Extracellular Vesicle–Based Biohybrid Enabling Synergistic Anti‐Oxidative Stress and Anti‐Inflammation for Targeted Therapy of Acute Kidney Injury

Abstract Acute kidney injury (AKI) presents a significant clinical challenge, driven by oxidative stress and inflammatory responses. To address these pathological factors, a biohybrid nanoplatform, ESAK1, is developed by integrating a gold cluster artificial enzyme (AU), an extracellular vesicle obtained from genetically engineered renal tubular epithelial cell (tecEV), and a kidney injury‐targeting peptide (ktPep) via a bio‐orthogonal SnoopCatcher‐SnoopTag system derived from Streptococcus pneumoniae adhesins. Upon intravenous administration to mice with AKI, ESAK1 preferentially accumulates in injured renal tissues through ktPep‐mediated targeting. Subsequently, the AU component, exhibiting superior superoxide dismutase‐ and catalase‐like activities, scavenges excess reactive oxygen species (ROS) in situ, alleviating oxidative stress and simultaneously protecting the tecEV from ROS‐induced damage. Consequently, the tecEV exerts potent anti‐inflammatory effects, acting synergistically with oxidative stress neutralization to enhance the therapeutic efficacy. This dual‐action mechanism facilitates the activation of endogenous repair mechanisms, promoting kidney recovery, as evidenced by significantly reduced levels of serum creatinine and urea, diminished renal histopathological damage, decreased inflammatory cytokines, and enhanced expression of repair‐associated proteins. By integrating targeted delivery, anti‐oxidant defense, and anti‐inflammatory properties into a single platform, ESAK1 offers a promising multi‐faceted approach for advanced kidney‐protective therapies and even broader inflammatory diseases.