Nanoparticu late STING agonists are potent lymph node-targeted vaccine adjuvants
Nanoparticu late STING agonists are potent lymph node-targeted vaccine adjuvants
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DOI：
10.1172/jci79915
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发表时间：
2015-06-01
影响因子：
15.9
通讯作者：
Irvine, Darrell J.
中科院分区：
文献类型：
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作者：
Hanson, Melissa C.;Crespo, Monica R.;Irvine, Darrell J.
环二核苷酸（Cyclic dinucleotides，CONS）是干扰素基因刺激因子（stimulator of IFN genes，STING）的激动剂，具有作为疫苗佐剂的潜力。然而，皮下注射环二GMP（cdGMP），显示出最小的吸收进入淋巴管/引流淋巴结（dLN），而是迅速分布到血流中，导致全身性炎症。在这里，我们将cdGMP封装在聚乙二醇化脂质纳米颗粒（NP-cdGMP）内以将该佐剂重定向至dLN。与未配制的CDN相比，包封阻断了小鼠模型中的全身传播并显著增强了dLN积累。NP-cdGMP的递送增加了由肽疫苗引发的CDEVT细胞应答并增强了治疗性抗肿瘤免疫。与脂质体HIV gp 41和可溶性CON的组合相比，免疫原性差的脂质体HIV gp 41肽抗原和NP-cdGMP的组合在dLN中稳健地诱导I型IFN，诱导疫苗特异性CD 4 * T细胞的更大扩增，并且大大增加dLN中的生发中心B细胞分化。NP-cdGMP促进持久的抗体滴度，其显著高于充分研究的TLR激动剂单磷酰脂质A所促进的抗体滴度，并且与大得多剂量的未配制的cdGMP相当，而没有后者的全身毒性。这些结果表明，纳米颗粒递送安全地将CDN靶向dLN并增强该佐剂的功效。此外，这种方法可以广泛应用于疫苗和免疫治疗的其他感兴趣的小分子免疫调节剂。
Cyclic dinucleotides (CONS) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CDEVT cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4* T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CON. Further, NP-cdGMP promoted durable antibody titers that were substantially higher than those promoted by the well-studied TLR agonist monophosphoryl lipid A and comparable to a much larger dose of unformulated cdGMP, without the systemic toxicity of the latter. These results demonstrate that nanoparticulate delivery safely targets CDNs to the dLNs and enhances the efficacy of this adjuvant. Moreover, this approach can be broadly applied to other small-molecule immunomodulators of interest for vaccines and immunotherapy.