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Here we show that mRNA function can be controlled by rational design of higher-order RNA architectures. We develop self-assembling mRNA origami (mRNA-OG), a class of unimolecular RNA nanostructures that encode protein-coding sequences within higher-order, programmable, and compact nucleic acid architectures. Using computational design and experimental validation, we demonstrate that mRNA-OG folds into well-defined nanostructures while remaining translationally competent in mammalian cells. Although folded mRNA-OG recruits ribosomes comparably to unfolded constructs, it produces lower protein output, indicating that RNA architecture can directly influence translational efficiency. The compact geometry of mRNA-OG also enhances encapsulation by cationic lipid delivery systems, suggesting a structural route to improved cargo packaging. Beyond its effects on translation, mRNA architecture modulates innate immune recognition. In primary human dendritic cells, folded and unfolded mRNA-OG elicit distinct cytokine programs and differential activation of stress-response pathways, including a modest induction of the integrated stress response that is not fully explained by canonical PKR signaling. Our results establish programmable structure as a new design parameter for mRNA therapeutics that can affect its functionality, delivery properties, and immune sensing.<\/jats:p>","DOI":"10.64898\/2026.09.14.751315","type":"posted-content","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:50:23Z","timestamp":1789645823000},"source":"Crossref","is-referenced-by-count":0,"title":["Engineered mRNA nanostructures expand the design space of mRNA therapeutics through programmable protein expression and immune stimulation"],"prefix":"10.64898","author":[{"given":"Mark D.","family":"Knappenberger","sequence":"first","affiliation":[{"name":"Center for Molecular Design and Biomimetics, The Biodesign Institute, Arizona State University, AZ 85287"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skylar J.W.","family":"Henry","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic in Arizona, Phoenix, AZ, 85054"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archana","family":"Kikla","sequence":"additional","affiliation":[{"name":"Center for Molecular Design and Biomimetics, The Biodesign Institute, Arizona State University, AZ 85287"},{"name":"School for Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, Arizona 85287, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Sample","sequence":"additional","affiliation":[{"name":"Center for Molecular Design and Biomimetics, The Biodesign Institute, Arizona State University, AZ 85287"},{"name":"School for Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, Arizona 85287, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Roy","sequence":"additional","affiliation":[{"name":"School of Molecular Sciences, Arizona State University, AZ 85287"},{"name":"Virginia G. 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