Chirality-Driven Metal–Phenolic Artificial Enzymes Enable Renal Targeting and Antioxidative Therapy Enhancement for Acute Kidney Injury

Despite advancements in artificial enzymes (AEs) for acute kidney injury (AKI) therapy through renal redox homeostasis modulation, the trade-off between organ-specific targeting and high multienzyme-mimicking catalytic efficiency is still a big challenge. Herein, we address this challenge through chirality-engineered Cu²⁺-phenolic AEs (l-phen@Cu-TA) via incorporation of l-phenylalanine (l-phen) to synergize stereoselective recognition and catalytic activity. Chiral l-phen induces electron density redistribution from phenolic ligands to Cu²⁺ in the cocatalytic center, significantly enhancing H₂O₂ adsorption while reducing catalytic energy barriers, thereby amplifying catalase (CAT)-mimicking activity and superoxide dismutase (SOD)-mimetic performance, with concurrent scavenging of secondary radicals (^•OH, ONOO^-, etc.). Critically, the stereoselective recognition of l-phen@Cu-TA AEs, based on the l-type amino acid transporter 1 (LAT1), enhances the renal tubular cell uptake by 5-fold over pristine Cu-TA AEs, respectively, thereby driving renal pathological-site enrichment and internalization to boost therapeutic bioavailability. In vivo investigation reveals that the l-phen@Cu-TA treatment can restore the physiological homeostasis of AKI via ROS-scavenging by SOD-CAT enzymatic cascades and remodel the renal microenvironmental stability, thereby achieving satisfactory AKI treatment. This work pioneers chirality-modulated AEs for organ-specific antioxidant therapy, establishing a transformative paradigm for precision intervention in oxidative stress-related pathologies.