Kidney‐Targeted Nanoparticles with ROS Scavenging and STING Inhibition for the Treatment of Acute Kidney Injury

ABSTRACT Acute kidney injury (AKI), particularly when caused by ischemia‐reperfusion injury (IRI), involves severe mitochondrial damage, excessive oxidative stress, and dysregulated innate immune activation, yet no effective pharmacological therapy is currently available. The cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS–STING) pathway has emerged as a central mediator of renal inflammation triggered by mitochondrial DNA release after IRI. Here, we present a kidney‐targeted dual‐modality strategy that integrates reactive oxygen species (ROS)‐responsive delivery of the antioxidant D‐α‐tocopherol succinate (VES) with pharmacological suppression of STING signaling. The kidney‐targeting VES nanoparticles (T‐VES NP) selectively accumulated in injured renal tissue and enabled efficient ROS scavenging. In hypoxia/reoxygenation (HR)‐challenged tubular epithelial cells, the combined treatment preserved mitochondrial integrity, reduced STING phosphorylation, and attenuated downstream NF‐κB and chemokine signaling. In a unilateral renal IRI mouse model, administration of T‐VES NP together with STING antagonist H‐151 significantly decreased p‐STING levels, reduced inflammation, restored renal function, and improved survival. Overall, these results identify STING signaling as a key therapeutic target in IRI‐AKI and demonstrate the potential of kidney‐targeted nanomedicine as a dual‐modality therapeutic strategy for AKI.