纳米复合肺靶向递送突破Ad5预存免疫屏障

杨益隆, 吴诗坡, 王玉东, 邵方泽, 吕鹏, 李汭桦, 赵晓帆, 张军, 张晓鹏, 李建民, 侯利华, 徐俊杰, 陈薇

工程（英文） ›› 2023, Vol. 27 ›› Issue (8) : 127-139.

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工程（英文） ›› 2023, Vol. 27 ›› Issue (8) : 127-139. DOI: 10.1016/j.eng.2022.12.007
研究论文
Article

纳米复合肺靶向递送突破Ad5预存免疫屏障

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Lung-Targeted Transgene Expression of Nanocomplexed Ad5 Enhances Immune Response in the Presence of Preexisting Immunity

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摘要

重组5型腺病毒载体（Ad5）已成功用于埃博拉病毒、新型肺炎冠状病毒等新发突发传染病防控，然而针对病毒载体的预存免疫会对疫苗的免疫原性造成一定影响。维持重组Ad5型疫苗的高免疫原性并减少预存免疫效应，已成为该领域的重要研究方向。基于生物相容性纳米颗粒，本研究尝试通过调控Ad5与宿主的相互作用应对上述挑战。制备出的正电人血清白蛋白纳米颗粒[(+)HSAnp]能够与Ad5自组装形成复合物，针对柯萨奇病毒-腺病毒受体（CAR）阳性和阴性细胞均能显著提高靶基因表达量。在小鼠模型中，滴鼻吸入Ad5/(+)HSAnp复合物实现了高效（高达227倍）和长期（长达60天）的肺靶向靶基因表达，且增强效应可通过表面电位和给药剂量进行调控。经纳米复合的5型腺病毒载体埃博拉疫苗和新冠疫苗，在Ad5预存免疫模型中显著增强了体液免疫和黏膜免疫应答。本研究表明通过纳米颗粒调控病毒载体的聚集状态和表面电位，能够用于设计增强型的疫苗和基因治疗载体。

Abstract

Recombinant adenovirus serotype 5 (Ad5) vector has been widely applied in vaccine development targeting infectious diseases, such as Ebola virus disease and coronavirus disease 2019 (COVID-19). However, the high prevalence of preexisting anti-vector immunity compromises the immunogenicity of Ad5-based vaccines. Thus, there is a substantial unmet need to minimize preexisting immunity while improving the insert-induced immunity of Ad5 vectors. Herein, we address this need by utilizing biocompatible nanoparticles to modulate Ad5-host interactions. We show that positively charged human serum albumin nanoparticles ((+)HSAnp), which are capable of forming a complex with Ad5, significantly increase the transgene expression of Ad5 in both coxsackievirus-adenovirus receptor-positive and -negative cells. Furthermore, in charge- and dose-dependent manners, Ad5/(+)HSAnp complexes achieve robust (up to 227-fold higher) and long-term (up to 60 days) transgene expression in the lungs of mice following intranasal instillation. Importantly, in the presence of preexisting anti-Ad5 immunity, complexed Ad5-based Ebola and COVID-19 vaccines significantly enhance antigen-specific humoral response and mucosal immunity. These findings suggest that viral aggregation and charge modification could be leveraged to engineer enhanced viral vectors for vaccines and gene therapies.

关键词

5型腺病毒 / 疫苗 / 预存免疫 / 纳米颗粒 / 靶基因表达

Keywords

Adenovirus serotype 5 / Vaccine / Preexisting immunity / Nanoparticles / Transgene expression

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杨益隆, 吴诗坡, 王玉东. 纳米复合肺靶向递送突破Ad5预存免疫屏障. Engineering. 2023, 27(8): 127-139 https://doi.org/10.1016/j.eng.2022.12.007

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