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Herein, inspired by intestinal Akkermansia muciniphila, the use of Akkermansia muciniphila membrane vesicles (AMVs) is introduced as an effective tool for oral delivery of siRNA. It is revealed that, distinct from common passive mucus\u2010penetrating nanoparticles, AMVs enable active mucus penetration by degrading intestinal mucins, thereby enhancing their ability to traverse the intestinal barrier by approximately 4.6 times. Additionally, AMVs can markedly heighten siRNA penetration into tumor tissues. Once inside tumor cells, AMVs bypass the traditional endosomal\u2010lysosomal degradation pathway typical of lipid\u2010based delivery systems. Instead, they utilize a rapid transport expressway from the Golgi apparatus to the endoplasmic reticulum (ER), facilitating the accumulation of siRNA within the ER and thereby markedly enhancing gene silencing efficiency. In a mouse model of colorectal cancer, this formulation effectively inhibits tumor growth by 91.6%, and it exhibits a favorable biosafety profile. Overall, this research unveils a unique and promising bioinspired platform for oral siRNA delivery, advancing the development of safe and efficient oral nucleic acid therapeutics.<\/jats:p>","DOI":"10.1002\/adma.202515901","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T14:02:57Z","timestamp":1763474577000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Akkermansia Muciniphila\u2010Inspired Oral siRNA Delivery by Active Matrix\u2010Penetration and Intracellular Endoplasmic Reticulum Accumulation"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3929-4387","authenticated-orcid":false,"given":"Chao","family":"Pan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Drug Research &amp; Center of Pharmaceutics Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 P. R. 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