Protein‐Interference‐Free and Kidney‐Targeting NIR Fluorophores for Accurate in Vivo Imaging of H₂S₂ during Kidney Ferroptosis

High-fidelity kidney function imaging is important for assessing the nephrotoxicity of drugs and diagnosing renal diseases. However, the current challenges in achieving accurate kidney imaging include unspecific signal enhancement due to albumin binding and relatively low distribution of imaging agents in kidneys. Here, for the first time, a side-chain engineering strategy that incorporates hydrophilic six-membered heterocycles into aza-hemicyanine for generating high-performance kidney imaging agents with protein-interference-free and kidney-targeting features is proposed. Based on these unique aza-hemicyanine dyes, the first kidney-targeting and albumin-insensitive H₂S₂ near-infrared (NIR) fluorescent probe NA-H₂S₂ is designed, which demonstrates effective kidney distribution following intravenous injection and is specifically activated by H₂S₂. The designed probe presents a highly rapid, selective and sensitive response to H₂S₂ with a detection limit as low as 24.21 nm. Additionally, it successfully achieves real-time in vivo NIR fluorescence imaging of H₂S₂ during erastin/cisplatin induced renal ferroptosis. Moreover, it also enables rapid detection of H₂S₂ through in vitro optical urinalysis, offering significant diagnostic value for renal ferroptosis. Overall, this study not only presents a practical kidney-targeting H₂S₂ fluorescent probe NA-H₂S₂ with increased imaging accuracy but also provides promising kidney-targeting and albumin-insensitive aza-hemicyanine dyes for further development of kidney disease-related probes.