Objective:Photoacoustic(PA)tomography(PAT)hasattractedextensiveinterestbecauseofitsopticalabsorptioncontrastandultrasonicdetection.ThisstudyaimstodevelopabiocompatibleandbiodegradablePAcontrastagentparticularlypromisingforclinicalapplicationsinhumanbody.Methods:Inthisstudy,wepresentedaPAcontrastagent:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)](DSPE-PEG)-coatedsuperparamagneticironoxide(SPIO)nanoparticles(NPs)loadedwithindocyaninegreen(ICG).WeusedICGandSPIONPsbecausebothdrugsareapprovedbytheU.S.FoodandDrugAdministration.Giventhestrongabsorptionofnear-infraredlaserpulses,SPIO@DSPE-PEG/ICGNPswithauniformdiameterof~28nmcouldsignificantlyenhancePAsignals.Results:WedemonstratedthecontrastenhancementoftheseNPsinphantomandanimalexperiments,inwhichtheinvivocirculationtimeofSPIO@DSPE-PEG/ICGNPswasconsiderablylongerthanthatoffreeICG.ThesenovelNPsalsodisplayedahighefficiencyoftumortargeting.Conclusions:SPIO@DSPE-PEG/ICGNPsarepromisingPATcontrastagentsforclinicalapplications.