Treating Autoimmune Inflammatory Diseases with an siERN1-Nanoprodrug That Mediates Macrophage Polarization and Blocks Toll-like Receptor Signaling
Treating Autoimmune Inflammatory Diseases with an siERN1-Nanoprodrug That Mediates Macrophage Polarization and Blocks Toll-like Receptor Signaling
复制标题
使用介导巨噬细胞极化并阻断 Toll 样受体信号转导的 siERN1-Nanoprodrug 治疗自身免疫性炎症疾病。
DOI：
10.1021/acsnano.1c03726
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发表时间：
2021-09-29
期刊：
影响因子：
17.1
通讯作者：
Guo, Fengjin
中科院分区：
文献类型：
--
作者：
Feng, Naibo;Liang, Li;Guo, Fengjin
小干扰RNA（siRNA）药物的临床应用为开发自身免疫性炎症性疾病的治疗策略提供了有希望的机会。本研究筛选了靶向内质网至核信号传导1（ERN 1）基因的siRNA（siERN 1）。两种阳离子聚合物，聚乙烯亚胺（PEI）和聚（β-氨基胺）（PBAA），这可以提高siRNA的转染效率，被用作siERN 1的递送载体。它们被实施以构建具有巨噬细胞靶向能力和双重响应性的纳米药物递送系统，用于治疗自身免疫性炎症性疾病。在机制上，siERN 1通过干扰三磷酸肌醇受体1/3（IP 3R 1/3）的功能，诱导巨噬细胞M2极化，从而调节细胞内钙离子浓度。此外，siERN 1-纳米前药[FA（叶酸）-PEG-R（RKKRRQRRR）-NPs（ss-PBAA-PEI）@siERN1]通过控制钙离子浓度充当巨噬细胞极化的导体，并且是MyD 88依赖性Toll样受体信号传导的抑制剂。结果表明，FA-PEG-R-NPs@ siERN 1具有普遍的生物相容性、长期的药物释放响应性、上级靶向性，并对小鼠胶原诱导的关节炎和炎症性肠病模型具有治疗作用。总之，这项研究揭示了一个潜在的策略来治疗自身免疫性炎症性疾病。
The clinical application of small interfering RNA (siRNA) drugs provides promising opportunities to develop treatment strategies for autoimmune inflammatory diseases. In this study, siRNAs targeting the endoplasmic reticulum to nucleus signaling 1 (ERN1) gene (siERN1) were screened. Two cationic polymers, polyethylenimine (PEI) and poly(beta-amino amine) (PBAA), which can improve the efficiency of the siRNA transfection, were used as siERN1 delivery carriers. They were implemented to construct a nanodrug delivery system with macrophage-targeting ability and dual responsiveness for the treatment of autoimmune inflammatory diseases. In terms of the mechanism, siERN1 can regulate the intracellular calcium ion concentration by interfering with the function of inositol 1,4,5-trisphosphate receptor 1/3 (IP3R1/3) and thus inducing M2 polarization of macrophages. Furthermore, siERN1-nanoprodrug [FA (folic acid)-PEG-R(RKKRRQRRR)-NPs(ss-PBAA-PEI)@siERN1] acts as a conductor of macrophage polarization by controlling the calcium ion concentration and is an inhibitor of MyD88-dependent Toll-like receptor signaling. The results revealed that the FA-PEG-R-NPs@siERN1 has universal biocompatibility, long-term drug release responsiveness, superior targeting properties, and therapeutic effects in mouse collagen-induced arthritis and inflammatory bowel disease models. In conclusion, this study reveals a potential strategy to treat autoimmune inflammatory disorders.