Genetically engineered transfusable platelets using mRNA lipid nanoparticles

Author:

Leung Jerry1234ORCID,Strong Colton123ORCID,Badior Katherine E.5ORCID,Robertson Madelaine1234ORCID,Wu Xiaowu6ORCID,Meledeo Michael A.6ORCID,Kang Emma37,Paul Manoj5,Sato Yusuke8ORCID,Harashima Hideyoshi8,Cap Andrew P.6ORCID,Devine Dana V.2379,Jan Eric2ORCID,Cullis Pieter R.24,Kastrup Christian J.123510ORCID

Affiliation:

1. Michael Smith Laboratories, University of British Columbia, Vancouver, V6T 1Z4, Canada.

2. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, V6T 1Z3, Canada.

3. Centre for Blood Research, University of British Columbia, Vancouver, V6T 1Z3, Canada.

4. NanoMedicines Research Group, University of British Columbia, Vancouver, V6T 1Z3, Canada.

5. Blood Research Institute, Versiti, Milwaukee,WI 53226, USA.

6. Blood and Shock Resuscitation Program, United States Army Institute of Surgical Research, JBSA-FT Sam Houston, San Antonio, TX 78234, USA.

7. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, V6T 2B5, Canada.

8. Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido, 060-0812, Japan.

9. Centre for Innovation, Canadian Blood Services, Vancouver, V6T 1Z3, Canada.

10. Departments of Surgery, Biochemistry, Biomedical Engineering, and Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Abstract

Platelet transfusions are essential for managing bleeding and hemostatic dysfunction and could be expanded as a cell therapy due to the multifunctional role of platelets in various diseases. Creating these cell therapies will require modifying transfusable donor platelets to express therapeutic proteins. However, there are currently no appropriate methods for genetically modifying platelets collected from blood donors. Here, we describe an approach using platelet-optimized lipid nanoparticles containing mRNA (mRNA-LNP) to enable exogenous protein expression in human and rat platelets. Within the library of mRNA-LNP tested, exogenous protein expression did not require nor correlate with platelet activation. Transfected platelets retained hemostatic function and accumulated in regions of vascular damage after transfusion into rats with hemorrhagic shock. We expect this technology will expand the therapeutic potential of platelets.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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