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Optimizing the delivery of mRNA to mesenchymal stem cells for tissue engineering applications

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posted on 2024-04-29, 13:00 authored by Katie Mc CormickKatie Mc Cormick, Jorge Moreno Herrero, Heinrich Haas, Sarinj FattahSarinj Fattah, Andreas HeiseAndreas Heise, Fergal O'BrienFergal O'Brien, Sally-Ann CryanSally-Ann Cryan

Messenger RNA (mRNA) represents a promising therapeutic tool in the field of tissue engineering for the fast and transient production of growth factors to support new tissue regeneration. However, one of the main challenges to optimizing its use is achieving efficient uptake and delivery to mesenchymal stem cells (MSCs), which have been long reported as difficult-to-transfect. The aim of this study was to systematically screen a range of nonviral vectors to identify optimal transfection conditions for mRNA delivery to MSCs. Furthermore, for the first time, we wanted to directly compare the protein expression profile from three different types of mRNA, namely, unmodified mRNA (uRNA), base-modified mRNA (modRNA), and self-amplifying mRNA (saRNA) in MSCs. A range of polymer- and lipid-based vectors were used to encapsulate mRNA and directly compared in terms of physicochemical properties as well as transfection efficiency and cytotoxicity in MSCs. We found that both lipid- and polymer-based materials were able to successfully condense and encapsulate mRNA into nanosized particles (<200 nm). The overall charge and encapsulation efficiency of the nanoparticles was dependent on the vector type as well as the vector:mRNA ratio. When screened in vitro, lipid-based vectors proved to be superior in terms of mRNA delivery to MSCs cultured in a 2D monolayer and from a 3D collagen-based scaffold with minimal effects on cell viability, thus opening the potential for scaffold-based mRNA delivery. Modified mRNA consistently showed the highest levels of protein expression in MSCs, demonstrating 1.2-fold and 5.6-fold increases versus uRNA and saRNA, respectively. In summary, we have fully optimized the nonviral delivery of mRNA to MSCs, determined the importance of careful selection of the mRNA type used, and highlighted the strong potential of mRNA for tissue engineering applications.

Funding

Science Foundation Ireland (SFI) Centre for Advanced Materials and BioEngineering Research (AMBER) under grant code SFI12/RC/2278_P2

European Research Council under the European Community’s Horizon 2020 research and innovation program under ERC Advanced Grant agreement no. 788753 (ReCaP)

History

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The original article is available at https://pubs.acs.org/

Published Citation

McCormick K, et al. Optimizing the delivery of mRNA to mesenchymal stem cells for tissue engineering applications. Mol Pharm. 2024;21(4):1662-1676.

Publication Date

19 March 2024

PubMed ID

38504417

Department/Unit

  • Tissue Engineering Research Group (TERG)
  • Anatomy and Regenerative Medicine
  • School of Pharmacy and Biomolecular Sciences
  • Chemistry

Publisher

ACS Publications

Version

  • Published Version (Version of Record)

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