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A poly(beta-amino ester) activates macrophages independent of NF-κB signaling
Acta Biomaterialia ( IF 9.7 ) Pub Date : 2017-12-30 , DOI: 10.1016/j.actbio.2017.12.040
Neil M Dold 1 , Qin Zeng 1 , Xiangbin Zeng 1 , Christopher M Jewell 2
Affiliation  

Nucleic acid delivery vehicles are poised to play an important role in delivering gene therapy for vaccines and immunotherapies, and in delivering nucleic acid based adjuvants. A number of common polymeric delivery vehicles used in nucleic acid delivery have recently been shown to interact with immune cells and directly stimulate immunogenic responses, particularly in particle form. Poly(beta-amino esters) were designed for nucleic acid delivery and have demonstrated promising performance in a number of vaccine and therapeutic studies. Yet, little work has characterized the mechanisms by which these polymers activate immune cells. Here we demonstrate that a poly(beta-amino ester) activates antigen presenting cells in soluble and particulate forms, and that these effects are independent of TLR signaling pathways. Moreover, we show the polymers induce activation independent of NF-κB signaling, but do activate IRF, an important innate inflammatory pathway. New knowledge linking physicochemical features of poly(beta-amino esters) or other polymeric carriers to inflammatory mechanisms could support more rational design approaches for vaccines and immunotherapies harnessing these materials.

Significance Statement

The last several years have brought exciting work exploring biomaterials as delivery vehicles for immunotherapies, vaccines, and gene therapies. However, a gap remains between the striking finding that many biomaterials exhibit intrinsic immunogenic features, and the specific structural properties that drive these responses. The results in the current study indicate PBAEs cause macrophage activation by pathways that are distinct from pathways activated by common vaccine and immunotherapies components, such as toll-like receptor agonists. Thus, the work reveals new mechanistic details that can be exploited in investigating other materials, and to support more rational design of future biomaterial vaccines and immunotherapy carriers.



中文翻译:

聚(β-氨基酯)独立于 NF-κB 信号传导激活巨噬细胞

核酸递送载体有望在疫苗和免疫疗法的基因治疗以及基于核酸的佐剂递送中发挥重要作用。最近显示,用于核酸递送的许多常见聚合物递送载体可与免疫细胞相互作用并直接刺激免疫原性反应,特别是以颗粒形式。聚(β-氨基酯)被设计用于核酸递送,并在许多疫苗和治疗研究中表现出有希望的性能。然而,很少有人研究这些聚合物激活免疫细胞的机制。在这里,我们证明聚(β-氨基酯)以可溶性和颗粒形式激活抗原呈递细胞,并且这些作用独立于 TLR 信号通路。此外,我们表明聚合物诱导独立于 NF-κB 信号传导的激活,但确实激活 IRF,这是一种重要的先天炎症途径。将聚(β-氨基酯)或其他聚合物载体的物理化学特征与炎症机制联系起来的新知识可以支持利用这些材料的疫苗和免疫疗法的更合理的设计方法。

意义声明

过去几年出现了令人兴奋的工作,探索生物材料作为免疫疗法、疫苗和基因疗法的传递工具。然而,许多生物材料表现出内在免疫原性特征的惊人发现与驱动这些反应的特定结构特性之间仍然存在差距。当前研究的结果表明,PBAE 通过与常见疫苗和免疫治疗成分(例如 Toll 样受体激动剂)激活的途径不同的途径引起巨噬细胞激活。因此,这项工作揭示了新的机制细节,可用于研究其他材料,并支持未来生物材料疫苗和免疫治疗载体的更合理设计。

更新日期:2017-12-31
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