Despite tremendous efforts to develop stimuli-responsive enzyme delivery systems, their efficacy has been mostly limited to in vitro applications. Here we introduce, by using an approach of combining biomolecules with artificial compartments, a biomimetic strategy to create artificial organelles (AOs) as cellular implants, with endogenous stimuli-triggered enzymatic activity. AOs are produced by inserting protein gates in the membrane of polymersomes containing horseradish peroxidase enzymes selected as a model for natures own enzymes involved in the redox homoeostasis. The inserted protein gates are engineered by attaching molecular caps to genetically modified channel porins in order to induce redox-responsive control of the molecular flow through the membrane. AOs preserve their structure and are activated by intracellular glutathione levels in vitro. Importantly, our biomimetic AOs are functional in vivo in zebrafish embryos, which demonstrates the feasibility of using AOs as cellular implants in living organisms. This opens new perspectives for patient-oriented protein therapy.

中文翻译：

---

通过减少微环境触发具有体外和体内活性的仿生人工细胞器。


尽管在开发刺激响应酶递送系统方面付出了巨大努力，但其功效主要限于体外应用。在这里，我们介绍了一种仿生策略，通过使用生物分子与人工隔室相结合的方法，创建具有内源刺激触发酶活性的人工细胞器（AO）作为细胞植入物。 AO 是通过将蛋白质门插入含有辣根过氧化物酶的聚合物囊泡膜中而产生的，该酶被选为参与氧化还原稳态的天然酶的模型。插入的蛋白质门是通过将分子帽附着到基因修饰的通道孔蛋白上而设计的，以诱导对通过膜的分子流的氧化还原响应控制。 AO 保留其结构并在体外被细胞内谷胱甘肽水平激活。重要的是，我们的仿生 AO 在斑马鱼胚胎体内发挥功能，这证明了使用 AO 作为活体生物体细胞植入物的可行性。这为以患者为导向的蛋白质治疗开辟了新的前景。