{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:13:12Z","timestamp":1768511592134,"version":"3.49.0"},"posted":{"date-parts":[[2024,4,29]]},"group-title":"Synthetic Biology","reference-count":24,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,4,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  All approved RNA therapeutics require parenteral delivery. Here we demonstrate an orally bioavailable formulation wherein synthetic noncoding (nc) RNA, packaged into lipid nanoparticles, is loaded into casein-chitosan (C2) micelles. We used the C2 formulation to deliver TY1, a 24-nucleotide synthetic ncRNA which targets the DNA damage response pathway in macrophages. C2-formulated TY1 (TY1\n                  <jats:sup>C2<\/jats:sup>\n                  ) efficiently packages and protects TY1 against degradative enzymes. In healthy mice, oral TY1\n                  <jats:sup>C2<\/jats:sup>\n                  was well-tolerated and nontoxic. Oral TY1\n                  <jats:sup>C2<\/jats:sup>\n                  exhibited disease-modifying bioactivity in 2 models of tissue injury: 1) rat myocardial infarction, where a single oral dose of TY1\n                  <jats:sup>C2<\/jats:sup>\n                  was cardioprotective, on par with intravenously-delivered TY1; and 2) mouse acute lung injury, where a single dose of TY1\n                  <jats:sup>C2<\/jats:sup>\n                  attenuated pulmonary inflammation. Mechanistic dissection revealed that TY1\n                  <jats:sup>C2<\/jats:sup>\n                  is not absorbed into the systemic circulation but is, instead, taken up by intestinal macrophages, namely those of the lamina propria and Peyer\u2019s patches. This route of absorption may rationalize why an antisense oligonucleotide against Factor VII, which acts on hepatocytes, is not effective when administered in the C2 formulation. Thus, some (but not all) ncRNA drugs are bioavailable when delivered by mouth. Oral RNA delivery and uptake, relying on uptake via the gastrointestinal immune system, has broad-ranging therapeutic implications.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:p>\n                    Oral TY1\n                    <jats:sup>C2<\/jats:sup>\n                    is taken up in the small intestine mainly by macrophages of the lamina propria and the Peyer\u2019s patches. Macrophages that have taken up oral TY1\n                    <jats:sup>C2<\/jats:sup>\n                    mediate disease-modifying bioactivity in 2 animal models of acute tissue injury. The blue + denotes the as-yet-uncertain mechanisms\/mediators linking TY1 gut uptake to the drug\u2019s systemic therapeutic benefits.\n                  <\/jats:p>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"591474v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2024.04.27.591474","type":"posted-content","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T17:20:16Z","timestamp":1714411216000},"source":"Crossref","is-referenced-by-count":2,"title":["Oral bioavailability of a noncoding RNA drug, TY1, that acts on macrophages"],"prefix":"10.64898","author":[{"given":"Shukuro","family":"Yamaguchi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazutaka","family":"Miyamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xaviar M.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Ciullo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley","family":"Morris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kara","family":"Tsi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo","family":"Marb\u00e1n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed G.E.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024050300250985000_2024.04.27.591474v1.1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-017-0450-0"},{"key":"2024050300250985000_2024.04.27.591474v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01007-w"},{"key":"2024050300250985000_2024.04.27.591474v1.3","doi-asserted-by":"publisher","DOI":"10.2147\/Ppa.S87271"},{"key":"2024050300250985000_2024.04.27.591474v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2012.06.037"},{"key":"2024050300250985000_2024.04.27.591474v1.5","doi-asserted-by":"publisher","DOI":"10.1101\/2024.02.20.581294"},{"key":"2024050300250985000_2024.04.27.591474v1.6","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12045"},{"key":"2024050300250985000_2024.04.27.591474v1.7","doi-asserted-by":"publisher","DOI":"10.3168\/jds.S0022-0302(01)74485-2"},{"key":"2024050300250985000_2024.04.27.591474v1.8","doi-asserted-by":"publisher","DOI":"10.1021\/jf049202v"},{"key":"2024050300250985000_2024.04.27.591474v1.9","doi-asserted-by":"publisher","DOI":"10.1208\/s12249-019-1342-y"},{"key":"2024050300250985000_2024.04.27.591474v1.10","doi-asserted-by":"publisher","DOI":"10.2147\/Ijn.S17296"},{"key":"2024050300250985000_2024.04.27.591474v1.11","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.76.suppl_1.P245"},{"key":"2024050300250985000_2024.04.27.591474v1.12","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12178"},{"key":"2024050300250985000_2024.04.27.591474v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2011.07.003"},{"key":"2024050300250985000_2024.04.27.591474v1.14","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2021.628137"},{"key":"2024050300250985000_2024.04.27.591474v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2019.03.027"},{"key":"2024050300250985000_2024.04.27.591474v1.16","doi-asserted-by":"publisher","DOI":"10.1124\/pr.120.019554"},{"key":"2024050300250985000_2024.04.27.591474v1.17","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-023-00844-z"},{"key":"2024050300250985000_2024.04.27.591474v1.18","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/143524"},{"key":"2024050300250985000_2024.04.27.591474v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/nature07774"},{"key":"2024050300250985000_2024.04.27.591474v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2018.08.054"},{"key":"2024050300250985000_2024.04.27.591474v1.21","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines10111906"},{"key":"2024050300250985000_2024.04.27.591474v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2013.2"},{"key":"2024050300250985000_2024.04.27.591474v1.23","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15092361"},{"key":"2024050300250985000_2024.04.27.591474v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2011.02.010"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.04.27.591474","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:21:59Z","timestamp":1768458119000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.04.27.591474"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,29]]},"references-count":24,"URL":"https:\/\/doi.org\/10.1101\/2024.04.27.591474","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1002\/jex2.70081","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,4,29]]},"subtype":"preprint"}}