Abstract
1α25-dihydroxyvitamin D3, the active metabolite of vitamin D3 (VD3), is a modulator of inflammation well-known for its ability to promote anti-inflammatory and tolerogenic immune responses. It is therefore an attractive agent for the attenuation of inflammatory responses and the development of tolerogenic immunity in autoimmune diseases. To overcome VD3 toxicity and enhance its in vivo performance, nanoparticles (NPs) have emerged as a promising delivery platform. Therefore, in this study, we have developed VD3-loaded polymeric nanoparticles (VD3-NPs) as a therapeutical strategy for the treatment of autoimmune disorders. We demonstrate that VD3-NPs could successfully be generated and that they significantly inhibit secretion of IL-6, IL-10, IL-23, and TNFα in human whole blood cultures. We observed that poly(lactic-co-glycolic acid) (PLGA) NPs are efficiently taken up by neutrophils, monocytes and B cells, prompting further investigation into the effect of VD3-NPs on these subsets. Investigation into each of the immune cell subsets demonstrated that the VD3-NPs were able inhibit cytokine secretion by both monocytes and neutrophils. Moreover, VD3-NPs induced a tolerogenic phenotype in monocytes. In B cells, we observed that VD3-NPs impaired in vitro plasma B cell differentiation and suppressed antibody production. Together, our results validate for the first time in primary human cells the therapeutic potential of VD3 encapsulated in PLGA NPs, posing an attractive strategy for the treatment of autoimmune diseases.