{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:56:32Z","timestamp":1787032592678,"version":"build-2736575974"},"posted":{"date-parts":[[2026,3,21]]},"group-title":"Bioengineering","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T00:00:00Z","timestamp":1774051200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010537","name":"Nebraska Department of Health and Human Services","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010537","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH","award":["P30 GM127200"],"award-info":[{"award-number":["P30 GM127200"]}]},{"name":"NIH","award":["R01 CA235863"],"award-info":[{"award-number":["R01 CA235863"]}]},{"name":"NIH","award":["R01 DK120533"],"award-info":[{"award-number":["R01 DK120533"]}]},{"name":"NIH","award":["R01 DK124095"],"award-info":[{"award-number":["R01 DK124095"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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.<\/jats:p>\n                <jats:p>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 \u03b2-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.<\/jats:p>","DOI":"10.64898\/2026.03.20.712457","type":"posted-content","created":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T03:45:13Z","timestamp":1774151113000},"source":"Crossref","is-referenced-by-count":1,"title":["Structure-Activity Mapping of Intraperitoneal mRNA-LNPs: Decoupling Tumor and Liver Biodistribution in Pancreatic Cancer"],"prefix":"10.64898","author":[{"given":"Farhana","family":"Islam","sequence":"first","affiliation":[{"name":"Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE, USA"},{"name":"Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, Omaha, NE, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md","family":"Ashaduzzaman","sequence":"additional","affiliation":[{"name":"College of Information Science & Technology, University of Nebraska Omaha, Omaha, NE, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Ding","sequence":"additional","affiliation":[{"name":"Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE, USA"},{"name":"Clinical Pharmacology Laboratory, Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, NE, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Kumari","sequence":"additional","affiliation":[{"name":"Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE, USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4710-861X","authenticated-orcid":false,"given":"David","family":"Oupick\u00fd","sequence":"additional","affiliation":[{"name":"Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE, USA"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026032910422063000_2026.03.20.712457v1.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2116271119"},{"issue":"4","key":"2026032910422063000_2026.03.20.712457v1.2","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/s41565-020-0669-6","article-title":"Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR\u2013Cas gene editing","volume":"15","year":"2020","journal-title":"Nature nanotechnology"},{"key":"2026032910422063000_2026.03.20.712457v1.3","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ade1444"},{"issue":"15","key":"2026032910422063000_2026.03.20.712457v1.4","first-page":"2939","article-title":"Bioinspired alkenyl amino alcohol ionizable lipid materials for highly potent in vivo mRNA delivery. 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