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journal article·2026-01Open access

eVLP‐Mediated Cas9 Delivery for Preventing IBMIR in Islet Transplantation

Manju Shrestha, Yeonji Kim, Subin Park, Hu‐Lin Jiang, Jae‐Young Lee, Daesik Kim, Jee‐Heon Jeong

Small· Volume 22· Issue 1
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Source abstract

Abstract

Abstract Islet transplantation is a promising strategy for effective β‐cell replacement in patients with type 1 diabetes. However, its success is hindered significantly by instant blood‐mediated 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‐1 (PAI‐1) plays a critical role in IBMIR by inhibiting fibrinolysis and causing ischemic injury in the graft. TF and PAI‐1 contribute significantly to IBMIR, thus making them critical targets for genetic interventions to prevent IBMIR. In this study, an engineered virus‐like particle (eVLP)–mediated Cas9 nuclease is employed to knock out TF and PAI‐1 genes in rat islets. TF and PAI‐1 expression are effectively downregulated without inducing any off‐target effects or without compromising the viability and functionality of the islets. Streptozotocin‐induced diabetic mice transplanted with TF ‐ and PAI‐1 ‐knockout islets exhibited improved glycemic control and a significant reduction in the plasma levels of thrombin‐antithrombin (TAT) complex and complement component 3a (C3a), indicating the successful inhibition of IBMIR post‐transplantation.
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Research context

OpenAlex topics: Pancreatic function and diabetes · Complement system in diseases · Platelet Disorders and Treatments

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Precision Medicine Sungkyunkwan University School of Medicine Suwon 16419 Republic of Korea

Research Institute for Convergence Science Graduate School of Convergence Science and Technology Seoul National University Seoul 08826 Republic of Korea

Department of Metabiohealth Institute for Cross‐disciplinary Studies Sungkyunkwan University Suwon 16419 Republic of Korea

State Key Laboratory of Natural Medicines China Pharmaceutical University Nanjing 210009 China

Jiangsu Key Laboratory of Druggability of Biopharmaceuticals China Pharmaceutical University Nanjing 210009 China

Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases China Pharmaceutical University Nanjing 210009 China

NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients China Pharmaceutical University Nanjing 210009 China

College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National University Seoul 08826 Republic of Korea

Natural Products Research Institute Seoul National University Seoul 08826 Republic of Korea

Biomedical Institute for Convergence at SKKU (BICS) Sungkyunkwan University Suwon 16419 Republic of Korea

Funding

National Research Foundation of Korea · Ministry of Health and Welfare · Ministry of Science and ICT, South Korea

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