through molecular engineering of the meso-position substituents of IR780, we discovered that methylation of the meso-pyridine-modified heptamethine cyanine (CyP) dramatically quenched the fluorescence, probably due to the synergism of photoinduced electron transfer (PET) and twisted intramolecular charge transfer (TICT) effects. Intriguingly, cyanine derivatives with a pyridinium group demonstrated preferential and rapid renal clearance, primarily due to the additional positive charge-mediated electrostatic interactions with anionic proteoglycans in the kidneys. Subsequently, by introducing stimuli-responsive self-immolating groups onto the meso-pyridine ring, we developed a universal renal-clearable imaging platform and designed four representative fluorescent probes. All the probes possessed a distinct near-infrared (NIR) fluorescent "turn-on" response and preferential renal clearance. As a proof of concept, two of them were successfully utilized to visualize fluctuations of redox imbalance across various acute kidney injury (AKI) mouse models, showing sensitivity superior to that of traditional serum creatinine (SCr) and blood urea nitrogen (BUN) assays. In summary, our work not only provides a comprehensive understanding of the structure-property relationship between meso-substituents and quantum yields of cyanine derivatives but also establishes a renal-clearable fluorogenic platform for advanced bioimaging and biomedical diagnostics.