Abstract
The use of nucleic acid-based nanostructures as synthetic biological tools to interface with and regulate cell processes remains challenging. A major obstacle lies in nuclear delivery and retention within live eukaryotic cells. Here, we present a platform of single-stranded RNAs that can co-transcriptionally fold into defined nanostructures and assemble into rings, ribbons, and nanonet-like architectures. We validate the formation of these structures in vitro using atomic force microscopy. Then, we demonstrate the functional integration of fluorescent aptamers and RNA sensing capability within the single chain by co-folding with these structures. Notably, we show that the RNA nanonets can be co-transcriptionally produced and assembled directly inside the nucleus of live h…
Abstract
The use of nucleic acid-based nanostructures as synthetic biological tools to interface with and regulate cell processes remains challenging. A major obstacle lies in nuclear delivery and retention within live eukaryotic cells. Here, we present a platform of single-stranded RNAs that can co-transcriptionally fold into defined nanostructures and assemble into rings, ribbons, and nanonet-like architectures. We validate the formation of these structures in vitro using atomic force microscopy. Then, we demonstrate the functional integration of fluorescent aptamers and RNA sensing capability within the single chain by co-folding with these structures. Notably, we show that the RNA nanonets can be co-transcriptionally produced and assembled directly inside the nucleus of live human cells. We use confocal live-cell imaging and transmission electron microscopy to reveal well-defined nanostructure patterns retained in the nucleus. Together, these results establish a genetically encoded, self-assembling RNA nanostructure system with programmable geometry and localization, providing a foundation for the development of RNA-based nanodevices to examine biological properties in live cells and tissues.
Data availability
The data supporting the findings of this study are available within the main text and its Supplementary Information. The raw data and statistical analysis of fluorescence intensity in this study are provided in the Source Data files. Any additional requests for information can be directed to, and will be fulfilled by, the corresponding authors. Source data are provided with this paper.
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Acknowledgements
This work is supported by US National Science Foundation (NSF) grants (CCF-2007821) and (DMR-2046835), and a faculty Startup Fund from Rutgers University to F.Z., and the National Institute of Health (NIH) grants R01DK139790 and R21AI167079, and faculty Startup Funds from Rutgers University to J-P.E. We acknowledge the electron microscopy facilities of the Department of Biological Sciences, Laboratory for Advanced Imaging, and Rutgers School of Public Health Core Imaging Laboratory.
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Author notes
These authors contributed equally: Xu Chang, Maciej Jeziorek.
Authors and Affiliations
Department of Chemistry, Rutgers University, Newark, NJ, USA
Xu Chang, Qi Yang & Fei Zhang 1.
Department of Biological Sciences, Rutgers University, Newark, NJ, USA
Maciej Jeziorek, Edward M. Bonder & Jean-Pierre Etchegaray 1.
School of Molecular Sciences and Center for Molecular Design and Biomimetics, The Biodesign Institute, Arizona State University, Tempe, AZ, USA
Hao Yan
Authors
- Xu Chang
- Maciej Jeziorek
- Qi Yang
- Edward M. Bonder
- Hao Yan
- Jean-Pierre Etchegaray
- Fei Zhang
Contributions
F.Z. and H.Y. conceived the original idea. X.C. and F.Z. designed the structures. X.C. assigned the sequences, characterized the formation of single-stranded RNA nanostructures, and integrated light-up aptamers into the structures. Q.Y. performed the experiments for RNA sensing in vitro. M.J. and J-P.E. developed the expression constructs, transfection protocols in human cells, and projected the biological applications for the nanostructures. M.J. and E.M.B. conducted the TEM characterization and M.J completed the confocal imaging studies. The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript.
Corresponding authors
Correspondence to Jean-Pierre Etchegaray or Fei Zhang.
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Competing interests
F.Z., J-P.E., X.C., and M.J. have filed a provisional US patent based on this work. The remaining authors declare no competing interests.
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Nature Communications thanks Ebbe Andersen, Bryan Wei, Cody Geary and the other anonymous reviewer for their contribution to the peer review of this work. [A peer review file is available].
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Chang, X., Jeziorek, M., Yang, Q. et al. Designer RNA nanostructures co-transcribed and self-assembled inside human cell nuclei. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67817-y
Received: 05 June 2025
Accepted: 09 December 2025
Published: 26 December 2025
DOI: https://doi.org/10.1038/s41467-025-67817-y