Structure-Activity Mapping of Intraperitoneal mRNA-LNPs: Decoupling Tumor and Liver Biodistribution in Pancreatic Cancer
Year: 2026
Type: preprint
Abstract: Pancreatic ductal adenocarcinoma (PDAC) remains difficult to treat with nucleic acid therapeutics because efficient intratumoral delivery is limited and off-target liver accumulation is common. Here, we developed a structure-activity map for intraperitoneally administered mRNA lipid nanoparticles (mRNA-LNPs) to identify formulation features that improve delivery to pancreatic tumors while reducing liver expression. A full-factorial library of 48 mRNA-LNP formulations was generated by varying ionizable lipid, sterol, phospholipid, and PEG-lipid components. Formulations were characterized for size, polydispersity, zeta potential, and encapsulation, then evaluated in an orthotopic KPC8060 pancreatic tumor model after intraperitoneal administration of firefly luciferase mRNA-loaded LNPs. Biodistribution was assessed by Rhodamine B fluorescence and functional delivery by luciferase expression 12 h after dosing. Lipid composition strongly influenced both physicochemical properties and in vivo performance. G0-C14-based formulations produced the smallest and most homogeneous particles, whereas FTT5-containing formulations were generally larger. Across the 48-formulation library, mRNA expression and nanoparticle biodistribution varied significantly among tumor, pancreas, liver, and spleen. Statistical, decision-tree, and predictive modeling analyses identified composition rules associated with organ-selective delivery. High tumor expression was associated primarily with G0-C14 combined with DSPC and β-sitosterol, whereas liver expression was favored by C12-200 or DLin-MC3-DMA with DOPE and DSPE-PEG. Notably, a G0-C14/DSPC/DSPE-PEG formulation emerged as a lead candidate, producing a greater than 6-fold increase in tumor luciferase signal relative to the library median while reducing liver exposure by approximately 60%. Histopathology showed no treatment-related liver or lung toxicity. These findings define actionable formulation rules for tuning intraperitoneal mRNA-LNP delivery in PDAC and support further development of tumor-selective mRNA therapeutics for pancreatic cancer.
Authors: Farhana Islam, Ashish Das, Md Ashaduzzaman, Ling Ding, Neha Kumari, Ran Dai, David Oupický
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1202437685, G174083634, Nebraska Center for Nanomedicine, G207763913, G2304788540, Development of siRNA conjugates for combination treatment of acute kidney injury, G3141045454, G3304149081, Self-immolative prodrug/miRNA nanoparticle combinations for cancer treatment, Chloroquine-based polymer particles as oral non-absorbable treatment of inflammatory bowel disease, G7051293283
OpenAlex ID: W7140026162