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Engineered macrophage-biomimetic versatile nanoantidotes for inflammation-targeted therapy against Alzheimer’s disease by neurotoxin neutralization and immune recognition suppression

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Bioactive Materials 2023年第8期26卷 337-352页

作者： Meng Cheng Caihua Ye Chunxiao Tian Dongju Zhao Haonan Li Zuhao Sun Yuyang Miao Qiang Zhang Junping Wang Yan Dou Department of Radiology and Tianjin Key Laboratory of Functional Imaging Tianjin Medical University General HospitalTianjin300052PR China School of Biomedical Engineering and Technology Tianjin Medical UniversityTianjin300070PR China School of Life Sciences Tianjin UniversityTianjin300072PR China Department of Geriatrics Tianjin Medical University General HospitalTianjin Geriatrics InstituteTianjin300052PR China

immune recognition of excessive neurotoxins by microglia is a trigger for the onset of neuroinflammation in the brain,leading to neurodegeneration in Alzheimer’s disease(AD).Blocking active recognition of microglia while removing neurotoxins holds promise for fundamentally alleviating neurotoxin-induced immune responses,but is very challenging.Herein,an engineered macrophage-biomimetic versatile nanoantidote(OT-Lipo@M)is developed for inflammation-targeted therapy against AD by neurotoxin neutralization and immune recognition suppression.Coating macrophage membranes can not only endow OT-Lipo@M with anti-phagocytic and inflammation-tropism capabilities to target inflammatory lesions in AD brain,but also efficiently reduce neurotoxin levels to prevent them from activating microglia.The loaded oxytocin(OT)can be slowly released to downregulate the expression of immune recognition site Toll-like receptor 4(TLR4)on microglia,inhibiting TLR4-mediated pro-inflammatory signalling cascade.Benefiting from this two-pronged immunosuppressive strategy,OT-Lipo@M exhibits outstanding therapeutic effects on ameliorating cognitive deficits,inhibiting neuronal apoptosis,and enhancing synaptic plasticity in AD mice,accompanied by the delayed hippocampal atrophy and brain microstructural disruption by in vivo 9.4T MR imaging.This work provides new insights into potential AD therapeutics targeting microglia-mediated neuroinflammation at the source.

关键词： Alzheimer’s disease Biomimetic nanomedicine Biological neutralization Immune recognition and response Neuroinflammation-targeted therapy 9.4T MR imaging

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