Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
Blood. 2024 Nov 21;144(21):2223-2236. doi: 10.1182/blood.2024024405.
Platelets contribute to a variety of physiological processes, including inflammation, sepsis, and cancer. However, because of their primary role in hemostasis, platelet transfusions are largely restricted to managing thrombocytopenia and bleeding. One way to expand the utility of platelet transfusions would be to genetically engineer donor platelets with new or enhanced functions. We have previously shown that lipid nanoparticles containing mRNA (mRNA-LNP) can be used to genetically modify authentic platelets in a nonclinical crystalloid solution. Currently, platelets collected for transfusion are stored in plasma or in plasma supplemented with platelet additive solution (PAS) at supraphysiological concentrations at room temperature, or at 4°C if intended for use in acute hemorrhage. Here, we describe a new plasma-optimized mRNA-LNP for transfecting platelets directly in plasma and plasma supplemented with PAS that is scalable to physiological and supraphysiological platelet concentrations. Transfecting platelets in clinical solutions with mRNA-LNP does not affect aspects of in vitro physiology, and transfected platelets are storable. The compatibility of this transfection system with current clinical practices could enable future mRNA-LNP-based platelet products and cell therapies.
血小板参与多种生理过程，包括炎症、败血症和癌症。然而，由于其在止血中的主要作用，血小板输注主要限于治疗血小板减少症和出血。扩大血小板输注用途的一种方法是通过基因工程改造供体血小板以获得新的或增强的功能。我们之前已经表明，含有 mRNA 的脂质纳米颗粒（mRNA-LNP）可用于在非临床晶体溶液中对真实血小板进行基因修饰。目前，用于输注的血小板在室温下储存在血浆或含有血小板添加剂溶液（PAS）的血浆中，或在 4°C 下储存，如果用于急性出血。在这里，我们描述了一种新的血浆优化的 mRNA-LNP，可直接在血浆和添加 PAS 的血浆中转染血小板，可扩展到生理和超生理血小板浓度。用 mRNA-LNP 转染临床溶液中的血小板不会影响体外生理的各个方面，并且转染的血小板是可储存的。该转染系统与当前临床实践的兼容性可能使未来的基于 mRNA-LNP 的血小板产品和细胞疗法成为可能。
