Enabling sublingual peptide immunization with molecular self-assemblies
Enabling sublingual peptide immunization with molecular self-assemblies
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DOI：
10.1016/j.biomaterials.2020.119903
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发表时间：
2020-05-01
期刊：
影响因子：
14
通讯作者：
Collier, Joel H.
中科院分区：
文献类型：
--
作者：
Kelly, Sean H.;Wu, Yaoying;Collier, Joel H.
短肽在舌下递送时免疫原性较差。纳米材料递送多肽可用于提高设计的舌下疫苗的免疫原性，但由于通过舌下粘膜运输的挑战，纳米材料尚未在舌下疫苗中广泛成功。在这里，我们报道了肽的舌下免疫原性可以忽略不计，即使在舌下佐剂存在或聚乙二醇化时，但可以通过组装成具有低分子量PEG的超分子聚合物肽纳米纤维而显着增强，最佳在2000至3000 Da之间。聚乙二醇化和舌下佐剂都不能使肽在不组装成纳米纤维的情况下产生免疫原性。我们发现聚乙二醇减少了纳米纤维与粘蛋白的相互作用，并延长了在舌下免疫部位停留的时间。对缩短纳米纤维的平行研究表明，组装物的大小对舌下免疫原性的影响可以忽略不计。在小鼠实验中，优化后的配方能够提高强而持久的全身抗体反应、上呼吸道和生殖道抗体以及全身抗原特异性t细胞反应。这些基于纳米纤维的舌下疫苗对蛋白质和核苷酸佐剂都有效，并提高了对结核分枝杆菌模型肽表位和肽表位的反应。此外，PASylation（用富含Pro、Ala和Ser的肽序列修饰纳米纤维）也可以取代PEGylation来实现舌下免疫原性。这些发现表明，在调节舌下纳米材料的免疫原性方面，表面特性取代了纳米材料的大小，这对设计合成舌下疫苗具有重要意义。
Short peptides are poorly immunogenic when delivered sublingually - under the tongue. Nanomaterial delivery of peptides could be utilized to improve immunogenicity towards designed sublingual vaccines, but nanomaterials have not been widely successful in sublingual vaccines owing to the challenges of transport through the sublingual mucosa. Here, we report that the sublingual immunogenicity of peptides is negligible, even in the presence of sublingual adjuvants or when PEGylated, but can be dramatically enhanced by assembly into supramolecular polymer-peptide nanofibers bearing low-molecular weight PEG, optimally between 2000 and 3000 Da. Neither PEGylation nor a sublingual adjuvant were capable of rendering peptides immunogenic without assembly into nanofibers. We found that PEG decreased nanofiber interactions with mucin and promoted longer residence time at the sublingual immunization site. Parallel investigations with shortened nanofibers indicated that the size of the assemblies had a surprisingly negligible influence over sublingual immunogenicity. In mice, optimized formulations were capable of raising strong and highly durable systemic antibody responses, antibodies in the upper respiratory and reproductive tracts, and systemic antigen-specific T-cell responses. These nanofiber-based sublingual vaccines were effective with both protein and nucleotide adjuvants and raised responses against both a model peptide epitope and a peptide epitope from M. tuberculosis. Further, PASylation (modification of nanofibers with peptide sequences rich in Pro, Ala, and Ser) could be substituted for PEGylation to also achieve sublingual immunogenicity. These findings indicated that surface properties supersede nanomaterial size in modulating sublingual nanomaterial immunogenicity, having important implications for the design of synthetic sublingual vaccines.