Development of Renal‐Clearable NIR‐II Fluorescent Probes via Hydrophilicity Tuning for Imaging of Chronic Kidney Disease

ABSTRACT Chronic kidney disease (CKD) poses a major global health challenge, highlighting the urgent need for real‐time, noninvasive monitoring of early renal dysfunction. However, current imaging strategies are hindered by a lack of fluorophores that combine rapid renal clearance with high signal‐to‐background ratios. Here, we report CS‐CY5‐PEG, a renal‐clearable NIR‐II fluorophore (λ _em = 1035 nm) designed to overcome aggregation‐caused quenching (ACQ) via polyethylene glycol (PEG) modification. CS‐CY5‐PEG exhibits remarkable brightness (Φ _F × ε = 55.4 M ^{− 1} ·cm ^{− 1} ), offering a 6.4‐fold improvement over ICG in aqueous solution. Its compact hydrodynamic diameter (∼3.1 nm) and optimized hydrophilicity (log D = –0.83) enable efficient glomerular filtration and 80% renal clearance within 1 h. Importantly, CS‐CY5‐PEG sensitively detects renal injury in adenine‐induced CKD models, allowing dynamic tracking of kidney function from mild to severe disease stages. By leveraging this property and tracking its localized visible emission ( λ _em ≈ 530 nm), we further investigated the underlying mechanisms of renal injury in CKD. Our findings elucidate how functional impairment in the glomeruli leads to abnormal retention of exogenous substances within renal tissues. These results position CS‐CY5‐PEG as a versatile platform for noninvasive renal diagnostics and nephrotoxicity evaluation in preclinical research.