Chirality-Driven Metal-Phenolic Artificial Enzymes Enable Renal Targeting and Antioxidative Therapy Enhancement for...

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.