Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin Key Laboratory of Biomedical Materials, Tianjin 300192, China.
Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin 300192, China.
Biomaterials. 2019 Jun;206:25-40. doi: 10.1016/j.biomaterials.2019.03.012. Epub 2019 Mar 20.
Exploiting Toll-like receptor (TLR) agonists or their certain combinations can enhance the immune potency of subunit vaccine. Nevertheless, the design of co-delivery systems which can act in a synergistic and spatio-temporal way to achieve effective and durable specific immune response is still challenging. Here we fabricated mannose-functionalized lipid-hybrid polymersomes (MAN-IMO-PS) for co-delivery of ovalbumin antigen both inside the inner core and outside the lipid layer, TLR7/8 agonist imiquimod within the hydrophobic membrane, TLR4 agonist monophosphoryl lipid A in the lipid layer as programmed nanovaccine to synergistically activate immune responses for improving vaccine efficacy. After efficiently internalized by dendritic cells via mannose targeting and TLR4 ligating, MAN-IMO-PS significantly enhanced cross-presentation and cytokine production. In addition, MAN-IMO-PS showed depot effect at the injection site and enhanced migration to draining lymph nodes. Mice immunized with MAN-IMO-PS elicited greater lymphocyte activation, CD4 and CD8 T cell response, effector cytokines secretion, and induced Th-1 biased humoral responses. More importantly, prophylactic vaccination by MAN-IMO-PS significantly delayed tumor occurrence, suppressed tumor growth with prolonged survival, and achieved long-term immune effect. The present study demonstrates a rationally designed nanovaccine for combining antigen, different TLR agonists, and targeting moiety in a programmed manner to induce synergistic antitumor immune response.
利用 Toll 样受体 (TLR) 激动剂或它们的某些组合可以增强亚单位疫苗的免疫效力。然而，设计能够协同作用并在时空上发挥作用以实现有效和持久的特异性免疫反应的共递药系统仍然具有挑战性。在这里，我们制备了甘露糖功能化脂质混合聚合物囊泡 (MAN-IMO-PS)，用于在内部核心和脂质层外部共递送卵清蛋白抗原，在疏水性膜内 TLR7/8 激动剂咪喹莫特，在脂质层内 TLR4 激动剂单磷酰脂质 A 作为程序纳米疫苗，协同激活免疫反应以提高疫苗效力。通过甘露糖靶向和 TLR4 连接有效地被树突状细胞内化后，MAN-IMO-PS 显著增强了交叉呈递和细胞因子产生。此外，MAN-IMO-PS 在注射部位表现出储库效应，并增强向引流淋巴结的迁移。用 MAN-IMO-PS 免疫的小鼠引起更大的淋巴细胞活化、CD4 和 CD8 T 细胞反应、效应细胞因子分泌，并诱导 Th-1 偏向的体液反应。更重要的是，MAN-IMO-PS 的预防性疫苗接种显著延迟了肿瘤发生，抑制了肿瘤生长并延长了生存时间，并实现了长期免疫效果。本研究证明了一种合理设计的纳米疫苗，可将抗原、不同的 TLR 激动剂和靶向部分以程序化方式组合在一起，以诱导协同的抗肿瘤免疫反应。
