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

作者：Xinyu Qiu, Yuexia Yang, Qian Ma, Bingbing Zheng, Zhaoming Chen, Fapu Wu, Bin Zhou, Hu Xiong · 发表于：Journal of the American Chemical Society · 年份：2025 · DOI：10.1021/jacs.5c19387 · 被引用次数：11 · 研究领域：RNA Interference and Gene Delivery、Nanoparticle-Based Drug Delivery、Nanoplatforms for cancer theranostics

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...