A new biomaterial and molecular imaging platform: Click-Coupled Dual-Responsive Fluorescent Signaling for Deciphering the ROS-RSS Imbalance in Kidney Injury

As the sophisticated "purification factory", kidney performs pivotal functions from blood filtration to endocrine regulation. Consequently, renal injury will trigger "domino effect" culminating in multiple organ failure, posing unavoidable risks for patients with severe or chronic illnesses. Amidst complex etiology, ferroptosis is a key process mediated by redox dyshomeostasis, including oxidative burst and concomitant reductive depletion, while tracking isolated redox events fails to decipher dynamic pathogenesis. Therefore, simultaneously tracking fluctuations of oxidative and reductive hallmarks is essential to elucidate renal pathogenesis and enable early intervention. Herein, we engineered specific-radical imaging modules for synergistically monitoring core species associated with ferroptosis-mediated kidney injury, glutathione (GSH) and peroxynitrite (ONOO^-), by incorporating hydrophilic chains via "click" assembly. This click-coupled dual-responsive fluorescent probe (CY-LS) enabled real-time, in-situ tracking of reductive GSH and oxidative ONOO^- dynamics in vivo. In drug-acute and diabetic-chronic kidney injury models, CY-LS revealed that synchronous GSH depletion and ONOO^- accumulation synergistically exacerbate renal injury via ferroptosis. Notably, pharmacological inhibition of ferroptosis reversed redox-dyshomeostasis signals, validating dual-channel assessment for practical therapeutic monitoring. Furthermore, the exceptional renal clearance of CY-LS enables non-invasive diagnosis via simple urinalysis. Collectively, such modular toolkit is powerful for deciphering renal pathologies, paving avenues for precision diagnosis of redox-driven disorders.