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There is no curative treatment for autoimmune or chronic inflammatory diseases such as rheumatoid arthritis, and current treatments can induce off-target side effects due to systemic immune suppression. We have previously shown that dexamethasone-pulsed tolerogenic dendritic cells loaded with the RA-specific antigen human proteoglycan can suppress arthritis development in a proteoglycan-induced arthritis mouse model. To circumvent ex vivo dendritic cell culture, and enhance antigen-specific effects, drug delivery vehicles, such as liposomes, provide an interesting approach. Here, we use anionic 1,2-distearoyl-sn-glycero-3-phosphoglycerol liposomes with enhanced loading of human proteoglycan-dexamethasone conjugates by cationic lysine tetramer addition. Antigen-pulsed tolerogenic dendritic cells induced by liposomal dexamethasone in vitro enhanced antigen-specific regulatory T cells to a similar extent as dexamethasone-induced tolerogenic dendritic cells. In an inflammatory adoptive transfer model, mice injected with antigen-dexamethasone liposomes had significantly higher antigen-specific type 1 regulatory T cells than mice injected with antigen only. The liposomes significantly inhibited the progression of arthritis compared to controls in preventative and therapeutic proteoglycan-induced arthritis mouse models. This coincided with systemic tolerance induction and an increase in IL10 expression in the paws of mice. In conclusion, a single administration of autoantigen and dexamethasone-loaded liposomes seems to be a promising antigen-specific treatment strategy for arthritis in mice. This article is protected by copyright. All rights reserved.