Antigen-display exosomes provide adjuvant-free protection against SARS-CoV-2 disease at nanogram levels of spike protein.
Antigen-display exosomes provide adjuvant-free protection against SARS-CoV-2 disease at nanogram levels of spike protein.
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抗原展示外泌体以纳克水平的刺突蛋白提供针对 SARS-CoV-2 疾病的无佐剂保护。
DOI：
10.1101/2024.01.04.574272
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Gould,StephenJ
中科院分区：
文献类型：
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作者：
Guo,Chenxu;Sachithanandham,Jaiprasath;Zhong,William;Craney,Morgan;Villano,Jason;Pekosz,Andrew;Gould,StephenJ
作为唯一的生物正常纳米囊泡，外泌体作为递送疫苗和治疗药物的纳米囊泡具有很高的潜力。我们在这里表明，1型膜蛋白装载到外泌体膜是由外泌体膜锚定结构域（emad）诱导的，该结构域最大限度地将蛋白质递送到质膜，最大限度地减少蛋白质分选到其他区室，并将蛋白质引导到外泌体膜。以SARS-CoV-2刺突为例，以EMAD13作为最有效的外泌体膜锚点，研究人员发现，表达刺突-EMAD13融合蛋白的细胞产生的外泌体在50%的外泌体上携带密集的刺突三聚体阵列。此外，我们发现用spike- emad13外泌体免疫可以诱导强烈的中和抗体反应，并在不含佐剂的情况下，仅0.5 - 5ng刺突蛋白剂量下保护仓鼠免受SARS-CoV-2疾病的侵袭，这表明抗原展示外泌体具有特别的免疫原性，这对结构和表达依赖性疫苗都具有重要意义。
As the only bionormal nanovesicle, exosomes have high potential as a nanovesicle for delivering vaccines and therapeutics. We show here that the loading of type-1 membrane proteins into the exosome membrane is induced by exosome membrane anchor domains, EMADs, that maximize protein delivery to the plasma membrane, minimize protein sorting to other compartments, and direct proteins into exosome membranes. Using SARS-CoV-2 spike as an example and EMAD13 as our most effective exosome membrane anchor, we show that cells expressing a spike-EMAD13 fusion protein produced exosomes that carry dense arrays of spike trimers on 50% of all exosomes. Moreover, we find that immunization with spike-EMAD13 exosomes induced strong neutralizing antibody responses and protected hamsters against SARS-CoV-2 disease at doses of just 0.5–5 ng of spike protein, without adjuvant, demonstrating that antigen-display exosomes are particularly immunogenic, with important implications for both structural and expression-dependent vaccines.