Neutrophil‐Mediated Delivery of MRI‐Traceable Nanocarriers Ameliorates Acute Kidney Injury and Associated Cognitive Deficits and Anxiety‐Like Behaviors

ABSTRACT Acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD) and is increasingly linked to significant remote neuropsychiatric sequelae. However, current therapeutic strategies usually lack renal targeting and, critically, neglect to address these systemic comorbidities, particularly the associated cognitive deficits and anxiety‐like behaviors. In this study, we developed a biomimetic platform consisting of neutrophils loaded with superparamagnetic iron oxide nanoparticles encapsulating celastrol (termed NSPIOC), as an MRI‐visible theranostic system for targeted renal therapy and simultaneous mitigation of associated neuropsychiatric impairments. Systemically administered NSPIOC leverage innate neutrophil chemotaxis to home toward renal inflammatory gradients. Upon infiltration, inflammation‐triggered NETosis releases the cargo into vulnerable proximal tubules, while T 2 ‐weighted MRI enables real‐time monitoring of neutrophil recruitment. Our results demonstrate that NSPIOC effectively restore renal function and inhibits the AKI‐to‐CKD transition. Importantly, our findings provide new evidence that renal‐targeted intervention can alleviate AKI‐induced cognitive deficits and anxiety‐like behaviors. Mechanistically, restoring renal homeostasis prevents the pathological hyperactivation of glutamatergic neurons in the medial prefrontal cortex (mPFC). This biomimetic platform offers a holistic strategy for managing AKI by simultaneously addressing primary renal injury and remote neurological dysfunction, presenting a promising approach to systemic inflammatory complications.