Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA.
Nat Mater. 2023 Mar;22(3):369-379. doi: 10.1038/s41563-022-01404-0. Epub 2022 Nov 28.
Messenger RNA has now been used to vaccinate millions of people. However, the diversity of pulmonary pathologies, including infections, genetic disorders, asthma and others, reveals the lung as an important organ to directly target for future RNA therapeutics and preventatives. Here we report the screening of 166 polymeric nanoparticle formulations for functional delivery to the lungs, obtained from a combinatorial synthesis approach combined with a low-dead-volume nose-only inhalation system for mice. We identify P76, a poly-β-amino-thio-ester polymer, that exhibits increased expression over formulations lacking the thiol component, delivery to different animal species with varying RNA cargos and low toxicity. P76 allows for dose sparing when delivering an mRNA-expressed Cas13a-mediated treatment in a SARS-CoV-2 challenge model, resulting in similar efficacy to a 20-fold higher dose of a neutralizing antibody. Overall, the combinatorial synthesis approach allowed for the discovery of promising polymeric formulations for future RNA pharmaceutical development for the lungs.
信使 RNA 现已被用于为数百万人接种疫苗。然而，肺部病理学的多样性，包括感染、遗传疾病、哮喘等，表明肺部是一个重要的器官，可以直接作为未来 RNA 治疗和预防药物的靶点。在这里，我们报告了对 166 种聚合物纳米颗粒制剂进行的筛选，这些制剂是通过组合合成方法与用于小鼠的低死体积鼻内吸入系统相结合获得的，用于向肺部进行功能性传递。我们鉴定出 P76，一种聚β-氨基硫代酯聚合物，其表达水平高于缺乏巯基成分的制剂，能够将不同的 RNA cargos 递送到不同的动物物种，且毒性较低。在 SARS-CoV-2 挑战模型中，P76 用于递送由 mRNA 表达的 Cas13a 介导的治疗时，可以节省剂量，其效果与高 20 倍的中和抗体剂量相当。总的来说，组合合成方法为未来肺部 RNA 药物开发发现了有前途的聚合物制剂。
