Peeler David J, Yen Albert, Luera Nicholas, Stayton Patrick S, Pun Suzie H
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
Adv Ther (Weinh). 2021 Aug;4(8). doi: 10.1002/adtp.202100005. Epub 2021 Feb 22.
Endosomolytic vaccine nanocarriers can potentiate cellular immune responses by enhancing cross-presentation. We recently developed a cationic polymer-lytic peptide conjugate (VIPER) that greatly improves endosomal escape and intracellular activity of nucleic acid cargoes; furthermore, we hypothesize that VIPER's unique mechanism of endosomal disruption can increase cytoplasmic delivery of other biomacromolecules (e.g., peptides). Herein, we formulate VIPER as a polyplex subunit vaccine composed of conjugated peptide antigens and electrostatically complexed poly(I:C) nucleic acid adjuvant and evaluate whether the presence of the lytic peptide melittin conjugated to the pH-responsive micelle core improves vaccination outcomes. Although VIPER delivers peptide antigens intracellularly, disrupts endosomes in antigen-presenting cells (APCs) , and generates strong antigen-specific cytotoxic T cell responses , significantly enhanced cross-presentation is only observed in conjunction with VIPER-induced local cell death. While these results demonstrate that VIPER is a useful platform technology for the study of vaccine delivery, full elucidation of how endosomal disruption by VIPER improves vaccination outcomes will require decoupling of endosomolysis from cytotoxicity, as well as precise targeting of VIPER vaccine formulations to APC populations .
溶酶体裂解疫苗纳米载体可通过增强交叉呈递来增强细胞免疫反应。我们最近开发了一种阳离子聚合物-裂解肽共轭物（VIPER），它能极大地改善核酸货物的溶酶体逃逸和细胞内活性；此外，我们推测VIPER独特的溶酶体破坏机制可增加其他生物大分子（如肽）的细胞质递送。在此，我们将VIPER制备成一种多聚体亚单位疫苗，该疫苗由共轭肽抗原和静电复合的聚（I:C）核酸佐剂组成，并评估与pH响应性胶束核心共轭的裂解肽蜂毒肽的存在是否能改善疫苗接种效果。尽管VIPER能将肽抗原递送至细胞内，破坏抗原呈递细胞（APC）中的溶酶体，并产生强烈的抗原特异性细胞毒性T细胞反应，但仅在VIPER诱导局部细胞死亡时才观察到显著增强的交叉呈递。虽然这些结果表明VIPER是一种用于疫苗递送研究的有用平台技术，但要全面阐明VIPER的溶酶体破坏如何改善疫苗接种效果，需要将溶酶体解聚与细胞毒性分离，以及将VIPER疫苗制剂精确靶向APC群体。
