Acute kidney injury (AKI), especially that caused by ischemia-reperfusion injury (IRI), involves severe mitochondrial damage, excessive oxidative stress, and dysregulation of innate immune activation. However, there are currently no effective drug treatments available. The stimulation of the cyclic GMP-AMP synthase-interferon gene (cGAS-STING) pathway by the interferon-inducing GMP-AMP synthase has become the core mediator of renal inflammation triggered by mitochondrial DNA release after IRI. This article presents a dual-mode strategy for the kidneys, combining the reactive delivery of the antioxidant D-α-tocopheryl succinate (VES) with pharmacological inhibition of the STING signal. The VES nanoparticles targeted to the kidneys (T-VES NP) selectively accumulate in the damaged renal tissue, achieving efficient ROS clearance. In hypoxic/reoxygenation (HR) challenged tubular epithelial cells, combined treatment maintains mitochondrial integrity, reduces STING phosphorylation, and weakens downstream NF-κB and chemokine signals. In a unilateral kidney IRI mouse model, the co-administration of T-VES NP and the STING antagonist H-151 significantly reduced p-STING levels, decreased inflammation, restored renal function, and improved survival rate. Overall, these results identify STING signaling as a key therapeutic target for IRI-AKI and demonstrate the potential of renal-targeted nanomedicine as a dual-mode treatment strategy for AKI. This research was published under the title "Kidney-Targeted Nanoparticles with ROS Scavenging and STING Inhibition for the Treatment of Acute Kidney Injury" in Advanced Functional Materials.
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DOI: 10.1002/adfm.202525671