Oral Piwi‐Interacting RNA Delivery Mediated by Green Tea‐Derived Exosome‐Like Nanovesicles for the Treatment of Aortic Dissection

Abstract Aortic dissection (AD) is a severe cardiovascular disease necessitating active therapeutic strategies for early intervention and prevention. Nucleic acid drugs, known for their potent molecule‐targeting therapeutic properties, offer potential for genetic suppression of AD. Piwi‐interacting RNAs, a class of small RNAs, hold promise for managing cardiovascular diseases. Limited research on these RNAs and AD exists. This study demonstrates that an antagomir targeting heart‐apoptosis‐associated piRNA (HAAPIR) effectively regulates vascular remodeling, mitigating AD occurrence and progression through the myocyte enhancer factor 2D (Mef2D) and matrix metallopeptidase 9 (MMP9) pathways. Green tea‐derived plant exosome‐like nanovesicles (PELNs) are used for oral administration of antagomir. The antagomir‐HAAPIR‐nanovesicle complex, after purification and optimization, exhibits a high packing rate, while the antagomir is resistant to enzyme digestion. Administered to mice, the complex targets the aortic lesion, reducing AD incidence and improving survival. Moreover, MMP9 and Mef2D expression decrease significantly, inhibiting the phenotypic conversion of human aortic smooth muscle cells. PELNs encapsulate the antagomir‐HAAPIR complex, maintaining stability, mediating transport into the bloodstream, and delivering Piwi‐interacting RNAs to AD sites. Thus, HAAPIR is a potential target for persistent clinical AD prevention and treatment, and nanovesicle‐encapsulated nucleic acids offer a promising cardiovascular disease treatment, providing insights for other therapeutic targets.