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Engineering challenges and translational opportunities in emerging gene delivery platforms

Nature Biomedical Engineering (2026) Cite this article

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Abstract

The clinical success of gene therapy depends critically on the development of delivery platforms capable of achieving precise, efficient and tissue-specific delivery of genetic payloads in vivo. A diverse array of carriers, including viral, non-viral, synthetic and natural vectors, have been explored to address this challenge. Among them, adeno-associated viruses, lipid nanoparticles and extracellular vesicles have emerged as leading candidates, each offering distinct advantages and translational hurdles. Here we provide a comparative analysis of these delivery modalities, highlighting their respective design principles, targeting capabilities, immunogenicity profiles and clinical progress. We survey preclinical and clinically adopted delivery strategies and explore how the three delivery platforms can be tailored for gene therapeutics in different diseases. Finally, we discuss emerging strategies to overcome current limitations and outline future directions for the rational design of next-generation gene delivery platforms that combine safety, scalability and functional precision.

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Fig. 1: Overview of AAVs, LNPs and EVs as gene delivery platforms.
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Fig. 2: In vivo fate and intracellular trafficking pathways of AAVs, LNPs and EVs.
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Fig. 3: Engineering strategies, platform hybridization and administration routes.
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Fig. 4: Key differences and specific considerations in the manufacturing and translation workflows of AAVs, LNPs and EVs.
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Acknowledgements

We thank C. Wogan of MD Anderson’s Division of Radiation Oncology for editing the paper. This work was supported in part by the Cancer Prevention and Research Institute of Texas (grants RP240493 and RP250191 to W.J.), James P. Allison Institute (to B.Y.S.K.) and Andrew Sabin Family Foundation.

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Authors and Affiliations

  1. Department of Central Nervous System Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yifan Ma, Shiyan Dong, Annette Wu & Wen Jiang

  2. Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Seong Dong Jeong & Betty Y. S. Kim

  3. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China

    Andrew S. Lee

  4. Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China

    Andrew S. Lee

  5. Brain Tumor Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Betty Y. S. Kim

  6. James P. Allison Institute, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Betty Y. S. Kim

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Contributions

Y.M., A.S.L., W.J. and B.Y.S.K. conceived of the project and were responsible for all phases of paper preparation. All authors searched for literature and wrote and edited the paper. Y.M. and S.D. designed the figures and tables.

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Correspondence to Andrew S. Lee, Wen Jiang or Betty Y. S. Kim.

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Ma, Y., Dong, S., Wu, A. et al. Engineering challenges and translational opportunities in emerging gene delivery platforms. Nat. Biomed. Eng (2026). https://doi.org/10.1038/s41551-026-01643-5

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