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Cellulose nanocrystals (CNCs) have great potential in many areas of research, applications, and future commercialization prospects. Recently, CNCs have emerged as attractive candidates for biomedical applications such as drug and gene delivery systems. As such, cytotoxicity studies have been the major focus in the past decade. However, despite the rod-like nature of CNCs, the potential immune response of surface-modified CNCs is not well investigated. The current study examined the potential immune and antioxidant response induced by CNCs grafted with β -cyclodextrin (CNCs- β -CD) in a human monocyte cell line (THP-1) and a mouse macrophage-like cell line (J774A.1). We analyzed the secretion of the proinflammatory cytokine, interleukin 1 β (IL-1 β ), by ELISA and mitochondria-derived reactive oxygen species (ROS) using fluorescence cell imaging and examined the intracellular levels of proteins involved in the immune and antioxidant response by immunoblotting. Our results indicated a dramatic increase neither in the IL-1 β secretion nor in the mitochondria-derived ROS resulting in no changes in the intracellular antioxidant response in THP-1 cells treated with different concentrations of CNCs- β -CD. Overall, CNCs- β -CD is nonimmunogenic and do not induce an increased antioxidant response under the conditions tested and hence has the potential to be used as a drug delivery carrier.