Yan Yang,1,* Yiling Wang,1,* Xinran Jiang,1 Jiahao Mi,1 Dizhang Ge,2 Yuna Tong,3 Yuxuan Zhu1,2 

1Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, People’s Republic of China; 2Department of Pharmacy, People’s Hospital of Aba Tibetan and Qiang Autonomous Prefecture, Aba, 624000, People’s Republic of China; 3Department of Nephrology, The Third People’s Hospital of Chengdu, Chongqing Medical University, Chengdu, 610031, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yuna Tong; Yuxuan Zhu, Email tongyuna1985@163.com; zhuyuxuan6688@163.com

Introduction: Alzheimer’s disease (AD), a neurodegenerative condition, stands as the most prevalent form of dementia. Its complex pathological mechanisms and the formidable blood-brain barrier (BBB) pose significant challenges to current treatment approaches. Oxidative stress is recognized as a central factor in AD, underscoring the importance of antioxidative strategies in its treatment. In this study, we developed a novel brain-targeted nanoparticle, Ce/Zr-MOF@Cur-Lf, for AD therapy.
Methods: Layer-by-layer self-assembly technology was used to prepare Ce/Zr-MOF@Cur-Lf. In addition, the effect on the intracellular reactive oxygen species level, the uptake effect by PC12 and bEnd.3 cells and the in vitro BBB permeation effect were investigated. Finally, the mouse AD model was established by intrahippocampal injection of Aβ1-42, and the in vivo biodistribution, AD therapeutic effect and biosafety of the nanoparticles were researched at the animal level.
Results: As anticipated, Ce/Zr-MOF@Cur-Lf demonstrated efficient BBB penetration and uptake by PC12 cells, leading to attenuation of H2O2-induced oxidative damage. Moreover, intravenous administration of Ce/Zr-MOF@Cur-Lf resulted in rapid brain access and improvement of various pathological features of AD, including neuronal damage, amyloid-β deposition, dysregulated central cholinergic system, oxidative stress, and neuroinflammation.
Conclusion: Overall, Ce/Zr-MOF@Cur-Lf represents a promising approach for precise brain targeting and multi-target mechanisms in AD therapy, potentially serving as a viable option for future clinical treatment.

Keywords: metal-organic frameworks, Alzheimer’s disease, drug delivery, brain targeting, oxidative stress