Hierarchical Targeting Nanodrug with Holistic DNA Protection for Effective Treatment of Acute Kidney Injury

Abstract Acute kidney injury (AKI) manifests a hallmark pathological feature of extensive and severe DNA damage in renal tubules, primarily induced by the excessive of toxic reactive oxygen species (ROS) from the mitochondrial electron transport chain. The kidney's complex intricate physiological architecture and the heterogeneous intracellular environment pose significant challenges for effective sequential and high‐resolution drug delivery—an urgent issue that remains unresolved. To address this, a hierarchical‐targeting antioxidant nanodrug has been developed with a folic acid moiety (HAND) designed for high‐resolution drug delivery in AKI treatment. For the first time, HAND enables sequential targeting from the kidney to the most severely damaged proximal tubular epithelial cells (PTECs), ultimately concentrating in the DNA‐rich mitochondria and nucleus. As a result, HAND effectively scavenges ROS in situ, protecting both mitochondria and nuclei along with their vital genetic material. This action restores mitochondrial function, mitigates DNA oxidation and fragmentation, reduces apoptosis, and inhibits cGAS/STING‐mediated sterile inflammation. Consequently, HAND demonstrates remarkable efficacy in safeguarding injured kidneys during AKI. Overall, this work pioneers a hierarchical, high‐resolution antioxidant strategy, providing innovative guidance for the development of AKI therapies.