Tumor necrosis factor alpha delivers exogenous inflammation-related microRNAs to recipient cells with functional targeting capabilities.

Tumor necrosis factor alpha (TNF-α) is a critical pro-inflammatory cytokine in a wide range of tumors and infectious diseases. This study showed for the first time that TNF-α could specifically bind to certain intracellular or circulating inflammation-related microRNAs both in vitro and in vivo. The binding sites of TNF-α to microRNAs are located at the N-terminal of TNF-α and the 3'-GGUU motif of microRNAs. TNF-α could deliver exogenous unmodified single-stranded microRNAs into recipient cells through the TNF-α receptors (TNFRs) and stabilize them from being degraded by RNase in cells. Exogenous miR-146a or let-7c delivered into HCT116 cells by TNF-α could escape from lysosomes and specifically downregulate their target genes and then affect cell proliferation and migration in vitro, as well as tumorigenesis in vivo. Based on the above findings, the concept of "non-conjugated ligand-mediated RNA delivery (ncLMRD)" was proposed, which may serve as a promising strategy for therapeutic microRNA delivery in the future.