Macrophage Membrane‐Camouflaged Nanozymes for Combating the Oxidative Stress‐Microvascular Perfusion Negative Feedback in Ischemia‐Reperfusion Induced Acute Kidney Injury

Abstract Oxidative stress plays a critical role in the pathogenesis of ischemia‐reperfusion injury (IRI)‐induced acute kidney injury (AKI), driving necrosis of proximal tubule cells, inflammation, and capillary rarefaction. Inadequate perfusion resulting from capillary rarefaction can, in turn, induce chronic tissue hypoxia and exacerbate ischemic acute tubular necrosis, leading to an “oxidative stress‐microvascular perfusion” negative feedback that further aggravate kidney damage. In this study, a macrophage membrane‐camouflaged manganese‐based antioxidant nanozyme (MB@LM) is developed for targeted delivery and oxidative stress relief in AKI therapy. By inheriting macrophage surface proteins, MB@LM selectively targets damaged renal tissues that overexpress adhesion molecules like intercellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1), facilitating enhanced accumulation at the injury site. The manganese‐based nanozyme core provides antioxidant enzyme‐mimicking activities, effectively reducing oxidative stress and inhibiting apoptosis. In IRI‐induced AKI mouse model, MB@LM treatment significantly reduces renal damage, restores renal microvascular perfusion as assessed by ultrasound imaging, and alleviated inflammation, demonstrating remarkable therapeutic efficacy. Overall, MB@LM represents a promising targeted therapy for AKI, offering precise delivery, potent antioxidant protection, and anti‐inflammatory effects to support renal recovery and improve outcomes for AKI.