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 w...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.展开更多
基金financially supported by the National Natural Science Foundation of China(Grant No.81871431,82171905 and 81801828)the Tianjin Natural Science Foundation(Grant No.21JCQNJC01570 and 22JCYBJC01340)+2 种基金Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-001A)Tianjin Municipal Education Research Project(20140115)Fund for Distinguished Young Scholars of Tianjin Medical University General Hospital(22ZYYJQ03).
文摘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.
