Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination.

IF 2.3 1区数学 Q1 MATHEMATICS Duke Mathematical Journal Pub Date : 2022-03-23 DOI:10.1101/2022.03.22.485401

Alexandra Suberi, Molly K Grun, Tianyang Mao, Benjamin Israelow, Melanie Reschke, Julian Grundler, Laiba Akhtar, Teresa Lee, Kwangsoo Shin, Alexandra S Piotrowski-Daspit, Robert J Homer, Akiko Iwasaki, Hee Won Suh, W Mark Saltzman

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Abstract

An inhalable platform for mRNA therapeutics would enable minimally invasive and lung targeted delivery for a host of pulmonary diseases. Development of lung targeted mRNA therapeutics has been limited by poor transfection efficiency and risk of vehicle-induced pathology. Here we report an inhalable polymer-based vehicle for delivery of therapeutic mRNAs to the lung. We optimized biodegradable poly(amine-co-ester) polyplexes for mRNA delivery using end group modifications and polyethylene glycol. Our polyplexes achieved high transfection of mRNA throughout the lung, particularly in epithelial and antigen-presenting cells. We applied this technology to develop a mucosal vaccine for SARS-CoV-2. Intranasal vaccination with spike protein mRNA polyplexes induced potent cellular and humoral adaptive immunity and protected K18-hACE2 mice from lethal viral challenge.

One-sentence summary: Inhaled polymer nanoparticles (NPs) achieve high mRNA expression in the lung and induce protective immunity against SARS-CoV-2.

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可吸入的聚合物纳米颗粒用于通用mRNA传递和粘膜疫苗接种。

mRNA治疗的可吸入平台将使多种肺部疾病的微创和肺靶向递送成为可能。肺靶向mRNA治疗的发展一直受到转染效率低和载体诱导病理风险的限制。在这里，我们报告了一种可吸入的基于聚合物的载体，用于将治疗性mrna递送到肺部。我们利用端基修饰和聚乙二醇优化了可生物降解的聚(胺-共酯)多聚物用于mRNA传递。我们的复合物在整个肺中实现了mRNA的高转染，特别是在上皮细胞和抗原提呈细胞中。我们将该技术应用于SARS-CoV-2的粘膜疫苗的开发。鼻内接种刺突蛋白mRNA复合物可诱导有效的细胞和体液适应性免疫，并保护K18-hACE2小鼠免受致命病毒的攻击。一句话总结:吸入的聚合物纳米颗粒(NPs)在肺部实现mRNA的高表达，并诱导对SARS-CoV-2的保护性免疫。

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