Thioketal-Incorporated Biodegradable Lipid Nanoparticles Deliver mRNA to Ductal Epithelial Cells for Improved Pancreatic Cancer Treatment.

Delivery of mRNA to the ductal epithelial cells remains a formidable challenge but holds substantial potential for pancreatic ductal adenocarcinoma (PDAC) treatment. Herein, for the first time, we report a new class of thioketal-incorporated biodegradable ionizable lipids (TBILs) for potent mRNA delivery to the pancreas and ductal epithelial cells. 4A2-B8-PH, featuring four thioketal-bridged linkers, was identified as the optimal candidate, which possesses superior endosomal escape and mRNA release abilities. Unlike thioketal-free LNPs that mediated widespread mRNA expression across multiple organs following intraperitoneal administration, 4A2-B8-PH LNPs exclusively delivered mRNA to the pancreas with 98.3% targeting specificity. Furthermore, 4A2-B8-PH LNPs demonstrated significantly higher mRNA delivery efficiency to pancreatic tissue, surpassing those previous pancreas-targeted LNP benchmarks by 2 orders of magnitude. Notably, our optimized LNPs achieved robust mRNA expression in pancreatic ductal epithelial cells, transfecting 30.5% of the target cell population. More encouragingly, administration of 4A2-B8-PH LNPs encapsulating interleukin-12 (IL-12) mRNA induced complete tumor eradication in an orthotopic PDAC mouse model while avoiding systemic off-target toxicity. Collectively, this work paves the way for advancing the development of pancreas-targeted LNPs, as well as addresses the challenge of efficient mRNA delivery to ductal epithelial cells for treating intractable pancreatic diseases.