REVIEWOpenAccessExosomalcircRNAs:biogenesis,effectandapplicationinhumandiseasesYangxiaWang1,JinboLiu2,JunfenMa1,TingSun1,QuanboZhou2,WeiweiWang4,GuixianWang2,PingjunWu6,HaijiangWang3,LiJiang5,WeitangYuan2,ZhenqiangSun2*andLiangMing1*AbstractExosomeshaveemergedascriticalmediatorsofintercellularcommunication,bothlocallyandsystemically,byregulatingadiverserangeofbiologicalprocessesbetweencells.CircularRNA(circRNA)isanovelmemberofendogenousnoncodingRNAswithwidespreaddistributionanddiversecellularfunctions.Recently,circularRNAshavebeenidentifiedfortheirenrichmentandstabilityinexosomes.Inthisreview,weoutlinetheorigin,biogenesisandfunctionofexosomalcircRNAsaswellastheirrolesinvariousdiseases.Althoughtheirpreciserolesandmechanismsofgeneregulationremainlargelyelusive,exosomalcircRNAshavepotentialapplicationsasdiseasebiomarkersandnoveltherapeutictargets.Keywords:Exosome,CircRNA,ExosomalcircRNA,Tumormicroenvironment,BiomarkerBackgroundInthepast30years,oneofthemostrevolutionarycon-tributionstocellbiologywasthediscoveryofexosomes;exosomesarenanoscale(30–150nm)extracellularvesi-clesofendocyticoriginthatareshedbymosttypesofcellsandcirculateinbodilyfluidssuchasblood,urine,saliva,andbreastmilk[1].Exosomalcontentshavebeenshowntobebroad,composedofvariousgrowthfactors,proteins,lipids,andnucleicacids,longnoncodingRNAsandcircularRNAs(circRNAs)[2].Exosomesareintra-luminalvesiclesgeneratedwithintheendolysosomalsystemandsecretedbythefusionofmultivesicularendosomes(MVEs),whichareshedfromtheplasmamembrane[3].CircRNAsgetitsclosedloopstructuresfromback-splicedexonsinnucleus.Aftertransferringintocytoplasm,circRNAscannotonlybindwithmiR-NAsorproteintoexertvariousfunctions,butcanbesortedintoMVEsalongwithanabundantcargoofothernucleicacids,lipidandproteins[4].Thenexosomesaresecretedfromtheparentcellsintobodilyfluid,throughwhichcircRNAsstarttheircirculationandactivatetheirbiologicalfunctions.Afterreleasedintotheextracellularenvironment,exo-somescanreachrecipientcellsanddelivertheircargos(likecircR...
