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

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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.

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