Codiak BioSciences, Cambridge, MA 02140, USA.
Codiak BioSciences, Cambridge, MA 02140, USA.
Mol Ther. 2021 May 5;29(5):1729-1743. doi: 10.1016/j.ymthe.2021.01.020. Epub 2021 Jan 21.
Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo tethered to the EV surface or packaged inside the lumen are key strategies for generating therapeutic EVs. We identified two "scaffold" proteins, PTGFRN and BASP1, that are preferentially sorted into EVs and enable high-density surface display and luminal loading of a wide range of molecules, including cytokines, antibody fragments, RNA binding proteins, vaccine antigens, Cas9, and members of the TNF superfamily. Molecules were loaded into EVs at high density and exhibited potent in vitro activity when fused to full-length or truncated forms of PTGFRN or BASP1. Furthermore, these engineered EVs retained pharmacodynamic activity in a variety of animal models. This engineering platform provides a simple approach to functionalize EVs with topologically diverse macromolecules and represents a significant advance toward unlocking the therapeutic potential of EVs.
细胞外囊泡（EVs）是一种重要的细胞间通讯系统，促进细胞间大分子的转移。将连接到 EV 表面的外源性货物或包裹在腔室内的货物递送至 EV 是产生治疗性 EV 的关键策略。我们鉴定了两种“支架”蛋白，PTGFRN 和 BASP1，它们优先分选到 EV 中，并能够高密度地表征和腔室内装载各种分子，包括细胞因子、抗体片段、RNA 结合蛋白、疫苗抗原、Cas9 和 TNF 超家族成员。当融合到全长或截断形式的 PTGFRN 或 BASP1 时，分子以高浓度装载到 EV 中，并表现出强大的体外活性。此外，这些工程化的 EV 在多种动物模型中保留了药效学活性。该工程平台为用拓扑多样化的大分子功能化 EV 提供了一种简单的方法，代表着朝着解锁 EV 的治疗潜力迈出了重要一步。
