Nonviral mRNA delivery is an attractive therapeutic gene delivery strategy, as it achieves efficient protein overexpression in vivo and has a desirable safety profile. However, mRNA’s short cytoplasmic half-life limits its utility to therapeutic applications amenable to repeated dosing or short-term overexpression. Here, we describe a biomaterial that enables a durable in vivo response to a single mRNA dose via an “overexpress and sequester” mechanism, whereby mRNA-transfected cells locally overexpress a growth factor that is then sequestered within the biomaterial to sustain the biologic response over time. In a murine diabetic wound model, this strategy demonstrated improved wound healing compared to delivery of a single mRNA dose alone or recombinant protein. In addition, codelivery of anti-inflammatory proteins using this biomaterial eliminated the need for mRNA chemical modification for in vivo therapeutic efficacy. The results support an approach that may be broadly applicable for single-dose delivery of mRNA without chemical modification.

非病毒 mRNA 递送是一种有吸引力的治疗性基因递送策略，因为它可以在体内实现有效的蛋白质过度表达，并且具有理想的安全性。然而，mRNA 的短细胞质半衰期限制了其在重复给药或短期过度表达的治疗应用中的实用性。在这里，我们描述了一种生物材料，它能够通过“过度表达和隔离”机制对单次 mRNA 剂量产生持久的体内反应，其中 mRNA 转染的细胞局部过度表达生长因子，然后将生长因子隔离在生物材料内，以维持生物反应时间。在小鼠糖尿病伤口模型中，与单独递送单一 mRNA 剂量或重组蛋白相比，该策略显示出改善的伤口愈合。此外，使用这种生物材料共同递送抗炎蛋白消除了为了体内治疗功效而对 mRNA 进行化学修饰的需要。结果支持了一种可能广泛适用于无需化学修饰的单剂量递送 mRNA 的方法。