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Peer-reviewedCC BY-NC-NDProceedings of the National Academy of Sciences

Plug-and-play assembly of biodegradable ionizable lipids for potent mRNA delivery and gene editing in vivo

  • Xuexiang Han1,2,3
  • Ying Xu4,5,6,7
  • Adele S. Ricciardi1,8,9
  • Junchao Xu1,9
  • Yan Xiang10,9
  • Rohan Palanki1,8,9
  • Vivek Chowdhary11,9
  • Lulu Xue1,9
  • Ningqiang Gong1,9
  • Mohamad‐Gabriel Alameh4,5
  • William H. Peranteau8,12
  • James M. Wilson11,12
3 more authors
  • Daniel Reker10,13
  • Drew Weissman4,5
  • Michael J. Mitchell14,15,16,1,17,18,5
18 affiliations
  1. 1Department of Bioengineering, University of Pennsylvania
  2. 2State Key Laboratory of RNA Innovation, Science and Engineering, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences
  3. 3Shanghai Institute of Biochemistry and Cell Biology
  4. 4Department of Medicine, University of Pennsylvania
  5. 5Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania
  6. 6School of Pharmacy, East China Normal University
  7. 7East China Normal University
  8. 8Division of Pediatric General, Thoracic, and Fetal Surgery, The Center for Fetal Research, Children’s Hospital of Philadelphia
  9. 9University of Pennsylvania
  10. 10Department of Biomedical Engineering, Duke University
  11. 11Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania
  12. 12University of Pennsylvania Perelman School of Medicine
  13. 13UNIVERSITY OF PENNSYLVANIA
  14. 14Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania
  15. 15Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania
  16. 16Center for Precision Engineering for Health, University of Pennsylvania
  17. 17Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
  18. 18Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania
Open at sourceDOICite

Abstract

mRNA-based gene editing therapeutics offer the potential to permanently cure diseases but are hindered by suboptimal delivery platforms. Here, we devise a robust combinatorial chemistry for the plug-and-play assembly of structurally diverse biodegradable ionizable lipids from amines/thiols and dialkyl maleates. After screening 500 ionizable lipids, we obtained structure-activity relationships essential for effective in vitro mRNA delivery with the help of machine learning. Furthermore, we identified a lead ionizable lipid candidate that produced potent lipid nanoparticles for the delivery of various gene editing tools in wild-type and genetically modified mice compared to literature and industry benchmark lipid nanoparticles. Mechanistically, our lipid nanoparticles show favorable physicochemical properties, which could synergistically contribute to the superior delivery performance. This study highlights the utility of this synthetic method as well as the generality of this platform for potent in vivo gene editing.

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Cite

BibTeXRIS
BibTeX
@article{han2026plugandplay,
  title = {{Plug-and-play assembly of biodegradable ionizable lipids for potent mRNA delivery and gene editing in vivo}},
  author = {Xuexiang Han and Ying Xu and Adele S. Ricciardi and Junchao Xu and Yan Xiang and Rohan Palanki and Vivek Chowdhary and Lulu Xue and Ningqiang Gong and Mohamad‐Gabriel Alameh and William H. Peranteau and James M. Wilson and Daniel Reker and Drew Weissman and Michael J. Mitchell},
  journal = {Proceedings of the National Academy of Sciences},
  year = {2026},
  month = may,
  doi = {10.1073/pnas.2528144123},
  url = {https://doi.org/10.1073/pnas.2528144123},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Plug-and-play assembly of biodegradable ionizable lipids for potent mRNA delivery and gene editing in vivo
AU  - Xuexiang Han
AU  - Ying Xu
AU  - Adele S. Ricciardi
AU  - Junchao Xu
AU  - Yan Xiang
AU  - Rohan Palanki
AU  - Vivek Chowdhary
AU  - Lulu Xue
AU  - Ningqiang Gong
AU  - Mohamad‐Gabriel Alameh
AU  - William H. Peranteau
AU  - James M. Wilson
AU  - Daniel Reker
AU  - Drew Weissman
AU  - Michael J. Mitchell
PY  - 2026
DA  - 2026/05/26
JO  - Proceedings of the National Academy of Sciences
DO  - 10.1073/pnas.2528144123
UR  - https://doi.org/10.1073/pnas.2528144123
AB  - mRNA-based gene editing therapeutics offer the potential to permanently cure diseases but are hindered by suboptimal delivery platforms. Here, we devise a robust combinatorial chemistry for the plug-and-play assembly of structurally diverse biodegradable ionizable lipids from amines/thiols and dialkyl maleates. After screening 500 ionizable lipids, we obtained structure-activity relationships essential for effective in vitro mRNA delivery with the help of machine learning. Furthermore, we identified a lead ionizable lipid candidate that produced potent lipid nanoparticles for the delivery of various gene editing tools in wild-type and genetically modified mice compared to literature and industry benchmark lipid nanoparticles. Mechanistically, our lipid nanoparticles show favorable physicochemical properties, which could synergistically contribute to the superior delivery performance. This study highlights the utility of this synthetic method as well as the generality of this platform for potent in vivo gene editing.
SN  - 0027-8424
SN  - 1091-6490
ER  -