Sustained melatonin release was obtained via drug loading into nanoparticles. The cytotoxicity and anti-proliferative effects of melatonin in A549 lung carcinoma cells was significantly improved compared to free drug and cytotoxicity was low in normal cells. Overall results were attributed to effective suppression of the NRF2/Keap-1 pathway. The gene discussed is NFE2L2; the disease is lung carcinoma.