Construction of a Renal-Clearable NIR Fluorescent Probe with Sequential Response to Peroxynitrite/Hypochlorous Acid for Visualizing Autophagy Progression in Cisplatin-Induced Acute Kidney Injury

Acute kidney injury (AKI) caused by cisplatin (Cis) is still a clinical challenge that frequently leads to irreversible renal function decline. In situ monitoring of nitrosative/oxidative stress associated with early stage injury in AKI is essential for early AKI detection and elucidation of autophagy-related mechanisms. Targeted detection of peroxynitrite (ONOO⁻)/hypochlorous acid (HClO) within the kidneys may provide crucial insights for early diagnosis and therapeutic intervention of AKI. Fluorescence imaging, known for its excellent spatial resolution, sensitivity, and noninvasive nature, has demonstrated significant promise in biomedicine. This study developed a renal-clearable near-infrared (NIR) fluorescent probe (KNOP) capable of sequential recognition of ONOO⁻/HClO with high sensitivity and a rapid response. And this "sequential-lock" mechanism effectively reduces the false-positive results from single marker detection. KNOP allowed for sensitive monitoring of abnormal changes in ONOO⁻/HClO during both the induction and treatment of AKI with a good biocompatibility and was applied to monitoring autophagy in Cis-induced AKI. Furthermore, KNOP exhibited favorable renal clearance and high imaging contrast, enabling successful in situ visualization of these reactive species during AKI progression and therapeutic intervention. More significantly, the probe KNOP effectively identified patients with renal injury in clinical serum samples, as well. These findings demonstrate that KNOP serves as an effective renal-clearable tool for understanding nitrosative/oxidative stress and autophagy mechanisms while also underscoring the potential value of ONOO⁻/HClO as promising biomarkers for early AKI recognition and intervention.