Engineering platelets for therapeutic applications - PROPOSAL SUMMARY/ABSTRACT Scientists have uncovered the active role of platelets in the pathophysiology of cancer, rheumatoid arthritis, Alzheimer's disease, multiple sclerosis, and infections, in addition to their vital roles in hemostasis and cardiovascular diseases. Harnessing the multifaceted biological functions of platelets to develop novel therapies and treatment strategies for different diseases is an exciting yet challenging task. This is because, to develop platelet-based therapies, therapeutic agents (e.g., small molecular drugs or biologics) generally need to be integrated with platelets and delivered to the desired locations. On one hand, platelets are highly promising in achieving these tasks, considering their capacities in packing and secreting molecules, communicating with and modulating other cells, and targeting and homing toward injured or diseased tissues. However, on the other hand, platelets are difficult to engineer because of their anucleate nature, dynamic and multifunctional states, and poorly understood endocytic mechanisms. There is thus a pressing need in finding safe and effective strategies for platelet engineering to unleash their therapeutic potential. In the next five years, our group aims to (i) perform fundamental studies to understand how platelets interact with and internalize different synthetic materials and (ii) develop materials-based tools for engineering platelets through either intra-platelet gene delivery or surface modifications. Our approach emphasizes engineering polymers through architectural control. We will evaluate how polymers with different architectures enter and deliver genes into platelets and identify the most efficient pathways for the genetic modification of platelets using polymeric vectors. Also, as a proof-of-concept, we will investigate to what extent the dynamic topology of polyrotaxanes can facilitate efficient, stress-free surface binding toward resting platelets, given polyrotaxanes' self-adjustability in orientation and distance of the carried binding ligands. The MIRA award is essential for our lab to answer these questions through interdisciplinary approaches and train students from diverse backgrounds. We envision that long-term research in this field will generate fundamental insights into the platelet- biomaterials interactions and create new strategies in platelet engineering, leading new platelet therapies for various disease indications.
