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

Ya Wei; Xue Xia; Xiaorong Wang; Wenqin Yang; Siqin He; Lulu Wang; Yongke Chen; Yang Zhou; Feng Chen; Hanmei Li; Fu Peng; Guobo Li; Zheng Xu; Jintao Fu; Huile Gao

doi:10.1016/j.apsb.2025.01.015

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

Acta Pharm Sin B. 2025 Feb;15(2):1098-1111. doi: 10.1016/j.apsb.2025.01.015. Epub 2025 Jan 25.

Authors

Ya Wei^{1

2}, Xue Xia², Xiaorong Wang², Wenqin Yang², Siqin He², Lulu Wang¹, Yongke Chen², Yang Zhou¹, Feng Chen³, Hanmei Li⁴, Fu Peng², Guobo Li², Zheng Xu⁵, Jintao Fu¹, Huile Gao^{1

2}

Affiliations

¹ Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570200, China.
² Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
³ Department of Radiology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou 570311, China.
⁴ School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China.
⁵ State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.

Abstract

Intervention in chronically activated microglia-mediated neuroinflammation 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 acid-cleavable 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 peptides 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 improvements in late APP/PS1 mice.

Keywords: Alzheimer's disease; Blood‒brain barrier penetration; Chronic neuroinflammation; Immunotherapy; Microglial modulation; Microglial targeting; Resveratrol; TREM2.