Self‐Amplified Activatable Fluorescent Probe for Early Diagnosis of Acute Kidney Injury and High‐Throughput Screening of Natural Protectants

Early diagnosis of acute kidney injury (AKI) and identification of effective therapeutics remain significant clinical challenges. Herein, we developed an activatable near-infrared fluorescent nanoprobe (denoted PS-QRC) by encapsulating a self-amplifying fluorescent sensor (QRCy) within kidney-targetable L-serine-functionalized ultrasmall poly(amidoamine) (PAMAM-Ser) dendrimers. Upon activation by reactive oxygen species (ROS), QRCy undergoes self-fragmentation, releasing four fluorophores to amplify the fluorescence signal, affording an ultra-low detection limit of 81 nM for hydrogen peroxide. The L-serine modification enables specific binding of PS-QRC to kidney injury molecule-1 (KIM-1), which is overexpressed in injured renal tubules, thereby promoting renal accumulation and reducing background interference. Impressively, PS-QRC allows noninvasive real-time imaging of cisplatin-induced AKI in mice as early as 12 h, significantly earlier than conventional serum biochemical and histopathological analyses. Furthermore, a high-throughput screening platform was established using this nanoprobe to evaluate natural products, from which chrysin was identified as a promising renoprotective agent. Chrysin demonstrated both in vitro and in vivo renoprotective effects, with efficacy comparable to the established antioxidant N-acetylcysteine. Moreover, PS-QRC enabled quantitative monitoring of chrysin's dose-dependent therapeutic response. Overall, this integrated probe provides a sensitive and reliable tool for early AKI diagnosis and the high-throughput discovery of novel renoprotective drugs.