Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Nat Commun. 2024 Nov 2;15(1):9471. doi: 10.1038/s41467-024-53914-x.
Inhaled delivery of messenger RNA (mRNA) using lipid nanoparticle (LNP) holds immense promise for treating pulmonary diseases or serving as a mucosal vaccine. However, the unsatisfactory delivery efficacy caused by the disintegration and aggregation of LNP during nebulization represents a major obstacle. To address this, we develop a charge-assisted stabilization (CAS) strategy aimed at inducing electrostatic repulsions among LNPs to enhance their colloidal stability. By optimizing the surface charges using a peptide-lipid conjugate, the leading CAS-LNP demonstrates exceptional stability during nebulization, resulting in efficient pulmonary mRNA delivery in mouse, dog, and pig. Inhaled CAS-LNP primarily transfect dendritic cells, triggering robust mucosal and systemic immune responses. We demonstrate the efficacy of inhaled CAS-LNP as a vaccine for SARS-CoV-2 Omicron variant and as a cancer vaccine to inhibit lung metastasis. Our findings illustrate the design principles of nebulized LNPs, paving the way of developing inhaled mRNA vaccines and therapeutics.
利用脂质纳米颗粒（LNP）吸入传递信使 RNA（mRNA）为治疗肺部疾病或作为黏膜疫苗提供了巨大的潜力。然而，在雾化过程中 LNP 的崩解和聚集导致的递送效果不理想，这是一个主要的障碍。为了解决这个问题，我们开发了一种电荷辅助稳定（CAS）策略，旨在诱导 LNP 之间的静电排斥，以增强其胶体稳定性。通过使用肽脂质缀合物优化表面电荷，领先的 CAS-LNP 在雾化过程中表现出优异的稳定性，从而在小鼠、狗和猪中实现了有效的肺部 mRNA 递送。吸入的 CAS-LNP 主要转染树突状细胞，引发强烈的黏膜和全身免疫反应。我们证明了吸入的 CAS-LNP 作为 SARS-CoV-2 奥密克戎变体疫苗和癌症疫苗抑制肺转移的功效。我们的研究结果说明了雾化 LNP 的设计原则，为开发吸入 mRNA 疫苗和治疗剂铺平了道路。
