Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.
Nanoscale. 2018 May 24;10(20):9489-9503. doi: 10.1039/c8nr00355f.
Subunit vaccines that are designed based on recombinant antigens or peptides have shown promising potential as viable substitutes for traditional vaccines due to their better safety and specificity. However, the induction of adequate in vivo immune responses with appropriate effectiveness remains a major challenge for vaccine development. More recently, the implementation of a nanoparticle-based antigen delivery system has been considered a promising approach to improve the in vivo efficacy for subunit vaccine development. Thus, we have designed and prepared a nanoparticle-based antigen delivery system composed of three-armed PLGA, which is conjugated to PEG via the peroxalate ester bond (3s-PLGA-PO-PEG) and PEI as a cationic adjuvant (PPO NPs). It is known that during a foreign pathogen attack, NADPH, an oxidase, of the host organism is activated and generates an elevated level of reactive oxygen species, hydrogen peroxide (H2O2) primarily, as a defensive mechanism. Considering the sensitivity of the peroxalate ester bond to H2O2 and the cationic property of PEI for the induction of immune responses, this 3s-PLGA-PO-PEG/PEI antigen delivery system is expected to be both ROS responsive and facilitative in antigen uptake without severe toxicity that has been reported with cationic adjuvants. Indeed, our results demonstrated excellent loading capacity and in vitro stability of the PPO NPs encapsulated with the model antigen, ovalbumin (OVA). Co-culturing of bone marrow dendritic cells with the PPO NPs also led to enhanced dendritic cell maturation, antigen uptake, enhanced lysosomal escape, antigen cross-presentation and in vitro CD8+ T cell activation. In vivo experiments using mice further revealed that the administration of the PPO nanovaccine induced robust OVA-specific antibody production, upregulation of splenic CD4+ and CD8+ T cell proportions as well as an increase in memory T cell generation. In summary, we report here a ROS-triggered nanoparticle-based antigen delivery system that could be employed to promote the in vivo efficacy of vaccine-induced immune responses.
基于重组抗原或肽设计的亚单位疫苗由于其更好的安全性和特异性，已显示出作为传统疫苗可行替代品的有前途的潜力。然而，诱导具有适当有效性的足够体内免疫反应仍然是疫苗开发的主要挑战。最近，实施基于纳米颗粒的抗原递送系统被认为是提高亚单位疫苗开发体内功效的有前途的方法。因此，我们设计并制备了一种基于纳米颗粒的抗原递送系统，该系统由三臂 PLGA 组成，通过过氧酸盐酯键（3s-PLGA-PO-PEG）与 PEG 连接，并与聚酰胺-胺（PEI）作为阳离子佐剂（PPO NPs）。众所周知，在外来病原体攻击期间，宿主生物体的 NADPH 氧化酶被激活并产生高水平的活性氧物种，主要是过氧化氢（H2O2），作为一种防御机制。考虑到过氧酸盐酯键对 H2O2 的敏感性和 PEI 对诱导免疫反应的阳离子特性，这种 3s-PLGA-PO-PEG/PEI 抗原递送系统有望具有 ROS 响应性和促进抗原摄取的作用，而不会产生已报道的阳离子佐剂的严重毒性。事实上，我们的结果表明，模型抗原卵清蛋白（OVA）包封的 PPO NPs 具有出色的载药能力和体外稳定性。骨髓树突状细胞与 PPO NPs 共培养也导致树突状细胞成熟、抗原摄取、增强溶酶体逃逸、抗原交叉呈递和体外 CD8+T 细胞激活增强。使用小鼠的体内实验进一步表明，PPO 纳米疫苗的给药诱导了强烈的 OVA 特异性抗体产生，上调了脾脏 CD4+和 CD8+T 细胞的比例，并增加了记忆 T 细胞的产生。总之，我们在这里报告了一种 ROS 触发的基于纳米颗粒的抗原递送系统，可用于增强疫苗诱导的免疫反应的体内功效。
