Engineering ApoE3-incorporated biomimetic nanoparticle for efficient vaccine delivery to dendritic cells via macropinocytosis to enhance cancer immunotherapy
Engineering ApoE3-incorporated biomimetic nanoparticle for efficient vaccine delivery to dendritic cells via macropinocytosis to enhance cancer immunotherapy
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设计掺有 ApoE3 的仿生纳米颗粒，通过巨胞饮作用将疫苗有效递送至树突状细胞，以增强癌症免疫治疗
DOI：
10.1016/j.biomaterials.2020.119795
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发表时间：
2020
期刊：
影响因子：
14
通讯作者：
Chen Jun
中科院分区：
文献类型：
--
作者：
Zhou Songlei;Huang Yukun;Chen Yu;Liu Shanshan;Xu Minjun;Jiang Tianze;Song Qingxiang;Jiang Gan;Gu Xiao;Gao Xiaoling;Chen Jun
有效地将疫苗递送至树突状细胞（DC）对于诱导足够的免疫应答和实现有效的癌症免疫治疗至关重要。在过去的十年中，研究人员花费了巨大的努力，通过使用纳米颗粒来提供疫苗。然而，目前的大多数策略都是基于受体介导的内吞作用来增加DC对纳米疫苗的摄取，并且低估了巨胞饮作用在摄取外源性抗原中的作用。在这里，我们提出，巨胞饮，一个有效的途径，DC内化细胞外液相溶质，可能会被用作一个高度有效的方法，以促进纳米疫苗在DC中的摄取。因此，我们设计了一种仿生纳米疫苗（R837-α OVA-ApoE 3-HNP），其由聚-（D，l-丙交酯-共-乙交酯）（PLGA）核心包封佐剂咪喹莫特（R837）、磷脂膜负载抗原肽（αOVA）和载脂蛋白E3（ApoE 3）组成，以促进抗原内化到DC中。纳米疫苗通过巨胞饮途径表现出高效的细胞摄取到DC中，并显著促进DC成熟和抗原呈递。皮下注射后，纳米疫苗被有效地引流到淋巴结。R837-α OVA-ApoE 3-HNP疫苗免疫小鼠后，小鼠产生了较强的T细胞免疫应答，包括抗原特异性CD 8 + T细胞的产生、IFN-γ+ CD 8 +T细胞的扩增和IFN-γ+的分泌。作为预防性疫苗，它还有效地抑制了肿瘤在肺中转移的形成，并且当与αPD-1联合治疗时，对B16-OVA荷瘤小鼠具有上级治疗效率。总的来说，我们的工作表明，通过利用巨胞饮途径，ApoE 3掺入的仿生纳米颗粒具有很大的潜力，作为一种可行的，有效的，安全的纳米疫苗用于癌症免疫治疗。
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.