Engineering Receptors to Control Platelet Activation and Therapeutic Release

项目总结： 虽然使用活细胞作为治疗载体在最近几年已经成为一个突出的焦点领域 多年来，由于可用治疗负荷的限制，在实现临床翻译方面仍然存在挑战 方法以及缺乏可控的治疗释放机制。血小板提供了一个独特的传递平台 因为它们是无核细胞，自然地携带来自其巨核细胞前体细胞的蛋白质，并释放 一旦它们被激活，细胞内的内容就会被激活。我们已经证明，巨核细胞可以加载蛋白质， 被包装成血小板，创造出具有新型递送装置功能的工程血小板。然而，a 关键的挑战仍然是，血小板的天然激活途径可能导致活化和随后的 在不受欢迎的位置释放治疗有效载荷。因此，迫切需要一种可控的激活 在工程设计的血小板中触发，具体地说，是一种与天然激活途径垂直的触发。在这里，我们 设计了一组新的血小板受体，只有药理上不活泼的小分子才能激活 一种分子药物，能够控制释放由工程血小板携带的治疗有效载荷。

PROJECT SUMMARY: While the use of living cells as therapeutic delivery vehicles has become a prominent area of focus in recent years, challenges remain in achieving clinical translation due to limitations on available therapeutic loading methods as well as lack of controlled therapeutic release mechanisms. Platelets offer a unique delivery platform as they are anucleate cells naturally loaded with proteins from their megakaryocyte precursor cells, and release their intracellular contents once activated. We have shown that megakaryocytes can be loaded with proteins that are packaged into platelets, creating engineered platelets that function as novel delivery devices. However, a key challenge remains that the native activation pathway of platelets may cause the activation and subsequent release of therapeutic payloads in undesired locations. Thus, there is a critical need for a controllable activation trigger in engineered platelets, specifically, one that is orthogonal to the native activation pathway. Here, we engineered a set of novel platelet receptors that can be activated only by a pharmacologically inert small molecule drug to enable the controlled release of the therapeutic payload carried by engineered platelets.