Wheat germ agglutinin-nanoparticles encapsulating itacitinib target and suppress pro-inflammatory slan+ monocytes

6-sulfoLacNAc (slan)+ monocytes, a non-classical monocyte subset, play a pro-inflammatory role in autoimmune diseases like systemic lupus erythematosus (SLE). This study evaluates the therapeutic potential of itacitinib (ITA) encapsulated in wheat germ agglutinin-functionalized nanoparticles (WGA/F127/PNPs) to target and inhibit the JAK-STAT pathway in slan+ monocytes. We prepared ITA-loaded WGA/F127/PNPs and analyzed their binding and internalization in various leukocyte subsets using flow cytometry, focusing on slan+ and slan- monocytes. Further, peripheral blood samples from healthy controls (<i>n</i> = 37) and SLE patients (<i>n</i> = 50) were used to assess slan+ monocyte phenotypes. Co-cultures of slan+ and slan- monocytes stimulated with LPS revealed that slan+ monocytes significantly increased HLA-DR expression. Results showed that slan+ monocytes from SLE patients were reduced compared to healthy controls (<i>p</i> &lt; 0.001) and that slan+ monocytes effectively internalized WGA/F127/PNPs, unlike slan- cells. ITA-loaded nanoparticles decreased HLA-DR, CD69, and CD86 expression, STAT1 phosphorylation, and cytokine production in IFN-γ-stimulated slan+ monocytes. Findings support WGA/F127/PNPs as a promising drug delivery system for targeting slan+ monocytes, providing new therapeutic potential for SLE. ITA-loaded WGA/F127/PNPs effectively target and suppress pro-inflammatory slan+ monocytes, presenting a promising, cell-specific therapeutic approach for managing systemic lupus erythematosus and related autoimmune disorders.

表达6-硫酸化乳糖胺c（6-sulfoLacNAc，slan）的单核细胞（简称slan+单核细胞）作为一类非经典单核细胞亚群，在系统性红斑狼疮（systemic lupus erythematosus, SLE）等自身免疫性疾病中发挥促炎作用。本研究评估了包载于小麦凝集素功能化纳米粒（wheat germ agglutinin-functionalized nanoparticles, WGA/F127/PNPs）中的伊他替尼（itacitinib，ITA）靶向并抑制slan+单核细胞内JAK-STAT通路的治疗潜力。本研究制备了伊他替尼负载型WGA/F127/PNPs，并采用流式细胞术分析了其在各类白细胞亚群中的结合与内化情况，重点关注slan+与slan-单核细胞。此外，本研究纳入健康对照者（<i>n</i> = 37）与SLE患者（<i>n</i> = 50）的外周血样本，以评估slan+单核细胞的表型特征。经脂多糖（lipopolysaccharide, LPS）刺激的slan+与slan-单核细胞共培养实验结果显示，slan+单核细胞的人类白细胞抗原-DR（human leukocyte antigen-DR, HLA-DR）表达水平显著升高。结果显示，与健康对照者相比，SLE患者体内的slan+单核细胞数量显著减少（<i>p</i> < 0.001）；且与slan-单核细胞不同，slan+单核细胞可有效内化WGA/F127/PNPs。伊他替尼负载型纳米粒可降低干扰素γ（interferon-γ, IFN-γ）刺激后的slan+单核细胞的HLA-DR、分化簇69（cluster of differentiation 69, CD69）与分化簇86（cluster of differentiation 86, CD86）表达水平，同时抑制STAT1磷酸化与细胞因子产生。本研究结果证实WGA/F127/PNPs是一种极具前景的slan+单核细胞靶向药物递送系统，为SLE的治疗提供了新的潜在策略。伊他替尼负载型WGA/F127/PNPs可有效靶向并抑制促炎型slan+单核细胞，为系统性红斑狼疮及相关自身免疫性疾病的治疗提供了一种极具前景的细胞特异性治疗策略。