FMSG: Bio: Microbial Foundry for Distributed Manufacturing of mRNA-Containing Biomaterials

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This proposal will develop new microbrewery-like distributed manufacturing strategies for biomaterials containing messenger RNA or mRNA. There is a critical need for reliable manufacturing, storage, and distribution of mRNA-containing materials. For example, the current worldwide shortage of mRNA vaccines for COVID-19 is caused not only by a need for a cold chain, but also by centralized manufacturing and distribution. Since mRNA is fragile, it often requires lipid nanoparticle protection and can only be preserved at ultralow temperatures. In this context, DNA origami, a self-assembly method that relies on oligonucleotide sequence complementarity, can be developed into thermally stable drug carriers with the potential to carry mRNA. In this project, the investigators will use yeast to produce large volumes of mRNA and oligo DNA sequences with accuracy and scalability. The resulting single-stranded DNA will self-assemble into origami nanostructures based on in silico designs, which will cage a targeted mRNA that is natively made with all needed chemical modifications. The DNA origami cage will allow for the purification and harvest of mRNA. The DNA architectures will be programmed for on-demand mRNA release and 3D printed into a hydrogel formulation for stable storage and administration. The proposed research will also be complemented by an educational and workforce development program. The proposed activities will develop hands-on and accompanied instruction-based learning contents to prepare the future workforce for biomanufacturing sectors. The central goal of the research is to create a transformative biomanufacturing platform, where organisms such as Saccharomyces cerevisiae or S. cerevisiae are programmed to produce industrial-scale, custom-designed nucleic acids needed for DNA-caged mRNA biomaterials at decentralized locations. The research objectives include: (1) a mechanistic understanding of microbial processes to establish a scalable foundry for mRNA and oligonucleotide DNA; (2) the development of general principles for programmable environmentally responsive DNA origami cages; (3) streamlined manufacturing processes where bioreactors and thermal cyclers are integrated with 3D printers for drug formulations; and (4) the efficacy of the manufactured mRNA-containing materials. The fundamental knowledge from the proposed study could transform two critical industries, nucleic acid synthesis and therapeutic biomaterials. This Future Manufacturing award was supported by Molecular and Cellular Biosciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.