Creating bottom-up RNA transfer vehicles from synthetic protein assemblies
- Maren Kirstin Schuhmacher
- Christoph Gruber
- Christopher M. R. Lang
- Ricardo M. W. Ruijpers
- Lyupka Mazneykova
- Brice Beinsteiner
- Ariane Krus
- Barbara Tremmel
- Friederike Reinhardt
- Karoline Kadletz
- Zhe Ma
- Lucie Casalta
- Josep Miquel Cambra Bort
- Dina Y. Otify
- Iolo Balken
- Leon Hetzel
- Juliane Merl-Pham
- Tatjana Dorn
- Marina Luchner
- Lea Bauersachs
- Karin Ganea
- Natascha Wieser
- Alexander Emrich
- Emirhan Yağmur
- Katrin Rager
- Gauhar Sagindykova
- Niklas Armbrust
- Julian Geilenkeuser
- Gil G. Westmeyer
- Elvir Becirovic
- Martin Biel
- Rouzanna Istvanffy
- Daniela M. Vogt Weisenhorn
- Dong-Jiunn Jeffery Truong
- Fabian J. Theis
- Gregor Ebert
- Alessandra Moretti
- Ali Ertürk
- Andrea Bähr
- Christian Kupatt
- Marion Jasnin
- Nikolai Klymiuk
- Florian Giesert
- Wolfgang Wurst
2026-09-02
Evolution guides biological systems to populate ecological niches, with viruses among the most successful examples of this principle. Viruses evolved over billions of years to efficiently transfer genetic information. Although viruses are highly diverse, most have converged towards remarkable similarity in the size and shape of their capsids 1,2 . By contrast, generative models for protein design enable the creation of protein architectures that are absent from nature 3–5 . Here we investigate whether protein assemblies designed by artificial intelligence can be functionalized to construct nucleic acid transport vehicles that are independent of evolutionary trajectories. By combining natural protein domains with synthetic protein assemblies, we create more than 100 bottom-up RNA transfer vehicles with unique sizes and shapes. These vehicles surpass the RNA transfer efficiency of widely used delivery vehicles by several orders of magnitude. In addition, we demonstrate that their tropism can be programmed by incorporation of computationally designed peptide binders and use them to deliver therapeutically relevant cargo RNAs into a wide range of cellular models. We show the in vivo biodistribution of one of these vehicles in a mouse at near-single-cell resolution, confirm its safety, and use it to perform a gene-editing treatment strategy for Duchenne muscular dystrophy in patient-derived cells and a pig. Our work demonstrates how proteins created by generative artificial intelligence can be harnessed for the rational engineering of RNA transport systems with the desired properties by overcoming the limitations of natural protein diversity.