Ischemic stroke is currently the second leading cause of death worldwide,and insufficient endogenous neurogenesis is the greatest cause of post-stroke disability.MicroRNAs have been proven to hold therapeutic potentia...Ischemic stroke is currently the second leading cause of death worldwide,and insufficient endogenous neurogenesis is the greatest cause of post-stroke disability.MicroRNAs have been proven to hold therapeutic potential,unfortunately,they have a low stability that hinders their clinical usage.Our earlier work revealed that Panax notoginseng derived exosome like nanoparticles,namely PDNs have potential to bypass BBB and reduce the cerebral ischemia/reperfusion(CI/R)damage.In this study,we employed microRNA-124 as a model therapeutic gene,utilizing its engineered variant Agomir-124(Ago124)to optimize loading efficiency.The therapeutic effects of Ago124@R-PDN were further assessed in several sets of experiments.Pharmacokinetic study showed that erythrocyte membrane extended the half-life of PDNs from 7 min to 11.3 h,and the loading efficiency of Ago124 reached 40%.In an in vitro oxygen-glucose deprivation/reperfusion(OGD/R)model,Ago124@R-PDN enhanced IL-10 production in microglia by 67%(vs 11.7%with free Ago124),and promoted Tuj1+neuronal differentiation by 2.23-fold compared with vehicle.Also,Ago124@R-PDN brought gene cargo into the brain,alleviated infarct volume,and improved functional behaviors in model mice.At last,we demonstrated that surface glycosyl of PDN facilitated its brain-entering ability by being recognized by sodium-glucose linked transporter-1 protein.In conclusion,our erythrocyte fused PDNs offer a promising strategy for delivering biomacromolecule to treat brain diseases.展开更多
基金supported by National Natural Science Foundation of China(82374296,82271965,62331021)Development Project of Shanghai Peak Disciplines-Integrated Medicine(201801)+1 种基金Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)Shanghai Municipal Science and Technology Explorer Project(23TS1400500).
文摘Ischemic stroke is currently the second leading cause of death worldwide,and insufficient endogenous neurogenesis is the greatest cause of post-stroke disability.MicroRNAs have been proven to hold therapeutic potential,unfortunately,they have a low stability that hinders their clinical usage.Our earlier work revealed that Panax notoginseng derived exosome like nanoparticles,namely PDNs have potential to bypass BBB and reduce the cerebral ischemia/reperfusion(CI/R)damage.In this study,we employed microRNA-124 as a model therapeutic gene,utilizing its engineered variant Agomir-124(Ago124)to optimize loading efficiency.The therapeutic effects of Ago124@R-PDN were further assessed in several sets of experiments.Pharmacokinetic study showed that erythrocyte membrane extended the half-life of PDNs from 7 min to 11.3 h,and the loading efficiency of Ago124 reached 40%.In an in vitro oxygen-glucose deprivation/reperfusion(OGD/R)model,Ago124@R-PDN enhanced IL-10 production in microglia by 67%(vs 11.7%with free Ago124),and promoted Tuj1+neuronal differentiation by 2.23-fold compared with vehicle.Also,Ago124@R-PDN brought gene cargo into the brain,alleviated infarct volume,and improved functional behaviors in model mice.At last,we demonstrated that surface glycosyl of PDN facilitated its brain-entering ability by being recognized by sodium-glucose linked transporter-1 protein.In conclusion,our erythrocyte fused PDNs offer a promising strategy for delivering biomacromolecule to treat brain diseases.
