Normal kidney tissue derived extracellular vesicles suppress clear cell renal cell carcinoma progression via transfer their inhibitory miRNAs

• N-EVs treatment inhibited the proliferation and invasion of clear cell renal cell carcinoma in vitro. • N-EVs with intravenous administration were mainly retained within the tumors and suppressed ccRCC progression in cancer bearing murine models. • N-EVs treatment regulated tumor environment, inhibited cancer cell proliferation and suppressed tumor angiogenesis through transferring their inhibitory miRNAs. Tumor-derived extracellular vesicles (EVs) contribute to tumor progression and metastasis. We recently reported that EVs derived from normal kidney tissues (N-EVs) suppress sterile cardiac inflammation in myocardial ischemic injury models. However, whether N-EVs affect the progression of renal cancer remains elusive. In the present study, we demonstrated that N-EVs inhibit the proliferation and invasion of clear cell renal cell carcinoma (ccRCC) in vitro. When administered intravenously, N-EVs were mainly retained within the tumors and suppressed ccRCC progression in cancer-bearing murine models. Further miRNA sequencing revealed that the target genes of the top 20 miRNAs in N-EVs were primarily enriched in signaling pathways, including the MAPK and Ras pathways. Moreover, N-EVs treatment modulated the tumor microenvironment and inhibited cancer cell proliferation and angiogenesis through the transfer of their inhibitory miRNAs. Therefore, manipulating normal tissue-derived EVs (including those from cultured kidney organoids) or their miRNA cargo may represent a promising potential strategy for treating ccRCC in clinical settings.