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 can be an efficient way to reduce joint inflammation and bone erosion. Based on the characteristics of dextran sulphate (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-labelled 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.

Keywords:

• Nano-emulsions
• celastrol
• rheumatoid arthritis
• dextran sulphate
• apoptosis

Author contributions

Chenglong Li, Yangyun Han and Huaiyu Su contributed to the conception of the study; Chenglong Li, Yan Li, Qing Zeng and Yang Zhou performed the experiment; Chenglong Li and Chen Li contributed significantly to analysis and manuscript preparation; Chenglong Li performed the data analyses and wrote the manuscript; Yan Li, Qing Zeng, Yang Zhou and Huaiyu Su helped perform the analysis with constructive discussions. All authors read and approved the final manuscript.

Ethical approval

The justification for use of animals was that the mice were needed in study to develop novel therapies to treat RA. All animals were housed in a specific pathogen free environment (ventilated room, 24 ± 2 °C, 55–65% humidity, 12 h light and dark cycle) and have free access to sufficient food and water. Mice were subjected to deep anaesthesia with a concentration of 2–3% isoflurane, and the mice were euthanised via manual cervical dislocation. All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of Sichuan Cancer Hospital (Approved Number: SCCHEC-04-2023-004), and the authors have adhered to the Animal Research: Reporting of in vivo Experiments [ARRIVE] guidelines.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

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].