Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
Department of Orthopedics, The 2nd Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
ACS Nano. 2021 Oct 26;15(10):15874-15891. doi: 10.1021/acsnano.1c03726. Epub 2021 Sep 29.
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 () gene (siERN1) were screened. Two cationic polymers, polyethylenimine (PEI) and poly(β-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.
小干扰 RNA（siRNA）药物的临床应用为自身免疫性炎症疾病的治疗策略提供了有前景的机会。在本研究中，筛选了针对内质网到核信号 1（ERN1）基因的 siRNA。两种阳离子聚合物，聚乙烯亚胺（PEI）和聚（β-氨基胺）（PBAA），可以提高 siRNA 转染效率，被用作 siERN1 的递送载体。它们被用于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疾病。在机制方面，siERN1 通过干扰肌醇 1,4,5-三磷酸受体 1/3（IP3R1/3）的功能来调节细胞内钙离子浓度，从而诱导巨噬细胞 M2 极化。此外，siERN1-纳米药物[FA（叶酸）-PEG-R（RRKKRRQRRR）-NPs（ss-PBAA-PEI）@siERN1]通过控制钙离子浓度作为巨噬细胞极化的导体，并且是 MyD88 依赖性 Toll 样受体信号的抑制剂。结果表明，FA-PEG-R-NPs@siERN1 具有普遍的生物相容性、长期药物释放响应性、优越的靶向特性以及在小鼠胶原诱导性关节炎和炎症性肠病模型中的治疗效果。总之，本研究揭示了一种治疗自身免疫性炎症疾病的潜在策略。
