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Non-small cell lung carcinoma (NSCLC) is a highly lethal type of cancer with limited therapeutic avenues available to date. In the present study, we formulated PEGylated PLGA thymoquinone nanoparticles (TQ-Np) for improved TQ delivery to NSCLC cells. Transferrin (TF), a biodegradable, non-immunogenic and non-toxic protein, is well known to bind to TFR (transferrin receptor) over-expressed in non-small cell lung carcinoma A549 cells. Thus, the further decoration of the PEGylated PLGA thymoquinone nanoparticles with transferrin (TF-TQ-Np) enhanced the internalization of the nanoparticles within the A549 cells and the activity of TQ. We established TF-TQ-Np as a potent anti-tumorigenic agent through the involvement of p53 and the ROS feedback loop in regulating the microRNA (miRNA) circuitry to control apoptosis and migration of NSCLC cells. TF-TQ-Np-mediated p53 up-regulation favored the potential …