2. Academic Validation
  3. Safety and efficacy of KRAS antisense oligonucleotides and RIG-I agonists delivered by extracellular vesicles for pancreatic cancer peritoneal metastasis treatment

Safety and efficacy of KRAS antisense oligonucleotides and RIG-I agonists delivered by extracellular vesicles for pancreatic cancer peritoneal metastasis treatment

  • J Control Release. 2025 Nov 10:387:114239. doi: 10.1016/j.jconrel.2025.114239.
Tram T T Nguyen 1,  Xuan T T Dang 1,  Cao Dai Phung 1,  Lan Thi Ngoc Tran 1,  Nguyen Trong Phuoc Do 1,  Eric Y M Yeo 1,  Nhut Minh Tran 1,  Brendon Zhi Jie Yeo 1,  Celest P Lixuan 2,  Nhung T H Nguyen 3,  Hung Xuan Nguyen 4,  Huong Thu Ngo 5,  Glenn K Bonney 6,  Dahai Luo 2,  Minh T N Le 7
Affiliations

Affiliations

  • 1 Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 2 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Structural Biology, Nanyang Technological University, Singapore.
  • 3 Vinmec-VinUni Institute of Immunology, Vin University, Viet Nam.
  • 4 Vinmec-VinUni Institute of Immunology, Vin University, Viet Nam; Vinmec Hitech Center, Vinmec Healthcare System, Viet Nam.
  • 5 Center for Research and Production of Vaccines and Biologicals, Viet Nam.
  • 6 Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Institute for Health Innovation and Technology, National University of Singapore, Singapore.
  • 7 Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore. Electronic address: [email protected].
PMID: 40967408 DOI: 10.1016/j.jconrel.2025.114239
Abstract

Pancreatic ductal adenocarcinoma (PDAC) often metastasizes to the peritoneum and is highly resistant to treatments due to its immunosuppressive microenvironment. In this study, we evaluate the safety and efficacy of a novel therapeutic strategy that combines KRAS-targeting Antisense Oligonucleotides (ASOs) with immunomodulatory RNA (immRNA), a RIG-I agonist, both delivered by extracellular vesicles (EVs), in preclinical models using PDAC patient-derived organoids and mice bearing PDAC peritoneal metastasis. Our data demonstrate that the combination of KRAS ASO and immRNA synergistically activates anti-tumor immune responses. EV-mediated co-delivery of both agents significantly inhibits tumor growth, reduces peritoneal metastasis, and markedly prolongs overall survival through the induction of immunologic Cancer cell death. Importantly, this combination therapy is well-tolerated in non-human primates, with no observable changes in physical condition or behavior, blood parameters, or organ histology. These findings suggest that EV-delivered KRAS ASO and immRNA is a safe and potent therapeutic approach for treating PDAC and its peritoneal metastasis, positioning it as a promising strategy for future clinical advancement.

Keywords

Extracellular vesicles; KRAS mutation; Non-human primate toxicity; Pancreatic ductal adenocarcinoma; Peritoneal metastasis; RIG-I agonist.

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