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

Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE

Original Publication: Weinheim : WILEY-VCH, [2014]-

Acute Kidney Injury*/drug therapy ; Acute Kidney Injury*/metabolism ; Acute Kidney Injury*/genetics ; Antioxidants*/pharmacology ; Drug Delivery Systems*/methods ; DNA*/drug effects; Animals ; Reactive Oxygen Species/metabolism ; DNA Damage/drug effects ; Mitochondria/metabolism ; Mitochondria/drug effects ; Humans ; Mice ; Folic Acid/pharmacology ; Male ; Apoptosis/drug effects

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.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

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82373871 National Natural Science Foundation of China; 2021BEG01001：2023BEG02038 Key Research Project of Ningxia Hui Autonomous Region of China (Major Project); 2024JK2114 Key Research and Development Program of Hunan Province; 2023QYJC017 Central South University Research Programme of Advanced Interdisciplinary Studies; 2023LNJJ12 Project Program of National Clinical Research Center for Geriatric Disorders (Xiangya Hospital); 2022AAC02058 Key Program of Ningxia Hui Autonomous Region Natural Science Foundation of China

Keywords: AKI; antioxidative nanomedicine; mitochondria; nucleus; oxidative stress; subcellular organelle targeting

0 (Antioxidants)
0 (Reactive Oxygen Species)
935E97BOY8 (Folic Acid)
9007-49-2 (DNA)

Date Created: 20241220 Date Completed: 20250428 Latest Revision: 20250428

20250428

PMC11809360

10.1002/advs.202411254

39703158