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

Mar 3, 2025Journal of controlled release : official journal of the Controlled Release Society

Pancreas-targeted lipid nanoparticles for less invasive interleukin-12 mRNA treatment of pancreatic cancer

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Abstract

A single intraperitoneal injection of lipid nanoparticles encapsulating interleukin-12 mRNA may induce eradication of orthotopic pancreatic ductal adenocarcinoma in some cases.

Pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and typically unresponsive to immune therapy.
Cytokine-encoded mRNA therapy holds potential for transforming 'cold' tumors into 'hot' ones.
The lipid nanoparticle delivery system developed targets pancreatic tissue and immune cells effectively.
Injection of LNP encapsulating IL-12 mRNA activates myeloid and lymphoid cells in PDAC, altering the tumor microenvironment.

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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 a 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 design and develop 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 (LNP/mIL-12) activates both myeloid and lymphoid cells in PDAC, reprogramming the immunosuppressive TME. Remarkably, I.P. injection of 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.

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

Abstract

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