{"doi":"10.1002/jex2.70081","title":"Oral Bioavailability of a Noncoding RNA Drug, TY1, That Acts on Macrophages","abstract":"ABSTRACT 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 DNA damage and attenuates inflammation in macrophages. C2‐formulated TY1 (TY1 C2 ) efficiently packages and protects TY1 against degradative enzymes. In healthy mice, oral TY1 C2 was well‐tolerated and nontoxic. Oral TY1 C2 exhibited disease‐modifying bioactivity in two models of tissue injury: (1) rat myocardial infarction, where a single oral dose of TY1 C2 was cardioprotective, on par with intravenously‐delivered TY1; and (2) mouse acute lung injury, where a single dose of TY1 C2 attenuated pulmonary inflammation. Mechanistic dissection revealed that TY1 C2 is taken up by intestinal macrophages, namely those of the lamina propria and Peyer's patches. Afterwards, TY1 could be detected in circulating monocytes for up to 72 h post‐ingestion. Unlike TY1, which acts on macrophages, an antisense oligonucleotide against Factor VII, which acts on hepatocytes, is not effective when administered in the C2 formulation. Thus, not all ncRNA drugs are bioactive when delivered by mouth. Oral delivery of macrophage‐active RNA opens up a wide range of potential new therapeutic opportunities.","journal":"Journal of Extracellular Biology","year":2025,"id":534487,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9474,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":708680,"name":"Kazutaka Miyamoto","orcid":"0009-0005-8220-1205","position":1,"is_corresponding":false},{"id":953964,"name":"Xaviar M Jones","orcid":"0000-0003-1815-4166","position":2,"is_corresponding":false},{"id":465877,"name":"Alessandra Ciullo","orcid":"0000-0002-8681-3883","position":3,"is_corresponding":false},{"id":1263042,"name":"Kara Tsi","orcid":"0009-0003-8593-7037","position":4,"is_corresponding":false},{"id":1417088,"name":"Jessica Anderson","orcid":"0009-0006-2016-7109","position":5,"is_corresponding":false},{"id":1417089,"name":"Hiroaki Komuro","orcid":"0000-0002-8249-6761","position":6,"is_corresponding":false},{"id":1263542,"name":"Salwa Soussi","orcid":null,"position":7,"is_corresponding":false},{"id":761148,"name":"Ashley Morris","orcid":"0009-0006-8094-3560","position":8,"is_corresponding":false},{"id":1072625,"name":"Diána Kitka","orcid":"0000-0002-8319-5960","position":9,"is_corresponding":false},{"id":1417640,"name":"De-Zhao Liu","orcid":null,"position":10,"is_corresponding":false},{"id":638092,"name":"Nguyễn Thị Vân Anh","orcid":"0000-0003-1215-6910","position":11,"is_corresponding":false},{"id":108831,"name":"Eduardo Marbán","orcid":"0000-0002-3863-280X","position":12,"is_corresponding":false},{"id":644329,"name":"Ahmed Ibrahim","orcid":"0000-0002-1657-7432","position":13,"is_corresponding":false},{"id":1296146,"name":"Shukuro Yamaguchi","orcid":"0000-0002-5320-6366","position":0,"is_corresponding":true}],"reference_count":20,"raw_metadata":null,"created_at":"2026-07-19T02:51:47.434742Z","pmid":"40823342","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}