The immense applications of titanium dioxide nanoparticles (TiO 2 NPs) in consumer products have raised concerns about their health effects especially because TiO 2 NPs can interact with various biomolecules. Out of these, proteins are more prone to alterations owing to their dynamic nature. Different protein conformers co-exist in cellular systems, and studying the interaction of protein conformers with nanoparticles becomes crucial for mechanistic understanding and therapeutic applications of TiO 2 NPs. In the present study, the effect of TiO 2 NPs on native, unfolded, and misfolded luciferase has been investigated. TiO 2 NPs were found to destabilize native luciferase, interfere with the spontaneous refolding of unfolded luciferase, and promote luciferase misfolding; however, minor structural alterations were observed indicating weak interactions between the TiO 2 NPs and luciferase. Morphological analysis of TiO 2 NPs showed an average size of 24.57 ± 4.94 nm that increased to 50.52 ± 16.71 nm upon adsorption of luciferase on to TiO 2 NPs. This study provides an understanding on the implication of nanoparticle-protein interaction on structural and conformational changes in various protein conformers.