A pH‐Responsive Biomimetic Antioxidant Nanoplatform with Dual Renal Targeting for Synergistic Therapy of Acute Kidney Injury

Abstract Acute kidney injury (AKI) represents a critical clinical condition marked by abrupt deterioration of renal function, primarily driven by oxidative stress, inflammation, and apoptosis. However, effective targeted therapies remain limited. Here, a smart, biomimetic nanoplatform (CeAst@MK) that synergistically addresses oxidative and inflammatory injury in AKI is reported. CeAst nanoparticles are formed via coordination between Ce 3 ⁺ ions and astragalin (Ast), a natural flavonoid with intrinsic ROS‐scavenging and anti‐inflammatory properties. To enhance immune evasion and renal targeting specificity, CeAst is cloaked with macrophage membranes (MCM) and modified with a kidney‐targeting peptide (KTP), yielding the final CeAst@MK system. The platform exhibits pH‐responsive release in the acidic microenvironment of injured renal tissues, enabling precise and rapid therapeutic delivery. In both LPS‐ and ischemia reperfusion‐induced AKI models, CeAst@MK significantly improves renal function, suppresses proinflammatory cytokines, and promotes M2 macrophage polarization. Mechanistically, it modulates PI3K/Akt and NF‐κB pathways, achieving dual antioxidative and anti‐inflammatory effects. This study presents a translationally promising nanotherapeutic system integrating natural antioxidants, biomimetic camouflage, and tissue‐specific delivery, offering an effective and precise strategy for AKI intervention.