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

Nov 20, 2025Journal of the American Chemical Society

Biodegradable Lipid Nanoparticles with Thioketal Deliver mRNA to Pancreatic Duct Cells for Better Cancer Treatment

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

4A2-B8-PH LNPs achieved 98.3% targeting specificity for mRNA delivery to the pancreas.

A new class of biodegradable ionizable lipids was developed for mRNA delivery to pancreatic ductal epithelial cells.
4A2-B8-PH was identified as the optimal lipid, showing superior ability for escaping cellular compartments and releasing mRNA.
Unlike other lipid nanoparticles, 4A2-B8-PH LNPs specifically targeted the pancreas without widespread expression in other organs.
These LNPs demonstrated a mRNA delivery efficiency to pancreatic tissue that was 100 times greater than previous benchmarks.
In a mouse model of pancreatic cancer, LNPs carrying interleukin-12 mRNA led to complete tumor eradication without systemic toxicity.

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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.