Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College , Tianjin 300192, China.
Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University , Tianjin 300071, China.
Mol Pharm. 2018 Feb 5;15(2):508-518. doi: 10.1021/acs.molpharmaceut.7b00890. Epub 2018 Jan 25.
Currently, development of subunit vaccine based on recombinant antigens or peptides has gradually become an important alternative option for traditional vaccine. However, induction of potent immune response with desired efficacy remains a major challenge. The nanoparticle-based antigen delivery system has been considered a potential carrier system to improve the efficacy of subunit vaccine. In the present study, we have designed an immune-stimulatory delivery system by conjugating three-armed PLGA to PEG via the peroxalate ester bond which is sensitive to hydrogen peroxide (HO), a major reactive oxygen species (ROS). Hyaluronic acid (HA), a ligand for CD44 receptors was also modified onto the outer shell of the 3s-PLGA-PEG nanoparticles to promote immune cell uptake. For in vitro and in vivo immune response assessment, a model antigen ovalbumin (OVA) was enclosed within the core of the 3s-PLGA-PEG nanoparticles to form 3s-PLGA-PO-PEG/HA nanoparticles (PHO NPs). Our results showed that the PHO NPs enhanced dendritic cell maturation, antigen uptake, and antigen presentation in vitro, likely due to enhanced lysosomal escape. In vivo experiments further revealed that the PHO nanovaccine robustly promoted OVA-specific antibody production and T cell response accompanied by modest stimulation of memory T cells. In summary, the ROS-responsive PHO NPs with modified HA may be an effective vehicle antigen delivery system to promote antigen-induced immune response.
目前，基于重组抗原或肽的亚单位疫苗的开发已逐渐成为传统疫苗的重要替代方案。然而，诱导具有所需疗效的强烈免疫反应仍然是一个主要挑战。基于纳米颗粒的抗原递药系统已被认为是提高亚单位疫苗疗效的潜在载体系统。在本研究中，我们通过过氧酯键将三臂 PLGA 偶联到 PEG 上，设计了一种免疫刺激性递药系统，而过氧酯键对过氧化氢（HO）敏感，HO 是主要的活性氧（ROS）之一。透明质酸（HA），一种 CD44 受体的配体，也被修饰到 3s-PLGA-PEG 纳米颗粒的外壳上，以促进免疫细胞摄取。为了评估体外和体内免疫反应，我们将模型抗原卵清蛋白（OVA）包裹在 3s-PLGA-PEG 纳米颗粒的核心内，形成 3s-PLGA-PO-PEG/HA 纳米颗粒（PHO NPs）。我们的结果表明，PHO NPs 增强了树突状细胞的成熟、抗原摄取和抗原呈递，这可能是由于溶酶体逃逸增强所致。体内实验进一步表明，PHO 纳米疫苗可强力促进 OVA 特异性抗体产生和 T 细胞反应，并适度刺激记忆 T 细胞。总之，具有修饰的 HA 的 ROS 响应性 PHO NPs 可能是一种有效的载体抗原递药系统，可促进抗原诱导的免疫反应。
