State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.
J Control Release. 2020 May 10;321:576-588. doi: 10.1016/j.jconrel.2020.02.039. Epub 2020 Feb 26.
Biodegradable microparticles (MPs) as vaccine adjuvants have sparked the passion of researchers in recent decades. However, it is still a huge challenge to develop an efficient vaccine delivery system to reverse chronic hepatitis B (CHB). Herein, we integrated a physiochemical merit and an immunopotentiator property in poly (lactic acid) (PLA) MPs and verified the therapeutic effect on CHB model mice. We prepared uniform MPs with insertion of cationic lipid didodecyldimethylammonium bromide (DDAB), which endowed a physiochemical merit for MPs. Such a DDAB-PLA (DP) group raised the recruitment of immune cells to the injection site along with the secretion of chemokines and pro-inflammatory cytokines, promoting the activation of antigen-presenting cells (APCs). Further combination of stimulator of interferon genes (STING) agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) (DP-D) elevated 5.8-fold higher interferon regulatory factor 7 (IRF-7) expression compared to that for DP group. The DP group showed preferred lysosome escape advantage, which was in line with the DMXAA release behavior and the intracellular target of DMXAA. In addition, DP-D vaccine augmented the IFN-γ secreting splenocytes and motivated Th1-biased antibodies in a more efficient way than that for the DP group. In the CHB model, the MPs based vaccines achieved 50% HBsAg seroconversion rate, and HBcAg in the liver also got a reduction. DP-D produced higher amount of memory T/B cells to confer protection in a sustained manner. Present work thus provided a promising strategy, via integrating a fine-tuned physiochemical property and an immunopotentiator virtue in the MPs, which synergistically reinforced both humoral and cellular immune responses against CHB.
可生物降解的微球（MPs）作为疫苗佐剂在近几十年来激发了研究人员的热情。然而，开发一种有效的疫苗递送系统来逆转慢性乙型肝炎（CHB）仍然是一个巨大的挑战。在这里，我们将物理化学优势和免疫增强特性整合到聚乳酸（PLA） MPs 中，并验证了其在 CHB 模型小鼠中的治疗效果。我们制备了具有阳离子脂质双十二烷基二甲基溴化铵（DDAB）插入的均匀 MPs，赋予 MPs 物理化学优势。DDAB-PLA（DP）组提高了免疫细胞向注射部位的募集以及趋化因子和促炎细胞因子的分泌，促进了抗原呈递细胞（APC）的激活。进一步结合干扰素基因刺激物（STING）激动剂 5,6-二甲基黄嘌呤-4-乙酸（DMXAA）（DP-D）使干扰素调节因子 7（IRF-7）的表达比 DP 组高 5.8 倍。DP 组表现出优先的溶酶体逃逸优势，这与 DMXAA 的释放行为和 DMXAA 的细胞内靶标一致。此外，DP-D 疫苗比 DP 组更有效地增强了 IFN-γ 分泌的脾细胞，并激发了 Th1 偏向的抗体。在 CHB 模型中，基于 MPs 的疫苗实现了 50%的 HBsAg 血清转化率，并且肝脏中的 HBcAg 也得到了减少。DP-D 产生了更多的记忆 T/B 细胞，以持续的方式提供保护。目前的工作通过在 MPs 中整合精细调节的物理化学特性和免疫增强特性，提供了一种有前途的策略，协同增强了针对 CHB 的体液和细胞免疫反应。
