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When derived from platelets, a subset of EVs can exhibit remarkable anti\u2010inflammatory and antioxidant properties, making them attractive candidates to attenuate sterile inflammatory states such as limb skeletal muscle ischaemia\u2010reperfusion injury (IRI). Peripheral extremity IRI complicating acute limb revascularisation procedures, replantation of major traumatic amputations and limb allotransplants can trigger a life\u2010threatening reperfusion syndrome that leads to multi\u2010organ system failure and death. In this study, we used a platelet\u2010derived EVs\u2010enriched preparation as a therapeutic strategy for extremity IRI. To allow for a clinically translatable drug delivery strategy, we established and validated a catheter\u2010directed regional intra\u2010arterial limb infusion (RLI) delivery approach that permitted selective and effective targeting of pEVs to limb skeletal muscles and soft tissues in the vascularly isolated rodent extremity simulating pre\u2010reperfusion preservation and revascularisation conditions of the ischaemic or amputated extremity. In addition to being safe and feasible, we demonstrated robust retention of EVs by skeletal muscles of the operative limb during the early critical phase of reperfusion injury following RLI. We also show that pretreatment of ischaemic skeletal muscles using an pEVs\u2010enriched formulation just before reestablishing extremity blood flow alleviated metabolic derangements and suppressed the systemic and localised proinflammatory cytokine response associated with skeletal muscle reperfusion and reduced histologic markers of myofibre injury without adverse effects on serum chemistries. This work opens a new perspective to investigate novel approaches for regional delivery of therapeutic pEVs to skeletal muscle to mitigate limb IRI in vivo, and to achieve both in situ and ex vivo targeted delivery of nanocarriers to the isolated limb tissue for other therapeutic applications.<\/jats:p>","DOI":"10.1002\/jev2.70247","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T12:50:28Z","timestamp":1776430228000},"source":"Crossref","is-referenced-by-count":0,"title":["Transcatheter Intra\u2010Arterial Delivery of a Platelet\u2010Derived Extracellular Vesicle\u2010Enriched Preparation for Attenuating Skeletal Muscle Ischaemia\u2010Reperfusion Injury in a Rodent Forelimb Model"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4178-2227","authenticated-orcid":false,"given":"Omar A.","family":"Selim","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery Mayo Clinic  Rochester Minnesota USA"},{"name":"T32 Musculoskeletal Research Training Program Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aida","family":"Sarcon","sequence":"additional","affiliation":[{"name":"Division of Plastic Surgery Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atta","family":"Behfar","sequence":"additional","affiliation":[{"name":"Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine Mato Clinic  Rochester Minnesota USA"},{"name":"Department of Cardiovascular Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunfeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven L.","family":"Moran","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Mayo Clinic  Rochester Minnesota USA"},{"name":"Division of Plastic Surgery Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjps.2017.11.002"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.avsg.2022.04.040"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijscr.2020.05.087"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.tvir.2011.02.004"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11061213"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1468969"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/GOX.0000000000004123"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0347(200010)22:7<700::AID-HED10>3.0.CO;2-H"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-016-0316-1"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.4c03869"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2018.01.006"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0000000000000507"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/00015458.1998.12098410"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00181"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehad636"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/btm2.10609"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vesic.2024.100041"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/lt.24770"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-19903-0"},{"key":"e_1_2_9_21_1","article-title":"The Value of Lactate Dehydrogenase in Predicting Rhabdomyolysis\u2010Induced Acute Renal Failure; 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