Journal article
Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy
Nature biotechnology, Vol.43(11), pp.1790-1799
11/2025
DOI: 10.1038/s41587-024-02490-y
PMCID: PMC12149338
PMID: 39658727
Abstract
Ionizable lipids are a key component of lipid nanoparticles, the leading nonviral messenger RNA delivery technology. Here, to advance the identification of ionizable lipids beyond current methods, which rely on experimental screening and/or rational design, we introduce lipid optimization using neural networks, a deep-learning strategy for ionizable lipid design. We created a dataset of >9,000 lipid nanoparticle activity measurements and used it to train a directed message-passing neural network for prediction of nucleic acid delivery with diverse lipid structures. Lipid optimization using neural networks predicted RNA delivery in vitro and in vivo and extrapolated to structures divergent from the training set. We evaluated 1.6 million lipids in silico and identified two structures, FO-32 and FO-35, with local mRNA delivery to the mouse muscle and nasal mucosa. FO-32 matched the state of the art for nebulized mRNA delivery to the mouse lung, and both FO-32 and FO-35 efficiently delivered mRNA to ferret lungs. Overall, this work shows the utility of deep learning for improving nanoparticle delivery.
Details
- Title: Subtitle
- Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy
- Creators
- Jacob Witten - Massachusetts Institute of TechnologyIdris Raji - Boston Children's HospitalRajith S Manan - Koch Institute for Integrative Cancer Research At MITEmily Beyer - Massachusetts Institute of TechnologySandra Bartlett - Koch Institute for Integrative Cancer Research At MITYinghua Tang - University of IowaMehrnoosh Ebadi - University of IowaJunying Lei - University of IowaDien Nguyen - Koch Institute for Integrative Cancer Research At MITFavour Oladimeji - Massachusetts Institute of TechnologyAllen Yujie Jiang - Koch Institute for Integrative Cancer Research At MITElise MacDonald - Koch Institute for Integrative Cancer Research At MITYizong Hu - Koch Institute for Integrative Cancer Research At MITHaseeb Mughal - Koch Institute for Integrative Cancer Research At MITAva Self - Koch Institute for Integrative Cancer Research At MITEvan Collins - Massachusetts Institute of TechnologyZiying Yan - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, USAJohn F Engelhardt - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, USARobert Langer - Massachusetts Institute of TechnologyDaniel G Anderson - Massachusetts Institute of Technology
- Resource Type
- Journal article
- Publication Details
- Nature biotechnology, Vol.43(11), pp.1790-1799
- DOI
- 10.1038/s41587-024-02490-y
- PMID
- 39658727
- PMCID
- PMC12149338
- NLM abbreviation
- Nat Biotechnol
- ISSN
- 1087-0156
- eISSN
- 1546-1696
- Publisher
- NATURE PORTFOLIO
- Grant note
- HL162564-02, R61AI161805 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) HL162564-02 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) HL152960, DK054759, 75N92019C00010 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) 5P30-CA14051 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) N/a / Sanofi WITTEN19XX0, 004831F5222 / Cystic Fibrosis Foundation (CF Foundation)
- Language
- English
- Electronic publication date
- 12/10/2024
- Date published
- 11/2025
- Academic Unit
- Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984757198402771
Metrics
77 Record Views