MicroRNA-208a(miR-208a)plays critical roles in the severe fibrosis and heart failure post myocardial ischemia/reperfusion(IR)injury.MiR-208a inhibitor(mI)with complementary RNA sequence can silence the expression of m...MicroRNA-208a(miR-208a)plays critical roles in the severe fibrosis and heart failure post myocardial ischemia/reperfusion(IR)injury.MiR-208a inhibitor(mI)with complementary RNA sequence can silence the expression of miR-208a,while it is challenging to achieve efficient and myocardium-targeted delivery.Herein,biomimetic nanocomplexes(NCs)reversibly coated with red blood cell membrane(RM)were developed for the myocardial delivery of mI.To construct the NCs,membrane-penetrating helical polypeptide(PG)was first adopted to condense mI and form the cationic inner core,which subsequently adsorbed catalase(CAT)via electrostatic interaction followed by surface coating with RM.The membrane-coated NCs enabled prolonged blood circulation after systemic administration,and could accumulate in the injured myocardium via passive targeting.In the oxidative microenvironment of injured myocardium,CAT decomposed H_(2)O_(2)to produce O_(2)bubbles,which drove the shedding of the outer RM to expose the positively charged inner core,thus facilitated effective internalization by cardiac cells.Based on the combined contribution of mI-mediated miR-208a silencing and CAT-mediated alleviation of oxidative stress,NCs effectively ameliorated the myocardial microenvironment,hence reducing the infarct size as well as fibrosis and promoting recovery of cardiac functions.This study provides an effective strategy for the cytosolic delivery of nucleic acid cargoes in the myocardium,and it renders an enlightened approach to resolve the blood circulation/cell internalization dilemma of cell membrane-coated delivery systems.展开更多
文摘目的探讨血清微小核糖核酸(microRNA,miR)-208a、miR-483联合氨基末端脑钠肽前体(N-terminal pro-brain natriuretic peptide,NT-proBNP)预测维持性血液透析(maintenance hemodialysis,MHD)患者心血管事件发生的价值。方法选取2016年1月至2019年12月海南西部中心医院收治的MHD患者163例,根据随访6个月期间是否发生心血管事件,分为65例心血管事件组和98例无心血管事件组。采用实时定量聚合酶链反应(quantitative real time polymerase chain reaction,qRT-PCR)法检测两组患者血清miR-208a及miR-483浓度,采用酶联免疫吸附法测定NT-proBNP浓度。应用多因素Logistic回归分析对MHD患者心血管事件发生的危险因素进行分析。采用受试者工作特征曲线(receiver operating characteristic curve,ROC)分析miR-208a、miR-483及NT-proBNP预测MHD患者心血管事件发生的价值。结果心血管事件组患者血清miR-208a(3.28±1.50 vs.1.15±0.46,P<0.001)、miR-483(2.26±1.06 vs.0.73±0.24,P<0.001)及NT-proBNP[(5682.73±290.50)pg/mL vs.(1835.40±174.36)pg/mL,P<0.001]浓度均明显高于无心血管事件组,差异有统计学意义。多因素Logistic回归分析结果显示,血清miR-208a(OR=2.473,95%CI:1.752~5.490)、miR-483(OR=1.962,95%CI:1.358~3.704)及NT-proBNP(OR=2.750,95%CI:1.926~6.483)浓度升高是MHD患者心血管事件发生的危险因素(P<0.05)。ROC分析结果显示,miR-208a、miR-483联合NT-proBNP预测MHD患者心血管事件发生的曲线下面积(area under the curve,AUC)最大(0.942,95%CI:0.882~0.995),其敏感度和特异度分别为97.3%和85.0%。相关分析显示,心血管事件患者血清miR-208a、miR-483浓度与NT-proBNP均呈正相关(P<0.001)。结论心血管事件患者血清miR 208a、miR-483及NT-proBNP浓度明显升高,是MHD患者心血管事件发生的危险因素,3项联合预测心血管事件发生的敏感度较高。
基金supported by the National Natural Science Foundation of China(Nos.82172076,52273144,and 52033006)111 project,Collaborative Innovation Center of Suzhou Nano Science&Technology,Joint International Research Laboratory of Carbon-Based Functional Materials and Devices,and Suzhou Key Laboratory of Nanotechnology and Biomedicine.
文摘MicroRNA-208a(miR-208a)plays critical roles in the severe fibrosis and heart failure post myocardial ischemia/reperfusion(IR)injury.MiR-208a inhibitor(mI)with complementary RNA sequence can silence the expression of miR-208a,while it is challenging to achieve efficient and myocardium-targeted delivery.Herein,biomimetic nanocomplexes(NCs)reversibly coated with red blood cell membrane(RM)were developed for the myocardial delivery of mI.To construct the NCs,membrane-penetrating helical polypeptide(PG)was first adopted to condense mI and form the cationic inner core,which subsequently adsorbed catalase(CAT)via electrostatic interaction followed by surface coating with RM.The membrane-coated NCs enabled prolonged blood circulation after systemic administration,and could accumulate in the injured myocardium via passive targeting.In the oxidative microenvironment of injured myocardium,CAT decomposed H_(2)O_(2)to produce O_(2)bubbles,which drove the shedding of the outer RM to expose the positively charged inner core,thus facilitated effective internalization by cardiac cells.Based on the combined contribution of mI-mediated miR-208a silencing and CAT-mediated alleviation of oxidative stress,NCs effectively ameliorated the myocardial microenvironment,hence reducing the infarct size as well as fibrosis and promoting recovery of cardiac functions.This study provides an effective strategy for the cytosolic delivery of nucleic acid cargoes in the myocardium,and it renders an enlightened approach to resolve the blood circulation/cell internalization dilemma of cell membrane-coated delivery systems.
