I-Corps: Thermostable liquid formulations of mRNAs and mRNA lipid nano-particles pharmaceuticals

I-Corps项目的更广泛影响/商业潜力是开发用于安全储存和运输的RNA配方技术。在不需要超低温的情况下运输和储存基于mRNA的药物的能力可能会大大降低mRNA药物和疫苗的分销成本。此外，消除对超冷冻和冻干的要求将大大提高mRNA药物的部署能力和速度，以及它们在偏远地区的可及性。最后，新mRNA配方具有优异的热稳定性，可以减少由于运输和储存过程中意外暴露于高温而造成的药物/疫苗浪费。这个I-Corps项目是基于两种制备mRNA和mRNA-脂质纳米颗粒（LNPs）的热稳定液体配方的方法的发展。第一种方法是制备含有mRNA缩合物诱导的非离子聚合物和盐的乳液。第二种方法是使用带拥挤剂的酸性缓冲液稳定mRNA-LNPs。COVID-19 mRNA疫苗的成功表明了这种药物模式的优势，包括快速开发、高效、高安全性和易于制造（与细胞培养生产相比）。然而，由于mRNA的内在不稳定性，COVID-19 mRNA疫苗的部署遇到了重大的后勤挑战。mrna在水溶液中快速降解，需要冷冻或冻干（冷冻干燥）运输和储存。对超冷链或冻干设施的要求不仅限制了mRNA药物的部署速度和可及性，而且增加了分销过程中的成本和浪费。使用所提出的技术，mRNA或mRNA- lnp溶液可以在室温或冷藏下保存数月而无需冷冻或冻干。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project is the development of an RNA formulation technology for safe storage and transport. The ability to transport and store mRNA-based pharmaceuticals without ultra-cold requirements may significantly lower the costs of distribution of mRNA drugs and vaccines. Also, elimination of the requirements for ultra-freezer and lyophilization will greatly increase the capacity and speed of deployment of mRNA pharmaceuticals as well as their accessibility to remote areas. Finally, the superior thermostability of the new mRNA formulations may reduce the wastage of drugs/vaccines caused by unexpected exposure to elevated temperature during transportation and storage.This I-Corps project is based on the development of two methods for preparing thermostable liquid formulations of mRNA and mRNA-Lipid Nano-Particles (LNPs), respectively. The first method is to prepare an emulsion containing mRNA condensate-induced non-ionic polymers and salts. The second method is to stabilize mRNA-LNPs using acidic buffers with crowding agents. The success of the COVID-19 mRNA vaccines showed the advantages of this pharmaceutical modality including rapid development, high efficacy, high safety, and ease of manufacturing (as compared to cell culture production). However, deployment of the COVID-19 mRNA vaccines has been met with major logistic challenges due to the intrinsic instability of mRNA. mRNAs undergo fast degradation in aqueous solutions and require freezing or lyophilization (freeze-drying) for transportation and storage. The requirements for ultra-cold chain or lyophilization facilities not only limit the speed of deployment and accessibility of mRNA pharmaceuticals, but also increase the costs and wastage during the distribution process. Using the proposed technologies, mRNA or mRNA-LNP solutions may be able to be stored at room temperature or under refrigeration for months without freezing or lyophilization.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.