Enhanced BBB penetration and microglia-targeting nanomodulator for the two-pronged modulation of chronically activated microglia-mediated neuroinflammation in Alzheimer's disease

被引：6

作者：

Wei, Ya ^{[1
,2
]}

Xia, Xue ^{[2
]}

Wang, Xiaorong ^{[2
]}

Yang, Wenqin ^{[2
]}

He, Siqin ^{[2
]}

Wang, Lulu ^{[1
]}

Chen, Yongke ^{[2
]}

Zhou, Yang ^{[1
]}

Chen, Feng ^{[3
]}

Li, Hanmei ^{[4
]}

Peng, Fu ^{[2
]}

Li, Guobo ^{[2
]}

Xu, Zheng ^{[5
]}

Fu, Jintao ^{[1
]}

Gao, Huile ^{[1
,2
]}

机构：

[1] Hainan Univ, Sch Pharmaceut Sci, Key Lab Trop Biol Resources, Minist Educ, Haikou 570200, Peoples R China

[2] Sichuan Univ, West China Sch Pharm, Key Lab Drug Targeting & Drug Delivery Syst, Educ Minist, Chengdu 610041, Peoples R China

[3] Hainan Med Univ, Hainan Affiliated Hosp, Hainan Gen Hosp, Dept Radiol, Haikou 570311, Peoples R China

[4] Chengdu Univ, Sch Food & Biol Engn, Chengdu 610106, Peoples R China

[5] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China

来源：

ACTA PHARMACEUTICA SINICA B | 2025年 / 15卷 / 02期

基金：

中国国家自然科学基金;

关键词：

Blood-brain barrier penetration; Microglial targeting; Microglial modulation; Chronic neuroinflammation; Alzheimer's disease; Immunotherapy; TREM2; Resveratrol; BRAIN; CELLS; NEURODEGENERATION; NANOPARTICLES; PHAGOCYTOSIS; STRATEGY; THERAPY; PEPTIDE;

D O I：

10.1016/j.apsb.2025.01.015

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Intervention in chronically activated microglia-mediated neuroinflammat ion is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood-brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acidcleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 pep- tides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improve- ments in late APP/PS1 mice. <feminine ordinal indicator> 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

引用

页码：1098 / 1111

页数：14

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