Targeted delivery of triptolide by dendritic cell-derived exosomes for colitis and rheumatoid arthritis therapy in murine models.

Abstract

Triptolide (TP) elicits a beneficial effect in the treatment of autoimmune diseases, such as ulcerative colitis (UC) and rheumatoid arthritis (RA). However, its multiorgan toxicity needs to be resolved. Dendritic cells (DCs) are the primary target of TP, which induces immunosuppression, and DC-derived exosomes (DEX) can selectively enter DCs in vivo. Here, we encapsulated TP with DEX (DEXTP) to generate TP-targeted delivery to reduce toxicity. The effect of DEXTP was evaluated in murine colitis and RA models. Toxicity was examined by haematoxylin and eosin staining and serum biochemical marker detection. Affinity of DEXs for DCs was tracked by fluorescent labelling. The immune environment was evaluated and mimicked in vitro for further analysis of the mechanism. DEXTP effectively carried TP to DCs in vivo, and alleviated local inflammation and damage in colitis and RA mice with no obvious toxicity. Additionally, DEXTP reshaped the immune milieu by decreasing CD4+ T-cell levels and increasing regulatory T-cell levels in vivo. Furthermore, consistent T-cell differentiation was observed in vitro, and DC activation was inhibited by alterations in surface factors and secrete cytokines, and by induction of apoptosis or other form of death. Encapsulating TP with DEX is a new method that both reduces the toxicity of TP and induces immunosuppression in UC and RA mice. The underlying immune mechanism involves DEXTP targeting DCs in vivo, to inhibit DC activation and induce DC apoptosis, which further induces T-cell immunosuppression.