Akkermansia Muciniphila‐Inspired Oral siRNA Delivery by Active Matrix‐Penetration and Intracellular Endoplasmic Reticulum Accumulation

Abstract Oral delivery of small interfering ribonucleic acid (siRNA) is highly challenging due to the multiple barriers present in the gastrointestinal tract and within cells. 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‐penetrating 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‐lysosomal degradation pathway typical of lipid‐based 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.