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

ABSTRACT 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 (Mg 2 + , Ca 2 + , Mn 2 + , Fe 3+ , Co 2 + , Cu 2 + , and Ce 3+ ), 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.