Toward understanding lipid reorganization in RNA lipid nanoparticles in acidic environments

• 成果类型: Article
• 署名作者: Garaizar, Adiran; Diaz- Oviedo, David; Zablowsky, Nina; Rissanen, Sami; Koebberling, Johannes; Sun, Jiawei; Steiger, Christoph; Steigemann, Patrick; Mann, Florian A.; Meier, Katharina
• 署名单位: Bayer AG; Bayer Healthcare Pharmaceuticals; Bayer AG; Bayer CropScience; Bayer AG; Bayer Healthcare Pharmaceuticals
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12047
• DOI: 10.1073/pnas.2404555121/-/DCSupplemental
• 发表日期: 2024-11-05
• 关键词: force-field; sirna; delivery; systems; surface

摘要

The use of lipid nanoparticles (LNPs) for therapeutic RNA delivery has gained significant interest, particularly highlighted by recent milestones such as the approval of Onpattro and two mRNA-based SARS-CoV-2 vaccines. However, despite substantial advancements in this field, our understanding of the structure and internal organization of RNA-LNPs -and their relationship to efficacy, both in vitro and in vivo- remains limited. In this study, we present a coarse- grained molecular dynamics (MD) approach that allows for the simulations of full- size LNPs. By analyzing MD- derived structural characteristics in conjunction with cellular experiments, we investigate the effect of critical parameters, such as pH and composition, on LNP structure and potency. Additionally, we examine the mobility and chemical environment within LNPs at a molecular level. Our findings highlight the significant impact that LNP composition and internal molecular mobility can have on key stages of LNP-based intracellular RNA delivery.