{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T09:50:33Z","timestamp":1791539433420,"version":"4.3.4"},"reference-count":21,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K18684"],"award-info":[{"award-number":["25K18684"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005865","name":"Mochida Memorial Foundation for Medical and Pharmaceutical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Owing to the intrinsic instability of mRNA, its routes of administration are limited, and to date, only injectable delivery has been clinically applied. In contrast, oral administration exposes mRNA to a variety of substances in the gastrointestinal (GI) tract. Despite these challenges, oral delivery remains the most familiar and convenient route for patients, making the development of orally administrable mRNA\u2010encapsulated lipid nanoparticles (mRNA\u2013LNPs) highly desirable. However, no studies have directly examined how mRNA\u2013LNPs are affected within the GI environment. In the present study, we investigated the effects of representative GI components on mRNA\u2013LNPs. Among several digestive enzymes, pepsin markedly reduced the protein\u2010expression efficiency of the particles, whereas amylase had no effect. Pepsin\u2010treated particles exhibited increased size, suggesting that structural alterations contributed to the observed functional loss. Lipase at high concentrations impaired nanoparticle function. Because lipase hydrolyzes ester bonds in lipids, we examined LNPs incorporating C12\u2010200, an ionizable lipid lacking ester bonds, instead of SM\u2010102. The C12\u2010200 formulation showed reduced susceptibility to lipase\u2010induced functional loss, indicating that enzymatic lipid degradation underlay the observed effects. Simulated gastric fluid also significantly diminished particle functionality. A detailed analysis of the relationship between functionality and pH revealed that impairment primarily occurred at approximately pH 1 but not at pH \u2265\u20093. Collectively, these findings identify the key GI factors that compromise mRNA\u2013LNP integrity and provide important insights into the rational design of orally administrable mRNA\u2013LNP formulations.<\/jats:p>","DOI":"10.1002\/ddr.70392","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T09:56:52Z","timestamp":1790157412000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive Evaluation of Gastrointestinal Factors Influencing the Stability and Function of mRNA\u2010Encapsulated Lipid Nanoparticles"],"prefix":"10.1002","volume":"87","author":[{"given":"Toma","family":"Shinkai","sequence":"first","affiliation":[{"name":"Drug Delivery and Nano Pharmaceutics Graduate School of Pharmaceutical Sciences, Nagoya City University Nagoya Aichi 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