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Smart Liposomal Nanocarrier Enhanced the Treatment of Ischemic Stroke through Neutrophil Extracellular Traps and Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase-Stimulator of Interferon Genes (cGAS-STING) Pathway Inhibition of Ischemic Penumbra
journal contribution
posted on 2023-09-15, 14:06 authored by Shanbo Sun, Wei Lv, Shengnan Li, Qi Zhang, Weichong He, Zhiyi Min, Chuanhui Teng, Yuqin Chen, Linfeng Liu, Jiaqing Yin, Baoli Zhu, Ming Xu, Dongwei Dai, Hongliang XinBrain
inflammation is regarded as one of the leading causes that
aggravates secondary brain injury and hinders the prognosis of ischemic
stroke. After ischemic stroke, high quantities of peripheral neutrophils
are recruited to brain lesions and release neutrophil extracellular
traps (NETs), leading to the aggravation of blood–brain barrier
(BBB) damage, activation of microglia, and ultimate neuronal death.
Herein, a smart multifunctional delivery system has been developed
to regulate immune disorders in the ischemic brain. Briefly, Cl-amidine,
an inhibitor of peptidylarginine deiminase 4 (PAD4), is encapsulated
into self-assembled liposomal nanocarriers (C-Lipo/CA) that are modified
by reactive oxygen species (ROS)-responsive polymers and fibrin-binding
peptide to achieve targeting ischemic lesions and stimuli-responsive
release of a drug. In the mouse model of cerebral artery occlusion/reperfusion
(MCAO), C-Lipo/CA can suppress the NETs release process (NETosis)
and further inhibit the cyclic guanosine monophosphate-adenosine monophosphate
synthase-stimulator of interferon genes (cGAS-STING) pathway in an
ischemic brain. In addition, MCAO mice treated with C-Lipo/CA significantly
mitigated ischemic and reperfusion injury, with a reduction in the
area of cerebral infarction to 12.1%, compared with the saline group
of about 46.7%. These results demonstrated that C-Lipo/CA, which integrated
microglia regulation, BBB protection, and neuron survival, exerts
a potential therapy strategy to maximize ameliorating the mortality
of ischemic stroke.
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ultimate neuronal deathregulate immune disordersreactive oxygen speciespotential therapy strategypeptidylarginine deiminase 4neutrophil extracellular trapsmcao mice treatedcyclic guanosine monophosphateassembled liposomal nanocarriersadenosine monophosphate synthase1 %, comparednets release processcerebral artery occlusionnets ), leadingintegrated microglia regulationmcao ), cpad4 ),responsive releaseleading causescerebral infarctionsaline groupresults demonstratedperipheral neutrophilsneuron survivalmouse modelmaximize amelioratingischemic strokeischemic braininterferon geneshigh quantitiesbrain lesionsbinding peptide7 %.
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