Macrophage targeted triptolide micelles capable of cGAS-STING pathway inhibition for rheumatoid arthritis treatment

Abstract

The abundant M1 macrophages in the joint synovium were the main factors that exacerbate rheumatoid arthritis (RA) by secreting various types of inflammatory cytokines. Here, we note that cGAS-STING, an important pro-inflammatory pathway, was significantly up-regulated in RA, enabling it be the potential target for RA therapy. Therefore, in this work, we developed M1 macrophages targeted micelles capable of cGAS-STING pathway inhibition for the smart treatment of RA. The folic acid (FA) and lauric acid (LA) were modified on dextran to obtain an amphiphilic polymer (FDL). Then, FDL was subsequently applied to encapsulate triptolide (TP) to form FDL@TP nanomicelles. The FDL@TP could target the joint and enhance the cell uptake of TP by M1 macrophages (overexpressing folate receptor-β), which also reduced the side effects of TP on normal tissues. In M1 macrophages, the released TP, acted as an anti-inflammatory and immunosuppressant, obviously down-regulated the expressions of cGAS and STING protein, and thus reduced the secretion of TNF-α, IL-1β and IL-6. Importantly, compared with the same dose of free TP, FDL@TP could significantly enhance the anti-inflammatory effect. Therefore, FDL@TP nanomicelles were believed to be superior candidates for the clinical treatment of RA.

Keywords:

• Triptolide
• rheumatoid arthritis
• cGAS-STING
• targeted delivery
• micelles

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

Additional information

Funding

This work was financially supported by the National Natural Science Foundation of China [No. 81673937] and the Postgraduate Research & Practice Innovation Program of Jiangsu Province [No. KYCX20_1571].