Genetically engineered transfusable platelets using mRNA lipid nanoparticles

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.

Engineering unactivated platelets for targeted drug delivery

“…Leung et al transfected mRNA into platelets via lipid nanoparticles to express exogenous proteins without affecting the normal functional activity of platelets. 34 Genetic engineering has found widespread application in various cell therapies, including CAR-T and stem cell therapies. Due to the absence of nuclei in platelets, genetic modifications must target platelet precursor cells, including megakaryocytes, progenitor cells, or hematopoietic stem cells, 69 to obtain functional platelets suitable for clinical in vitro applications.…”

Lipid Nanoparticle (LNP) Delivery Carrier-Assisted Targeted Controlled Release mRNA Vaccines in Tumor Immunity

“…As carriers of mRNA vaccines, LNPs show great potential in tumor immunotherapy, but they still face a series of challenges and development directions [ 200 , 201 , 202 , 203 , 204 , 205 ]. The future development trend of LNP carriers in tumor immunotherapy may see a focus on improving their delivery efficiency and accuracy [ 206 , 207 , 208 , 209 , 210 ]. This would include further improving the design of LNPs and optimizing their distribution and stability in vivo in order to improve the delivery efficiency and antitumor effect of mRNA vaccines [ 211 ].…”