Gordillo, Gayle M.Guda, Poornachander ReddySingh, KanhaiyaBiswas, AyanAbouhashem, Ahmed S.Rustagi, YashikaSen, AbhishekKumar, ManishekharDas, AmitavaGhatak, SubhadipKhanna, SavitaSen, Chandan K.Roy, Sashwati2024-08-012024-08-012023Gordillo GM, Guda PR, Singh K, et al. Tissue nanotransfection causes tumor regression by its effect on nanovesicle cargo that alters microenvironmental macrophage state. Mol Ther. 2023;31(5):1402-1417. doi:10.1016/j.ymthe.2022.11.003https://hdl.handle.net/1805/42536Extracellular vesicles (EVs) are nanovesicles released by all eukaryotic cells. This work reports the first nanoscale fluorescent visualization of tumor-originating vesicles bearing an angiogenic microRNA (miR)-126 cargo. In a validated experimental model of lethal murine vascular neoplasm, tumor-originating EV delivered its miR-126 cargo to tumor-associated macrophages (TAMs). Such delivery resulted in an angiogenic (LYVE+) change of state in TAM that supported tumor formation. Study of the trafficking of tumor-originating fluorescently tagged EV revealed colocalization with TAM demonstrating uptake by these cells. Ex vivo treatment of macrophages with tumor-derived EVs led to gain of tumorigenicity in these isolated cells. Single-cell RNA sequencing of macrophages revealed that EV-borne miR-126 characterized the angiogenic change of state. Unique gene expression signatures of specific macrophage clusters responsive to miR-126-enriched tumor-derived EVs were revealed. Topical tissue nanotransfection (TNT) delivery of an oligonucleotide comprising an anti-miR against miR-126 resulted in significant knockdown of miR-126 in the tumor tissue. miR-126 knockdown resulted in complete involution of the tumor and improved survival rate of tumor-affected mice. This work identifies a novel tumorigenic mechanism that relies on tumorigenic state change of TAM caused by tumor-originating EV-borne angiomiR. This disease process can be effectively targeted by topical TNT of superficial tumors.en-USPublisher PolicyExtracellular vesiclesMacrophageSingle-cell RNA sequencingangiomiRsmiR-126TumorHemangiomaArticle