Oral Celastrol Nanomedicine Targeting Intestinal Antigen-Presenting Cells to Effectively Mitigate Autoimmune Uveitis via Gut-Retina Axis.

Abstract

Activation of retina-specific CD4T cells capable of breaking through the blood-retinal barrier (BRB) was significantly associated with the onset and progression of autoimmune uveitis (AU). Antigen-presenting cells (APCs) orchestrate this process by presenting retinal antigens to naïve CD4T cells and driving their differentiation into autoreactive CD4T cells. Here, we report an intestinal APCs-targeted strategy for treating AU based on orally administered nanoCEL (diameter: 37.06 ± 0.12 nm), a pH-responsive nanomedicine exhibiting a great gastric acid stability and a pH-responsive drug release behavior. After oral administration, nanoCEL effectively penetrates the intestinal mucus barrier and targets APCs in the intestine. Using an experimental autoimmune uveitis rat model, oral administration of nanoCEL (2 mg/kg) exhibits a superior therapeutic efficacy than free CEL treatment by suppressing the antigen-presenting ability of APCs and impairing pathogenic T cell differentiation. Additionally, nanoCEL medication protects the BRB from the damage of pathogenic T cells by the reduction of the infiltration of peripheral immune cells and the activation of retinal glial cells. Compared to free CEL, oral administration of nanoCEL remarkably enhances drug bioavailability and improves biosafety without apparent systemic toxicity. Thus, the proposed APC-targeted nanodrug delivery system might be a promising strategy to treat AU.