Nanovaccines have attracted booming interests in vaccinology studies, but the profound impacts of their delivery mode on immune response remain unrealized. Herein, immunostimulatory CpG‐modified tumor‐derived nanovesicles (CNVs) are used as a nanovaccine testbed to initially evaluate the impacts of three distinct delivery modes, including mono‐pulse CNVs, staggered‐pulse CNVs, and gel‐confined CNVs. Fundamentally, delivery mode has enormous impacts on the immunomodulatory effects, altering the spatiotemporal distribution of nanovaccine residence and dendritic cell–T cell interaction in lymph nodes, and finally affecting subsequent T cell‐mediated immune performance. As a result, the gel‐confined delivery mode offers the best therapeutic performance in multiple tumor models. When extending evaluation to examine how the various delivery modes impact the performance of liposome‐based nanovaccines, similar trends in intralymph node distribution and antitumor effect are observed. This work provides a strong empirical foundation that nanovaccine researchers should position delivery mode near the top of their considerations for the experimental design, which should speed up nanovaccine development and facilitate efficient selection of appropriate delivery modes in the clinic.

中文翻译：

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纳米疫苗递送方式的选择对淋巴结内时空分布和免疫治疗功效产生深远影响

纳米疫苗已在疫苗学研究中引起了广泛的兴趣，但其递送方式对免疫应答的深远影响仍未实现。在本文中，将免疫刺激性CpG修饰的肿瘤衍生纳米囊泡（CNV）用作纳米疫苗试验台，初步评估了三种不同的递送方式的影响，包括单脉冲CNV，交错脉冲CNV和凝胶受限CNV。从根本上讲，递送方式对免疫调节作用有巨大影响，改变了纳米疫苗在淋巴结中的驻留和树突状细胞-T细胞相互作用的时空分布，并最终影响了随后的T细胞介导的免疫性能。结果，凝胶限制的递送模式在多种肿瘤模型中提供了最佳的治疗性能。当扩展评估以检查各种递送方式如何影响基于脂质体的纳米疫苗的性能时，观察到淋巴结内分布和抗肿瘤作用的相似趋势。这项工作提供了强大的经验基础，即纳米疫苗研究人员应将分娩方式置于实验设计考虑的首要位置，这应加快纳米疫苗的开发并促进临床中适当分娩方式的有效选择。