Kim Yoo C, Hsueh Henry T, Kim Namho, Rodriguez Jason, Leo Kirby T, Rao Divya, West Natalie E, Hanes Justin, Suk Jung Soo
Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231.
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231.
Adv Ther (Weinh). 2021 Feb;4(2). doi: 10.1002/adtp.202000228. Epub 2021 Feb 24.
We here introduce a new paradigm to promote pulmonary DNA vaccination. Specifically, we demonstrate that nanoparticles designed to rapidly penetrate airway mucus (mucus-penetrating particle or MPP) enhance the delivery of inhaled model DNA vaccine (i.e. ovalbumin-expressing plasmids) to pulmonary dendritic cells (DC), leading to robust and durable local and trans-mucosal immunity. In contrast, mucus-impermeable particles were poorly taken up by pulmonary DC following inhalation, despite their superior ability to mediate DC uptake compared to MPP. In addition to the enhanced immunity achieved in mucosal surfaces, inhaled MPP unexpectedly provided significantly greater systemic immune responses compared to gold-standard approaches applied in the clinic for systemic vaccination, including intradermal injection and intramuscular electroporation. We also showed here that inhaled MPP significantly enhanced the survival of an orthotopic mouse model of aggressive lung cancer compared to the gold-standard approaches. Importantly, we discovered that MPP-mediated pulmonary DNA vaccination induced memory T-cell immunity, particularly the ready-to-act effector memory-biased phenotype, both locally and systemically. The findings here underscore the importance of breaching the airway mucus barrier to facilitate DNA vaccine uptake by pulmonary DC and thus to initiate full-blown immune responses.
在此，我们引入一种促进肺部DNA疫苗接种的新范式。具体而言，我们证明了设计用于快速穿透气道黏液的纳米颗粒（黏液穿透颗粒或MPP）可增强吸入型模型DNA疫苗（即表达卵清蛋白的质粒）向肺部树突状细胞（DC）的递送，从而引发强大且持久的局部和跨黏膜免疫。相比之下，尽管与MPP相比，黏液不可渗透颗粒介导DC摄取的能力更强，但吸入后肺部DC对其摄取能力较差。除了在黏膜表面实现增强免疫外，与临床上用于全身疫苗接种的金标准方法（包括皮内注射和肌肉电穿孔）相比，吸入MPP意外地产生了显著更强的全身免疫反应。我们还在此表明，与金标准方法相比，吸入MPP显著提高了侵袭性肺癌原位小鼠模型的存活率。重要的是，我们发现MPP介导的肺部DNA疫苗接种在局部和全身均诱导了记忆性T细胞免疫，尤其是偏向于随时发挥作用的效应记忆表型。此处的研究结果强调了突破气道黏液屏障以促进肺部DC摄取DNA疫苗从而引发全面免疫反应的重要性。
