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：

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仿生人工细胞器具有通过微环境减少触发的体外和体内活性。

尽管开发了刺激响应性酶递送系统付出了巨大的努力，但它们的功效主要限于体外应用。在这里，我们通过使用将生物分子与人工区室相结合的方法，介绍一种仿生策略，以创建具有细胞内植入物，具有内源性刺激触发的酶活性的人工细胞器（AOs）。通过将蛋白质门插入含有辣根过氧化物酶的聚合物囊泡的膜中来产生AO，而所述辣根过氧化物酶被选作参与氧化还原同源性的自然界自身酶的模型。通过将分子帽连接到基因修饰的通道孔蛋白上来工程化插入的蛋白门，以诱导对通过膜的分子流的氧化还原响应控制。AO保持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在斑马鱼胚胎中具有体内功能，这证明了将AO用作活生物体中细胞植入物的可行性。这为面向患者的蛋白质治疗开辟了新的前景。