Celastrol nano-emulsions selectively regulate apoptosis of synovial macrophage for alleviating rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammation. Excessive proliferation and inadequate apoptosis of synovial macrophages are the crucial events of RA. Therefore, delivering therapeutic molecules to synovial macrophages specifically to tackle apoptotic insufficiency probably be an efficient way to reduce joint inflammation and bone erosion. Based on the characteristics of dextran sulfate (DS) specifically binding scavenger receptor A (SR-A) on macrophage and celastrol (CLT) inducing apoptosis, we designed synovial macrophage-targeted nano-emulsions encapsulated with CLT (SR-CLTNEs) and explored their anti-RA effect. After intravenous injection, fluorescence-labeled SR-CLTNEs successfully targeted inflammatory joints and synovial macrophages in a mouse model of RA, with the macrophage targeting efficiency of SR-CLTNEs, CLTNEs, and Free DID was 20.53%, 13.93%, and 9.8%, respectively. In vivo and in vitro studies showed that SR-CLTNEs effectively promoted the apoptosis of macrophages, reshaped the balance between apoptosis and proliferation, and ultimately treated RA in a high efficiency and low toxicity manner. Overall, our work demonstrates the efficacy of using SR-CLTNEs as a novel nanotherapeutic approach for RA therapy and the great translational potential of SR-CLTNEs.

Key words:

• Nano-emulsions
• Celastrol
• Rheumatoid arthritis
• Dextran sulfate
• Apoptosis

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Funding

This work was supported by the National Natural Science Foundation of China [32301192, 82300276], the Key Research and Development Project of Deyang Science and Technology Bureau (2023SZZ002), the Sichuan Medical Research Youth Innovation Project [Q22026], and the National Incubation Project of Deyang People’s Hospital [FHG202302].