Engineering Receptors to Control Platelet Activation and Therapeutic Release

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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.