biostudies-literatureDriedonks TMinistry of Science and TechnologyNIDA NIH HHSNIAID NIH HHSNIH Office of the DirectorAcademia SinicaNIMH NIH HHSNational Institute of Allergy and Infectious DiseasesNational Cancer InstituteNational Institute of Mental HealthNCI NIH HHSNational Institute on Drug AbuseNIH HHSMichael J. Fox Foundation for Parkinson&apos;s Researche59https://www.ebi.ac.uk/biostudies/studies/S-EPMC9799283biostudies-literatureUnknown1(10)Extracellular vesicles (EVs) have potential in disease treatment since they can be loaded with therapeutic molecules and engineered for retention by specific tissues. However, questions remain on optimal dosing, administration, and pharmacokinetics. Previous studies have addressed biodistribution and pharmacokinetics in rodents, but little evidence is available for larger animals. Here, we investigated the pharmacokinetics and biodistribution of Expi293F-derived EVs labelled with a highly sensitive nanoluciferase reporter (palmGRET) in a non-human primate model (Macaca nemestrina), comparing intravenous (IV) and intranasal (IN) administration over a 125-fold dose range. We report that EVs administered IV had longer circulation times in plasma than previously reported in mice and were detectable in cerebrospinal fluid (CSF) after 30-60 minutes. EV association with PBMCs, especially B-cells, was observed as early as one minute post-administration. EVs were detected in liver and spleen within one hour of IV administration. However, IN delivery was minimal, suggesting that pretreatment approaches may be needed in large animals. Furthermore, EV circulation times strongly decreased after repeated IV administration, possibly due to immune responses and with clear implications for xenogeneic EV-based therapeutics. We hope that our findings from this baseline study in macaques will help to inform future research and therapeutic development of EVs.Journal of extracellular biologyPharmacokinetics and biodistribution of extracellular vesicles administered intravenously and intranasally to <i>Macaca nemestrina</i>.PMC9799283U42OD013117AS‐CDA‐109‐M04109‐2628‐B‐001‐032UH3 CA241694AI144997CA241694U42 OD013117R33 MH118164DA047807R01 AI144997R21 MH118164T32 OD011089MH11816400900821UG3 CA241694R01 DA047807Gololobova OJiang LHan ZGarcia-Contreras MCastell NHutchinson EKPaniushkina LMachairaki VIzzi JMDriedonks TLiao ZNyberg LHRichardson RSchonvisky KGuerrero-Martin SSmith BCarlson BStover MLai CPWitwer KWShirk ENLima GPate KAMQueen SELiu GfalsePharmacokinetics and biodistribution of extracellular vesicles administered intravenously and intranasally to <i>Macaca nemestrina</i>.Extracellular vesicles (EVs) have potential in disease treatment since they can be loaded with therapeutic molecules and engineered for retention by specific tissues. However, questions remain on optimal dosing, administration, and pharmacokinetics. Previous studies have addressed biodistribution and pharmacokinetics in rodents, but little evidence is available for larger animals. Here, we investigated the pharmacokinetics and biodistribution of Expi293F-derived EVs labelled with a highly sensitive nanoluciferase reporter (palmGRET) in a non-human primate model (Macaca nemestrina), comparing intravenous (IV) and intranasal (IN) administration over a 125-fold dose range. We report that EVs administered IV had longer circulation times in plasma than previously reported in mice and were detectable in cerebrospinal fluid (CSF) after 30-60 minutes. EV association with PBMCs, especially B-cells, was observed as early as one minute post-administration. EVs were detected in liver and spleen within one hour of IV administration. However, IN delivery was minimal, suggesting that pretreatment approaches may be needed in large animals. Furthermore, EV circulation times strongly decreased after repeated IV administration, possibly due to immune responses and with clear implications for xenogeneic EV-based therapeutics. We hope that our findings from this baseline study in macaques will help to inform future research and therapeutic development of EVs.2022-01-01T00:00:00Z2022 Oct2026-03-27T16:16:36.484Z2025-04-06T11:37:44.902ZS-EPMC97992833659153710.1002/jex2.59