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However, its success is hindered significantly by instant blood\u2010mediated inflammatory reaction (IBMIR), which leads to rapid graft loss. IBMIR is triggered when the transplanted islets come in contact with blood, activating the coagulation cascade, complement pathways, and innate immune responses. Tissue factor (TF), abundantly expressed on the islet surface, initiates the coagulation cascade, leading to thrombin formation, platelet activation, and neutrophil infiltration. Plasminogen activator inhibitor\u20101 (PAI\u20101) plays a critical role in IBMIR by inhibiting fibrinolysis and causing ischemic injury in the graft.\n                    <jats:italic>TF<\/jats:italic>\n                    and\n                    <jats:italic>PAI\u20101<\/jats:italic>\n                    contribute significantly to IBMIR, thus making them critical targets for genetic interventions to prevent IBMIR. In this study, an engineered virus\u2010like particle (eVLP)\u2013mediated Cas9 nuclease is employed to knock out\n                    <jats:italic>TF<\/jats:italic>\n                    and\n                    <jats:italic>PAI\u20101<\/jats:italic>\n                    genes in rat islets.\n                    <jats:italic>TF<\/jats:italic>\n                    and\n                    <jats:italic>PAI\u20101<\/jats:italic>\n                    expression are effectively downregulated without inducing any off\u2010target effects or without compromising the viability and functionality of the islets. Streptozotocin\u2010induced diabetic mice transplanted with\n                    <jats:italic>TF<\/jats:italic>\n                    \u2010 and\n                    <jats:italic>PAI\u20101<\/jats:italic>\n                    \u2010knockout islets exhibited improved glycemic control and a significant reduction in the plasma levels of thrombin\u2010antithrombin (TAT) complex and complement component 3a (C3a), indicating the successful inhibition of IBMIR post\u2010transplantation.\n                  <\/jats:p>","DOI":"10.1002\/smll.202508128","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T10:09:29Z","timestamp":1763460569000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["eVLP\u2010Mediated Cas9 Delivery for Preventing IBMIR in Islet Transplantation"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0757-5299","authenticated-orcid":false,"given":"Manju","family":"Shrestha","sequence":"first","affiliation":[{"name":"Department of Precision Medicine Sungkyunkwan University School of Medicine  Suwon 16419 Republic of Korea"},{"name":"Research Institute for Convergence Science Graduate School of Convergence Science and Technology Seoul National University  Seoul 08826 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeonji","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Metabiohealth Institute for Cross\u2010disciplinary Studies Sungkyunkwan University  Suwon 16419 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subin","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine Sungkyunkwan University School of Medicine  Suwon 16419 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu\u2010Lin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine Sungkyunkwan University School of Medicine  Suwon 16419 Republic of Korea"},{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing 210009 China"},{"name":"Jiangsu Key Laboratory of Druggability of Biopharmaceuticals China Pharmaceutical University  Nanjing 210009 China"},{"name":"Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases China Pharmaceutical University  Nanjing 210009 China"},{"name":"NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients China Pharmaceutical University  Nanjing 210009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae\u2010Young","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National University  Seoul 08826 Republic of Korea"},{"name":"Natural Products Research Institute Seoul National University  Seoul 08826 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daesik","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine Sungkyunkwan University School of Medicine  Suwon 16419 Republic of Korea"},{"name":"Department of Metabiohealth Institute for Cross\u2010disciplinary Studies Sungkyunkwan University  Suwon 16419 Republic of Korea"},{"name":"Biomedical Institute for Convergence at SKKU (BICS) Sungkyunkwan University  Suwon 16419 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7120-169X","authenticated-orcid":false,"given":"Jee\u2010Heon","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine Sungkyunkwan University School of Medicine  Suwon 16419 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31320-5"},{"key":"e_1_2_9_2_1","author":"Magliano D. 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