Yang Liang, Sha Yongjie, Wei Yuansong, Yin Lichen, Zhong Zhiyuan, Meng Fenghua
Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China; College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou 215123, China.
Acta Biomater. 2025 Mar 15;195:338-349. doi: 10.1016/j.actbio.2025.02.005. Epub 2025 Feb 6.
Rheumatoid arthritis (RA) is an autoimmune disease that has a complex pathogenesis and remains tough to treat. The clinical treatments with e.g. methotrexate (MTX) and TNF-α antibodies show fractional responses and lessen the symptoms only to a certain extent. Here, we developed inflammation-targeted vesicles codelivering methotrexate and TNF-α small interfering RNA (siTNFα) (ITV-MT) for effective ablation of collagen-induced arthritis (CIA) in mice. ITV-MT with tetra-mannose ligand and high loading of MTX (17.1 wt%) and siTNFα (9.0 wt%) displayed a small and uniform size (53 nm) and augmented uptake by inflammatory macrophages leading to superior regulation of macrophage phenotype from M1 to M2 in vitro compared to monotherapies. The intravenous injection of ITV-MT revealed clearly enhanced accretion in the inflamed joints. Interestingly, ITV-MT effectively repolarized M1 macrophages to M2 type, markedly reduced proinflammatory cytokine levels, and significantly attenuated symptoms including joint swelling, arthritis scores and bone damage in the CIA mouse models, by concurrently downregulating both adenosine and TNF-α pathways. This study highlights inflammation-targeted vesicles codelivering methotrexate and TNFα siRNA as a potential strategy to improved RA treatment. STATEMENT OF SIGNIFICANCE: Rheumatoid arthritis (RA) is regarded as an incurable disease, often referred to as an "incurable cancer". Current therapies, such as methotrexate (MTX) and anti-TNFα monoclonal antibodies, exhibit limited efficacy and severe adverse effects. The distinct physiochemical properties of MTX and siTNFα hinder their codelivery to RA joints and inflammatory cells. Here, we engineered inflammation-targeted vesicles (ITV-MT) for the codelivery of MTX and siTNFα to enhance therapeutic outcomes. Our findings reveal that ITV-MT significantly improves the drug uptake by macrophages, facilitating repolarization from M1 to M2 phenotypes. In CIA models, ITV-MT effectively downregulated proinflammatory cytokines while upregulating anti-inflammatory cytokines in RA joints, inhibited inflammatory cell infiltration in the synovium and protected against bone erosion. This study highlights that inflammation-targeted co-delivery of small molecular anti-RA agents and RNAi therapeutics may offer a compelling alternative to existing RA treatments, representing a promising strategy for RA treatment.
类风湿性关节炎（RA）是一种自身免疫性疾病，其发病机制复杂，治疗难度大。使用甲氨蝶呤（MTX）和肿瘤坏死因子-α（TNF-α）抗体等进行的临床治疗显示出部分疗效，仅能在一定程度上减轻症状。在此，我们开发了一种炎症靶向性囊泡，其可共递送甲氨蝶呤和TNF-α小干扰RNA（siTNFα）（ITV-MT），用于有效消除小鼠胶原诱导性关节炎（CIA）。带有四甘露糖配体且甲氨蝶呤（17.1 wt%）和siTNFα（9.0 wt%）负载量高的ITV-MT呈现出小而均匀的尺寸（53纳米），与单一疗法相比，其在体外可增强炎性巨噬细胞的摄取，从而导致巨噬细胞表型从M1向M2的更优调控。静脉注射ITV-MT显示其在发炎关节中的蓄积明显增强。有趣的是，ITV-MT通过同时下调腺苷和TNF-α途径，有效将M1巨噬细胞重极化至M2型，显著降低促炎细胞因子水平，并显著减轻CIA小鼠模型中的症状，包括关节肿胀、关节炎评分和骨损伤。本研究强调了共递送甲氨蝶呤和TNFα siRNA的炎症靶向性囊泡作为改善RA治疗的潜在策略。重要性声明：类风湿性关节炎（RA）被视为一种无法治愈的疾病，常被称为“不治之癌”。当前的疗法，如甲氨蝶呤（MTX）和抗TNFα单克隆抗体，疗效有限且有严重不良反应。MTX和siTNFα不同的物理化学性质阻碍了它们向RA关节和炎性细胞的共递送。在此，我们设计了炎症靶向性囊泡（ITV-MT）用于MTX和siTNFα的共递送以提高治疗效果。我们的研究结果表明，ITV-MT显著提高了巨噬细胞对药物的摄取，促进了从M1到M2表型的重极化。在CIA模型中，ITV-MT有效下调RA关节中的促炎细胞因子，同时上调抗炎细胞因子，抑制滑膜中的炎性细胞浸润并防止骨侵蚀。本研究强调，小分子抗RA药物和RNAi疗法的炎症靶向性共递送可能为现有RA治疗提供一种有吸引力的替代方案，是RA治疗的一种有前景的策略。
