Manganese-Chelating L-Serine Nanoarchitectures: Targeting Kidney Injury Molecule-1 for Reversing Renal Ischemia-Reperfusion Injury via Senescence Regulation.

Oxidative stress is a central driver of renal ischemia-reperfusion (I/R) injury, and developing targeted antioxidant systems against it remains an unmet challenge. Here, we address this challenge by engineering a dual-functional metal-ion/L-serine nanoarchitecture integrating two key components: precise kidney targeting via L-serine's molecular recognition of the injury biomarker kidney injury molecule-1 (Kim-1), and bioinspired antioxidant catalysis through metal-ion/amino-acid-coordinated enzyme mimicry. Through systematic screening of metal ions (Mg2 +, Ca2 +, Mn2 +, Fe3+, Co2 +, Cu2 +, and Ce3+), we identified Mn-chelating L-serine (L-SerMn) as the optimal nanoarchitecture, displaying robust superoxide dismutase (SOD)- and catalase (CAT)-like activities. Molecular dynamics simulations revealed stronger binding affinity of L-SerMn to Kim-1 compared to free L-serine. In vitro, L-SerMn protected renal tubular epithelial cells from hypoxia/reoxygenation (H/R)-induced damage by functioning as a dual SOD/CAT mimic. In vivo, L-SerMn achieved selective accumulation in injured kidneys via Kim-1-mediated targeting, enabling sustained restoration of redox homeostasis that ameliorated renal pathological injury. Mechanistically, L-SerMn ameliorated renal I/R injury and blocked the acute kidney injury (AKI)-chronic kidney disease (CKD) transition via suppression of cellular senescence, through regulating the JAK2-STAT3 and p53 signaling pathways. This work elegantly integrates coordination chemistry and biomimetic enzymology for the rational design of organ-targeted nanotherapeutics, offering a promising strategy against ischemic diseases.