David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Adv Healthc Mater. 2024 Nov;13(29):e2400509. doi: 10.1002/adhm.202400509. Epub 2024 Oct 1.
Despite great promise, application of mRNA therapeutics in the lung has proven challenging. Many groups have reported success instilling liquid mRNA formulations in animal models, but direct intratracheal administration of large liquid quantities to the human lung presents significant safety and distribution concerns. To accomplish safe and effective mRNA delivery to the lung, formulations must be prepared for dosing via inhalation. An inhaled mRNA delivery system for the lung must be both robust enough to survive inhalation conditions and potent enough to deliver mRNA upon reaching the lung. In this work dry powder lipid nanoparticle formulations are developed, using spray-freeze-drying, to produce stable, biologically active, inhalable dry powders for mRNA delivery. The final powders have suitable aerosolization properties, with mean mass aerodynamic diameter (MMAD) of 3-4 microns, and fine particle fraction (FPF) ≈40%, allowing for efficient mRNA delivery to the deep lung following inhalation. Importantly, the formulations developed here are suitable for use with different ionizable lipids. Four different ionizable lipid-based formulations are evaluated as powders, and all exhibit in vivo pulmonary mRNA delivery equal to that of instilled liquid formulations. These results lay promising groundwork for the eventual development of an inhalable mRNA dry powder therapeutic.
尽管前景广阔，但将 mRNA 疗法应用于肺部已被证明具有挑战性。许多研究小组已经成功地将液体 mRNA 制剂注入动物模型中，但直接向人体肺部注入大量液体的气管内给药方式存在显著的安全性和分布问题。为了实现 mRNA 向肺部的安全有效递药，制剂必须为吸入途径给药而准备。用于肺部的吸入性 mRNA 递药系统必须足够坚固以在吸入条件下存活，并且足够有效以在到达肺部时递送 mRNA。在这项工作中，采用喷雾冷冻干燥法开发了干脂质纳米粒制剂，以生产稳定、具有生物活性的可吸入干粉末用于 mRNA 递药。最终的粉末具有合适的气溶胶化特性，平均质量空气动力学直径（MMAD）为 3-4 微米，细颗粒分数（FPF）≈40%，允许吸入后高效递送至肺部深处。重要的是，这里开发的制剂适用于不同的可离子化脂质。四种不同的基于可离子化脂质的制剂作为粉末进行评估，所有制剂均表现出与注入的液体制剂相当的体内肺部 mRNA 递药效果。这些结果为可吸入性 mRNA 干粉治疗剂的最终开发奠定了有希望的基础。
