Zhou Songlei, Huang Yukun, Chen Yu, Liu Shanshan, Xu Minjun, Jiang Tianze, Song Qingxiang, Jiang Gan, Gu Xiao, Gao Xiaoling, Chen Jun
Shanghai Pudong Hospital & Department of Pharmaceutics, School of Pharmacy,Fudan University, Lane 826, Zhangheng Road, Shanghai, 201203, PR China; Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, PR China.
Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
Biomaterials. 2020 Mar;235:119795. doi: 10.1016/j.biomaterials.2020.119795. Epub 2020 Jan 16.
Efficient delivery of vaccines to dendritic cells (DCs) is critical for inducing sufficient immune response and realizing effective cancer immunotherapy. In the past decade, researchers have spent tremendous effort in delivering vaccines by using nanoparticles. However, most of the present strategies are designed based on receptor-mediated endocytosis to increase nanovaccines uptake by DCs, and underestimate the role of macropinocytosis in taking up exogenous antigen. Here, we proposed that macropinocytosis, an efficient pathway for DCs to internalize extracellular fluid-phase solutes, might be utilized as a highly-effective approach to facilitate nanovaccines uptake in DCs. Accordingly, we designed a biomimetic nanovaccine (R837-αOVA-ApoE3-HNP), composing of a poly-(D, l-lactide-co-glycolide) (PLGA) core to encapsulate adjuvant imiquimod (R837), a phospholipid membrane to load antigen peptide (αOVA), and apolipoprotein E3 (ApoE3), to boost the internalization of antigens into DCs. The nanovaccine exhibited highly efficient cellular uptake into DCs through the macropinocytosis pathway, and significantly promoted DCs maturation and antigen presentation. After subcutaneous injection, the nanovaccine was efficiently drained to lymph nodes. Strong T cell immune responses including the generation of antigen-specific CD8 T cells, expansion of IFN-γ CD8 T cells and the secretion of IFN-γ were observed after the vaccination of R837-αOVA-ApoE3-HNP. It also efficiently inhibited the formation of tumor metastasis in lung as a prevention vaccine, and exerted superior therapeutic efficiency on B16-OVA tumor-bearing mice when in combination with αPD-1 therapy. Overall, our work demonstrated that by utilizing the macropinocytosis pathway, ApoE3-incorporated biomimetic nanoparticle has great potential to function as a feasible, effective, and safe nanovaccine for cancer immunotherapy.
将疫苗有效递送至树突状细胞（DCs）对于诱导足够的免疫反应和实现有效的癌症免疫治疗至关重要。在过去十年中，研究人员在使用纳米颗粒递送疫苗方面付出了巨大努力。然而，目前大多数策略是基于受体介导的内吞作用设计的，以增加DCs对纳米疫苗的摄取，而低估了巨胞饮作用在外源抗原摄取中的作用。在此，我们提出巨胞饮作用作为DCs内化细胞外液相溶质的有效途径，可能被用作促进DCs摄取纳米疫苗的高效方法。因此，我们设计了一种仿生纳米疫苗（R837-αOVA-ApoE3-HNP），它由一个聚（D，L-丙交酯-共-乙交酯）（PLGA）核心包裹佐剂咪喹莫特（R837）、一个负载抗原肽（αOVA）的磷脂膜和载脂蛋白E3（ApoE3）组成，以促进抗原内化至DCs中。该纳米疫苗通过巨胞饮作用途径在DCs中表现出高效的细胞摄取，并显著促进DCs成熟和抗原呈递。皮下注射后，纳米疫苗有效地引流至淋巴结。接种R837-αOVA-ApoE3-HNP后，观察到强烈的T细胞免疫反应，包括抗原特异性CD8 T细胞的产生、IFN-γ CD8 T细胞的扩增和IFN-γ的分泌。作为预防性疫苗，它还能有效抑制肺部肿瘤转移的形成，并且在与αPD-1疗法联合使用时，对荷B16-OVA肿瘤小鼠具有卓越的治疗效果。总体而言，我们的工作表明，通过利用巨胞饮作用途径，掺入ApoE3的仿生纳米颗粒具有作为一种可行、有效且安全的癌症免疫治疗纳米疫苗的巨大潜力。
