2. Academic Validation
  3. Structure-Activity Mapping of Intraperitoneal mRNA-LNPs: Decoupling Tumor and Liver Biodistribution in Pancreatic Cancer

Structure-Activity Mapping of Intraperitoneal mRNA-LNPs: Decoupling Tumor and Liver Biodistribution in Pancreatic Cancer

  • bioRxiv. 2026 Mar 21:2026.03.20.712457. doi: 10.64898/2026.03.20.712457.
Farhana Islam 1 2,  Ashish Das 3,  Md Ashaduzzaman 4,  Ling Ding 1 5,  Neha Kumari 1 6,  Ran Dai 7,  David Oupický 1 6 8
Affiliations

Affiliations

  • 1 Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE, USA.
  • 2 Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE, USA.
  • 3 Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, Omaha, NE, USA.
  • 4 College of Information Science & Technology, University of Nebraska Omaha, Omaha, NE, USA.
  • 5 Clinical Pharmacology Laboratory, Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, NE, USA.
  • 6 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • 7 Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, USA.
  • 8 Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
PMID: 41889911 DOI: 10.64898/2026.03.20.712457
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.

Keywords

IP delivery; LNPs; formulation composition; mRNA therapeutics; pancreatic cancer.

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