文献类型：期刊文献

英文题名：Targeting NOX4 with Quercetagetin-PLGA nanomaterials: a novel therapeutic strategy for Alzheimer's disease

作者：Jiang, Zhenxiu[1,2];Zhang, Junli[2];Zhang, Xiaojuan[3];Xie, Chen[1,2];Chen, Xiaoming[1,2];Ma, Guifang[2];Lu, Xiangyu[4];Ai, Yinghua[5];Jia, Tingting[6]

第一作者：Jiang, Zhenxiu

通信作者：Zhang, XJ[1]

机构：[1]Lanzhou Univ, Hosp 1, Dept Neurol, Lanzhou 730000, Peoples R China;[2]Lanzhou Univ, Clin Med Coll 1, Lanzhou 730000, Peoples R China;[3]Gansu Univ Chinese Med, Affiliated Hosp, Dept Endocrinol, Lanzhou 730000, Peoples R China;[4]Sch Management, Lanzhou 730000, Peoples R China;[5]Lanzhou Univ, Clin Med Coll 2, Lanzhou 730000, Peoples R China;[6]Sch Stomatol, Lanzhou 730000, Peoples R China

第一机构：Lanzhou Univ, Hosp 1, Dept Neurol, Lanzhou 730000, Peoples R China

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Affiliated Hosp, Dept Endocrinol, Lanzhou 730000, Peoples R China.|[10735b845793de6ae2b30]甘肃中医药大学第二附属医院;[10735]甘肃中医药大学;

年份：2026

外文期刊名：NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY

收录：;Scopus(收录号：2-s2.0-105042963370);WOS:【SCI-EXPANDED(收录号:WOS:001802249500001)】；

基金：This work was supported by the Natural Science Foundation of Gansu Province (21JR7RA365), the Lanzhou University Innovation and Entrepreneurship Training Program for College Students (20250060032), and the Intramural Fund of the First Hospital of Lanzhou University (ldyyyn2020-10).

语种：英文

外文关键词：Alzheimer's disease; NOX4; Quercetagetin; PLGA nanoparticles

摘要：This study aims to address NOX4 (NADPH oxidase 4)-driven oxidative injury in Alzheimer's disease (AD) and the poor bioavailability of the natural flavonoid Quercetagetin, we developed an alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR)-targeted, Quercetagetin-loaded PLGA nanocarrier (PLGA@Quercetagetin@alpha 7-nAChR) for receptor-mediated delivery, NOX4 suppression, and neuroprotection. Using the GSE97760 dataset, bioinformatic screening combined with LASSO regression was performed to identify candidate targets. Single-cell RNA sequencing (scRNA-seq) with pseudotime analysis was applied to delineate cell type-resolved and trajectory-associated expression patterns. Nanoparticles were fabricated by a double-emulsion method and characterized for physicochemical properties. In an A beta-induced HT-22 neuronal injury model, genetic perturbation, western blotting, and flow cytometry were used to validate the pathogenic role of NOX4 and to evaluate the pharmacological efficacy of the nanoplatform. NOX4 emerged as the key gene, showing enriched expression in oligodendrocytes and endothelial cells and an increase along the inferred disease-associated trajectory. In vitro, A beta stimulation upregulated NOX4, whereas NOX4 knockdown or Quercetagetin treatment alleviated A beta-induced cytotoxicity and apoptosis. The nanoparticles exhibited an average diameter and sustained drug release over 72 h. alpha 7-nAChR targeting enhanced neuronal uptake by similar to fivefold, markedly reduced NOX4 mRNA levels, and decreased the apoptotic rate from 18.3% to 5.0%. Notably, encapsulation also mitigated the hepatorenal toxicity observed with high-dose free Quercetagetin. These in vitro findings suggest NOX4 as a potential target in AD, and the PLGA@Quercetagetin@alpha 7-nAChR nanoplatform shows improved cellular uptake and reduced short-term toxicity compared to free drug. However, claims regarding brain targeting and translational potential are limited by the absence of in vivo validation, non-targeted controls, drug exposure normalization, and key formulation parameters (e.g., encapsulation efficiency). Future in vivo studies are required to substantiate this targeted strategy for AD.