Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
J Am Chem Soc. 2023 Sep 13;145(36):19800-19811. doi: 10.1021/jacs.3c05574. Epub 2023 Sep 1.
A central goal of chemical and drug delivery sciences is to maximize the therapeutic efficacy of a given drug at the lowest possible dose. Here, we report a generalizable strategy that can be utilized to improve the delivery of mRNA drugs using lipid nanoparticles (LNPs), the clinically approved chemistry platforms utilized in the Moderna and Pfizer/BioNTech COVID-19 vaccines. In brief, our strategy updates the chemistry of LNPs to incorporate adenosine triphosphate (ATP) alongside mRNA, a modification that results in upward of a 79-fold increase in LNP-delivered mRNA-encoded protein expression and a 24-fold increase when compared to parent mRNA LNP formulations that do not contain ATP. Notably, we find that our ATP co-delivery strategy increases LNP-delivered mRNA-encoded protein expression across eight different LNP chemistries and three different cell lines, under normoxia and hypoxia, and in a well-tolerated fashion. Notably, our strategy also improves the expression of mRNA encoding for intracellular and secreted proteins both and , highlighting the utility of leveraging ATP co-delivery within mRNA LNPs as a means to increase protein expression. In developing this strategy, we hope that we have provided a simple yet powerful approach to improving mRNA LNPs that may one day be useful in developing therapies for human disease.
化学和药物输送科学的一个核心目标是在尽可能低的剂量下最大限度地提高给定药物的治疗效果。在这里，我们报告了一种可推广的策略，可用于使用脂质纳米颗粒（LNPs）改善 mRNA 药物的递送，LNPs 是现代和辉瑞/BioNTech COVID-19 疫苗中使用的临床批准的化学平台。简而言之，我们的策略更新了 LNPs 的化学性质，使其能够与 mRNA 一起结合三磷酸腺苷（ATP），这种修饰使 LNP 递送的 mRNA 编码蛋白表达增加了 79 倍以上，与不包含 ATP 的亲本 mRNA LNP 制剂相比增加了 24 倍。值得注意的是，我们发现我们的 ATP 共递送策略在常氧和缺氧条件下以及在可耐受的方式下，增加了八种不同的 LNPs 化学物质和三种不同的细胞系中 LNP 递送的 mRNA 编码蛋白的表达。值得注意的是，我们的策略还提高了细胞内和分泌蛋白编码的 mRNA 的表达，这突出了在 mRNA LNPs 中利用 ATP 共递送来增加蛋白表达的效用。在开发这种策略时，我们希望我们提供了一种简单而强大的方法来改进 mRNA LNPs，这些 LNPs 有朝一日可能有助于开发人类疾病的疗法。
