Enhanced BBB penetration and microglia-targeting nanomodulator for the two-pronged modulation of chronically activated microglia-mediated neuroinflammation in Alzheimer's disease
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,...
| الحاوية / القاعدة: | Acta Pharmaceutica Sinica B |
|---|---|
| المؤلفون الرئيسيون: | , , , , , , , , , , , , , , |
| التنسيق: | مقال |
| اللغة: | الإنجليزية |
| منشور في: |
Elsevier
2025-02-01
|
| الموضوعات: | |
| الوصول للمادة أونلاين: | http://www.sciencedirect.com/science/article/pii/S2211383525000218 |
| _version_ | 1849813947009466368 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Ya Wei |
| collection | DOAJ |
| container_title | Acta Pharmaceutica Sinica B |
| description | 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. |
| format | Article |
| id | doaj-art-b64c449700a54e84ad664ff89d71ae93 |
| institution | Directory of Open Access Journals |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| spelling | doaj-art-b64c449700a54e84ad664ff89d71ae932025-08-20T01:33:01ZengElsevierActa Pharmaceutica Sinica B2211-38352025-02-011521098111110.1016/j.apsb.2025.01.015Enhanced BBB penetration and microglia-targeting nanomodulator for the two-pronged modulation of chronically activated microglia-mediated neuroinflammation in Alzheimer's diseaseYa Wei0Xue Xia1Xiaorong Wang2Wenqin Yang3Siqin He4Lulu Wang5Yongke Chen6Yang Zhou7Feng Chen8Hanmei Li9Fu Peng10Guobo Li11Zheng Xu12Jintao Fu13Huile Gao14Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570200, China; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, ChinaKey Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, ChinaKey Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, ChinaKey Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, ChinaKey Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570200, ChinaKey Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570200, ChinaDepartment of Radiology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou 570311, ChinaSchool of Food and Biological Engineering, Chengdu University, Chengdu 610106, ChinaKey Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, ChinaKey Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570200, China; Corresponding authors.Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570200, China; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S2211383525000218Blood‒brain barrier penetrationMicroglial targetingMicroglial modulationChronic neuroinflammationAlzheimer's diseaseImmunotherapy |
| spellingShingle | 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 Enhanced BBB penetration and microglia-targeting nanomodulator for the two-pronged modulation of chronically activated microglia-mediated neuroinflammation in Alzheimer's disease Blood‒brain barrier penetration Microglial targeting Microglial modulation Chronic neuroinflammation Alzheimer's disease Immunotherapy |
| title | Enhanced BBB penetration and microglia-targeting nanomodulator for the two-pronged modulation of chronically activated microglia-mediated neuroinflammation in Alzheimer's disease |
| title_full | Enhanced BBB penetration and microglia-targeting nanomodulator for the two-pronged modulation of chronically activated microglia-mediated neuroinflammation in Alzheimer's disease |
| title_fullStr | Enhanced BBB penetration and microglia-targeting nanomodulator for the two-pronged modulation of chronically activated microglia-mediated neuroinflammation in Alzheimer's disease |
| title_full_unstemmed | Enhanced BBB penetration and microglia-targeting nanomodulator for the two-pronged modulation of chronically activated microglia-mediated neuroinflammation in Alzheimer's disease |
| title_short | Enhanced BBB penetration and microglia-targeting nanomodulator for the two-pronged modulation of chronically activated microglia-mediated neuroinflammation in Alzheimer's disease |
| title_sort | enhanced bbb penetration and microglia targeting nanomodulator for the two pronged modulation of chronically activated microglia mediated neuroinflammation in alzheimer s disease |
| topic | Blood‒brain barrier penetration Microglial targeting Microglial modulation Chronic neuroinflammation Alzheimer's disease Immunotherapy |
| url | http://www.sciencedirect.com/science/article/pii/S2211383525000218 |
| work_keys_str_mv | AT yawei enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT xuexia enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT xiaorongwang enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT wenqinyang enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT siqinhe enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT luluwang enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT yongkechen enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT yangzhou enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT fengchen enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT hanmeili enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT fupeng enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT guoboli enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT zhengxu enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT jintaofu enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease AT huilegao enhancedbbbpenetrationandmicrogliatargetingnanomodulatorforthetwoprongedmodulationofchronicallyactivatedmicrogliamediatedneuroinflammationinalzheimersdisease |