Short chain fatty acid (SCFAs), such as butyrate, have shown promising therapeutic potential due to their immunomodulatory effects, particularly in maintaining immune homeostasis. However, the clinical application of SCFAs is limited by the need for frequent and high oral dosages. Rheumatoid arthritis (RA) is characterized by aberrant activation of peripheral T cells and myeloid cells. In this study, we aimed to deliver butyrate directly to the lymphatics using a polymeric micelle-based butyrate prodrug to induce long-lasting immunomodulatory effects. Notably, negatively charged micelles (Neg-ButM) demonstrated superior efficacy in targeting the lymphatics following subcutaneous (s.c.) administration and were retained in the draining lymph nodes, spleen, and liver for over one month. In the collagen antibody-induced arthritis (CAIA) mouse model of RA, only two s.c. injections of Neg-ButM successfully prevented disease onset and promoted tolerogenic phenotypes in T cells and myeloid cells, both locally and systemically. These results underscore the potential of this strategy in managing inflammatory autoimmune diseases by directly modulating immune responses lymphatic delivery.

中文翻译：

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可注射的丁酸盐前药胶束诱导长效免疫调节并预防小鼠自身免疫性关节炎


短链脂肪酸（SCFA），例如丁酸盐，由于其免疫调节作用，特别是在维持免疫稳态方面显示出有希望的治疗潜力。然而，SCFA 的临床应用由于需要频繁和高口服剂量而受到限制。类风湿性关节炎 (RA) 的特征是外周 T 细胞和骨髓细胞的异常激活。在这项研究中，我们的目标是使用基于聚合胶束的丁酸盐前药将丁酸盐直接递送至淋巴管，以诱导持久的免疫调节作用。值得注意的是，带负电荷的胶束 (Neg-ButM) 在皮下 (sc) 给药后在靶向淋巴管方面表现出卓越的功效，并在引流淋巴结、脾脏和肝脏中保留超过一个月。在 RA 的胶原抗体诱导关节炎 (CAIA) 小鼠模型中，仅皮下注射两次 Neg-ButM 即可成功预防疾病发作，并促进局部和全身 T 细胞和骨髓细胞的耐受表型。这些结果强调了该策略通过直接调节免疫反应淋巴输送来控制炎症性自身免疫性疾病的潜力。