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Biomaterials, Available online 3 March 2025 | https://doi.org/10.1016/j.biomaterials.2025.123237 Kidney-targeting DNA tetrahedral molecular cage synergistically inhibits acute kidney injury by clearing ROS and activating HO-1

Yu Ren ^a,1, Yuhang Dong ^a,1, Zhi Li ^b, Keying Xu^a, Jiafeng Xu ^a, Xiangyu Li ^a, Mengmeng Zhang ^a, Changlu Xu ^b, Min Yang ^c, Min Lee ^b,d, Xiaoming Meng ^a, Jie Wang ^c

^aInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China
^bDivision of Oral and Systemic Health Sciences, School of Dentistry, University of California, Los Angeles, CA, 90095, United States
^cThe Second Department of Critical. Care Medicine, The Second Affiliated Hospital of Anhui- Medical University, Anhui, Hefei, 230601, PR China
^dDepartment of Bioengineering, University of California, Los Angeles, CA, 90095, United States

¹These authors contributed equally to this work.
Corresponding authors: Min Lee, Xiaoming Meng, Jie Wang

Abstract

Acute kidney injury (AKI) is a major cause of mortality in hospitalized patients, yet effective therapeutic interventions remain underdeveloped. To address this critical need, we have employed tetrahedral framework nucleic acid (tFNA) as a carrier to self-assemble a complex incorporating G-quadruplex and hemin (G4/Hemin). This novel formulation exhibits uniform particle size, targeted delivery, and significant therapeutic efficacy for AKI. In a chemotherapy-induced AKI model, G4/Hemin-tFNA preferentially accumulated in the renal tubules, significantly mitigating drug-induced renal tubular injury. In healthy mice, G4/Hemin-tFNA was rapidly cleared from circulation due to efficient renal filtration. Safety evaluations conducted over a continuous 30-day period indicated minimal side effects associated with G4/Hemin-tFNA administration. Mechanistic studies elucidated three primary molecular mechanisms through which G4/Hemin-tFNA exerts its therapeutic effects in AKI: 1) Enhanced Renal Targeting. G4/Hemin-tFNA facilitates effective renal targeting and protection during blood circulation, leading to significant accumulation of drug within the kidneys. 2) Reactive Oxygen Species (ROS) Clearance. The complex exhibits peroxidase-like activity, enabling the rapid clearance of ROS at the site of AKI lesions, thereby inhibiting the oxidative stress progression. 3) Activation of heme oxygenase-1 (HO-1). G4/Hemin-tFNA selectively activates HO-1, enhancing the concentration of anti-inflammatory factors at inflamed sites and promoting an anti-inflammatory microenvironment. Collectively, these findings demonstrate that G4/Hemin-tFNA is a safe and effective therapeutic agent for AKI. By activating HO-1 and clearing ROS, G4/Hemin-tFNA inhibits disease progression, offering a promising approach for the development of future AKI therapies.

논문정보

형식Research article
게재일2025년 03월 (BRIC 등록일 2025-03-13)
연구진국외 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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