Pancreas-targeted lipid nanoparticles for relatively non-invasive interleukin-12 mRNA therapy in orthotopic pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) represents 90 % of pancreatic cancers and shows limited response to immune therapy owing to the highly immunosuppressive tumor microenvironment (TME). Cytokine-encoded mRNA therapy demonstrates great promise in converting “cold” tumors into “hot” ones, while it is typically administered through intratumoral injection and applicable only to superficial tumors, which limites their application in PDAC. In this study, we introduce a lipid nanoparticle (LNP) delivery system capable of targeting pancreatic tissue via intraperitoneal (I·P.) injection. This system not only efficiently delivers mRNA to pancreatic tissues but also selectively targets immune cells in PDAC. A single I.P. injection of LNP encapsulating interleukin-12 (IL-12) mRNA activates both myeloid and lymphoid cells in PDAC, reprogramming the immunosuppressive TME. Remarkably, I.P. injection of LNP encapsulating IL-12 mRNA (LNP/mIL-12) induces eradication of orthotopic PDAC in some cases. Our work represents the first relatively non-invasive method to deliver IL-12 mRNA for targeted treatment of orthotopic PDAC, offering a novel approach for PDAC immunotherapy.