A Unified Strategy to Improve Lipid Nanoparticle Mediated mRNA Delivery Using Adenosine Triphosphate.
A Unified Strategy to Improve Lipid Nanoparticle Mediated mRNA Delivery Using Adenosine Triphosphate.
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使用三磷酸腺苷改善脂质纳米颗粒介导的 mRNA 递送的统一策略。
DOI：
10.1021/jacs.3c05574
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发表时间：
2023
影响因子：
15
通讯作者：
Fenton,OwenS
中科院分区：
文献类型：
--
作者：
Ma,Yutian;Fenton,OwenS
化学和药物输送科学的中心目标是以尽可能低的剂量最大化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（LNP）改善 mRNA 药物的递送，LNP 是 Moderna 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 LNP 的化学成分，将三磷酸腺苷 (ATP) 与 mRNA 结合在一起，与不含 ATP 的母体 mRNA LNP 制剂相比，这种修饰导致 LNP 递送的 mRNA 编码蛋白表达在体外增加 79 倍，在体内增加 24 倍。值得注意的是，我们发现，在常氧和缺氧条件下，我们的 ATP 共同递送策略以良好的耐受性，增加了八种不同 LNP 化学物质和三种不同细胞系中 LNP 递送的 mRNA 编码蛋白的表达。值得注意的是，我们的策略还改善了体外和体内编码细胞内和分泌蛋白的 mRNA 表达，突出了利用 mRNA LNP 内的 ATP 共传递作为增加蛋白表达的手段的效用。在开发这一策略的过程中，我们希望能够提供一种简单而强大的方法来改进 mRNA LNP，有一天可能会有助于开发人类疾病的疗法。
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 expressionin vitroand a 24-fold increasein vivowhen 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 bothin vitroandin vivo, 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.