Radiotherapy has been a central part in curing non-small cell lung cancer (NSCLC). However, it is possible that not all of the tumor cells are destroyed by radiation; therefore, it is important to effectively control residual tumor cells that could become aggressive and resistant to radiotherapy. In this study, we aimed to investigate the molecular mechanism of decreased NSCLC radioresistance by low-dose radiation (LDR) pretreatment. The results indicated that miR-30a and miR-30b, which effectively inhibited plasminogen activator inhibitor-1 (PAI-1), were overexpressed by treatment of LDR to NSCLC cells. Phosphorylation of Akt and ERK, the downstream survival signals of PAI-1, was decreased by PAI-1 inhibition. Reduced cell survival and epithelial-mesenchymal transition by PAI-1 inhibition were confirmed in NSCLC cells. Moreover, in vivo orthotopic xenograft mouse models with 7C1 nanoparticles to deliver miRNAs showed that tumor growth and aggressiveness were efficiently decreased by LDR treatment followed by radiotherapy. Taken together, the present study suggested that PAI-1, whose expression is regulated by LDR, was critical for controlling surviving tumor cells after radiotherapy.Recent reports have suggested that increased expression of plasminogen activator inhibitor-1 (PAI-1) indicates poor prognosis of many cancer types, including NSCLC. 12,13 PAI-1 is an inhibitor of fibrinolysis. It is a physiological process that degrades fibrin and the extracellular matrix (ECM) proteins by inhibiting the urokinasetype plasminogen activator (uPA), which cleaves plasminogen to form plasmin. PAI-1, which is associated with the remodeling of the surrounding tissues, is a key factor in cancer proliferation, invasion, dissemination, and release of tumor growth factors and