Investigation of triptolide delivery by M2 macrophages for safe and effective treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a complex autoimmune condition primarily affecting synovial joints, with limited efficacy from first-line medications. The traditional Chinese medicinal herb Triptergium wilfordii Hook F effectively suppresses RA symptoms, but its severe systemic toxicity limits clinical use. We previously identified triptolide (TP) as a key active component of T. wilfordii, which significantly reduced joint inflammation in adjuvant-induced arthritis (AIA) rat models. However, TP raised serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratios and creatinine levels,
indicating liver and kidney damage, respectively. This led us to explore a targeted delivery system to minimize the toxicity of TP while retaining its anti-inflammatory efficacy.
Building on successful macrophage-based drug delivery studies and the antiinflammatory properties of autologous M2 macrophages (M2Ф), we developed an M2Фbased in vivo delivery approach for TP. We encapsulated TP in liposomes (LipTP) and loaded them into M2Ф derived from primary human monocytes (LipTP-M2Ф). Characterization of LipTP-M2Ф revealed satisfactory drug uptake and release profiles. LipTP-M2Ф significantly increased apoptotic rates in fibroblast-like ynoviocytes from RA patients (RA-FLS). In AIA rats, LipTP-M2Ф outperformed free TP, LipTP, and LipTP loaded in non-activated (M0Ф) and pro-inflammatory (M1Ф) macrophages in anti-RA effects. LipTP-M2Ф notably inhibited joint inflammation, reducing clinical scores, hind paw thickness, and inflammatory cell infiltration and synovial cell
hyperplasia in ankle joints. It also exhibited a much better safety profile in AIA rats with the lowest hepatotoxicity (serum AST/ALT ratio) and nephrotoxicity (creatinine level). Therefore, our preliminary studies indicate that LipTP-M2Ф provides a safe and effective RA treatment by minimizing TP toxicity.
Based on these findings, we hypothesize that TP delivered via M2Ф can provide a safe and effective RA treatment. Our objectives are: 1) to comprehensively evaluate the antiRA efficacy and safety of LipTP-MФ both in vitro and in vivo; 2) to investigate the specificity of M2Ф-based TP delivery in vivo; and 3) to optimize the M2Ф-based TP delivery.
This project is significant as it aims to minimize TP toxicity while maximizing its therapeutic potential for RA, by delivering LipTP in well-characterized antiinflammatory M2Ф. Enhancing the clinical application of TP and other potent therapeutics could provide a groundbreaking and safer treatment option for RA management, potentially transforming current therapeutic strategies and improving patient outcomes.