Administration of ROS-Scavenging Cerium Oxide Nanoparticles Simply Mixed with Autoantigenic Peptides Induce Antigen-Specific Immune Tolerance against Autoimmune Encephalomyelitis

The scavenging ability of cerium oxide nanoparticles (CeNPs) for reactive oxygen species has been intensively studied in the field of catalysis. However, the immunological impact of these particles has not yet been thoroughly investigated, despite intensive research indicating that modulation of the reactive oxygen species could potentially regulate cell fate and adaptive immune responses. In this study, we examined the intrinsic capability of CeNPs to induce tolerogenic dendritic cells via their reactive oxygen species-scavenging effect when the autoantigenic peptides were simply mixed with CeNPs. CeNPs effectively reduced the intracellular reactive oxygen species levels in dendritic cells in vitro, leading to the suppression of costimulatory molecules as well as NLRP3 inflammasome activation, even in the presence of pro-inflammatory stimuli. Subcutaneously administrated PEGylated CeNPs were predominantly taken up by antigen-presenting cells in lymph nodes and to suppress cell maturation in vivo. The administration of a mixture of PEGylated CeNPs and myelin oligodendrocyte glycoprotein peptides, a well-identified autoantigen associated with antimyelin autoimmunity, resulted in the generation of antigen-specific Foxp3⁺ regulatory T cells in mouse spleens. The induced peripheral regulatory T cells actively inhibited the infiltration of autoreactive T cells and antigen-presenting cells into the central nervous system, ultimately protecting animals from experimental autoimmune encephalomyelitis when tested using a mouse model mimicking human multiple sclerosis. Overall, our findings reveal the potential of CeNPs for generating antigen-specific immune tolerance to prevent multiple sclerosis, opening an avenue to restore immune tolerance against specific antigens by simply mixing the well-identified autoantigens with the immunosuppressive CeNPs.