Inhibition of c-Rel expression in myeloid and lymphoid cells with distearoyl -phosphatidylserine (DSPS) liposomal nanoparticles encapsulating therapeutic siRNA.
Inhibition of c-Rel expression in myeloid and lymphoid cells with distearoyl -phosphatidylserine (DSPS) liposomal nanoparticles encapsulating therapeutic siRNA.
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DOI：
10.1371/journal.pone.0276905
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
c-Rel是核因子κ B（NF-κB）家族的成员，其优先由免疫细胞表达，并且已知其调节炎症、自身免疫性疾病和癌症。然而，缺乏特异性抑制免疫细胞中c-Rel的治疗干预。最近辉瑞和Moderna mRNA脂质包封疫苗以及FDA批准的基于siRNA的药物的成功促使我们测试基于脂质纳米颗粒的策略来沉默免疫细胞中的c-Rel。具体而言，我们将c-Rel靶向siRNA封装到含有二硬脂酰磷脂酰丝氨酸（DSPS）的纳米颗粒中。DSPS是一种饱和磷脂，其充当免疫系统的专业吞噬细胞如巨噬细胞和嗜中性粒细胞的“吃我”信号。我们在此证明，将DSPS掺入脂质体纳米颗粒（LNP）中改善了免疫细胞对其的摄取。含有高浓度DSPS的LNP不仅对巨噬细胞和嗜中性粒细胞，而且对淋巴细胞都非常有效，对细胞的毒性有限。然而，含有低浓度DSPS的LNP对髓样细胞比淋巴样细胞更有效。重要的是，负载有c-Rel siRNA的DSPS-LNP高度有效地抑制几种测试的专职吞噬细胞中的c-Rel表达，其持续数天。综上所述，我们的结果表明，可以利用配备有c-Rel siRNA的DSPS-LNP来靶向免疫细胞，以限制由c-Rel上调引起的炎性疾病或癌症的发展。此外，这种新开发的DSPS-LNP系统可以进一步测试，以封装和递送其他小分子药物到免疫细胞，特别是巨噬细胞，中性粒细胞和淋巴细胞，用于治疗疾病。
c-Rel, a member of the nuclear factor kappa B (NF-κB) family, is preferentially expressed by immune cells and is known to regulate inflammation, autoimmune diseases and cancer. However, there is a lack of therapeutic intervention to specifically inhibit c-Rel in immune cells. Recent success with Pfizer and Moderna mRNA lipid-encapsulated vaccines as well as FDA approved medicines based on siRNA prompted us to test a lipid nanoparticle-based strategy to silence c-Rel in immune cells. Specifically, we encapsulated c-Rel-targeting siRNA into distearoyl-phosphatidylserine (DSPS)-containing nanoparticles. DSPS is a saturated phospholipid that serves as the “eat-me” signal for professional phagocytes such as macrophages and neutrophils of the immune system. We demonstrated here that incorporation of DSPS in liposome nanoparticles (LNP) improved their uptake by immune cells. LNP containing high concentrations of DSPS were highly effective to transfect not only macrophages and neutrophils, but also lymphocytes, with limited toxicity to cells. However, LNP containing low concentrations of DSPS were more effective to transfect myeloid cells than lymphoid cells. Importantly, DSPS-LNP loaded with a c-Rel siRNA were highly effective to inhibit c-Rel expression in several professional phagocytes tested, which lasted for several days. Taken together, our results suggest that DSPS-LNP armed with c-Rel siRNA could be exploited to target immune cells to limit the development of inflammatory diseases or cancer caused by c-Rel upregulation. In addition, this newly developed DSPS-LNP system may be further tested to encapsulate and deliver other small molecule drugs to immune cells, especially macrophages, neutrophils, and lymphocytes for the treatment of diseases.
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