Journal article
Radioprotection of healthy tissue via nanoparticle-delivered mRNA encoding for a damage-suppressor protein found in tardigrades
Nature biomedical engineering, Vol.9(8), pp.1240-1253
08/2025
DOI: 10.1038/s41551-025-01360-5
PMCID: PMC12919043
PMID: 40011582
Abstract
Patients undergoing radiation therapy experience debilitating side effects because of toxicity arising from radiation-induced DNA strand breaks in normal peritumoural cells. Here, inspired by the ability of tardigrades to resist extreme radiation through the expression of a damage-suppressor protein that binds to DNA and reduces strand breaks, we show that the local and transient expression of the protein can reduce radiation-induced DNA damage in oral and rectal epithelial tissues (which are commonly affected during radiotherapy for head-and-neck and prostate cancers, respectively). We used ionizable lipid nanoparticles supplemented with biodegradable cationic polymers to enhance the transfection efficiency and delivery of messenger RNA encoding the damage-suppressor protein into buccal and rectal tissues. In mice with orthotopic oral cancer, messenger RNA-based radioprotection of normal tissue preserved the efficacy of radiation therapy. The strategy may be broadly applicable to the protection of healthy tissue from DNA-damaging agents.
Details
- Title: Subtitle
- Radioprotection of healthy tissue via nanoparticle-delivered mRNA encoding for a damage-suppressor protein found in tardigrades
- Creators
- Ameya R Kirtane - Brigham and Women's HospitalJianling Bi - University of IowaNetra U Rajesh - Massachusetts Institute of TechnologyChaoyang Tang - Massachusetts Institute of TechnologyMiguel Jimenez - Massachusetts Institute of TechnologyEmily Witt - University of IowaMegan K McGovern - University of IowaArielle B Cafi - University of IowaSamual J Hatfield - University of IowaLauren Rosenstock - University of IowaSarah L Becker - Brigham and Women's HospitalNicole Machado - Massachusetts Institute of TechnologyVeena Venkatachalam - Brigham and Women's HospitalDylan Freitas - Brigham and Women's HospitalXisha Huang - Brigham and Women's HospitalAlvin Chan - Massachusetts Institute of TechnologyAaron Lopes - Massachusetts Institute of TechnologyHyunjoon Kim - Massachusetts Institute of TechnologyNayoon Kim - University of WashingtonJoy E Collins - Brigham and Women's HospitalMichelle E Howard - University of IowaSrija Manchkanti - University of IowaTheodore S Hong - Massachusetts General HospitalJames D Byrne - University of IowaGiovanni Traverso - Broad Institute
- Resource Type
- Journal article
- Publication Details
- Nature biomedical engineering, Vol.9(8), pp.1240-1253
- DOI
- 10.1038/s41551-025-01360-5
- PMID
- 40011582
- PMCID
- PMC12919043
- NLM abbreviation
- Nat Biomed Eng
- ISSN
- 2157-846X
- eISSN
- 2157-846X
- Publisher
- NATURE PORTFOLIO
- Grant note
- MIT Department of Mechanical Engineering: W81XWH-20-1-0225 Prostate Cancer Foundation Young Investigator Award: IRG-21-141-45-IRG American Cancer Society: P30 CA086862, P30-CA014051, K08CA276908, DP2CA301081 Holden Comprehensive Cancer Center: D24AC00040-00 Advanced Research Projects Agency for Health
We thank the team at SayoStudio for their illustration in Fig. 1. Figure 5a,b,g was created with http://BioRender.com. We also thank the staff of the University of Iowa Central Microscopy Research Facility, M. Dailey, and the MIT Koch Institute for their rapid and detailed work on the histology. We are grateful for flow cytometry facilities in the Koch Institute Genomics Core High Throughput Sciences facility (J. Cheah and C. Sellinger) and the Holden Comprehensive Cancer Center (H. Vignes). This work was funded in part by grants from the Prostate Cancer Foundation Young Investigator Award (J.D.B.), Department of Defense Prostate Cancer Program Early Investigator Award W81XWH-20-1-0225 (J.D.B.), Hope Funds for Cancer Research fellowship (J.D.B.), American Cancer Society IRG-21-141-45-IRG (J.D.B.), NIH/NCI Cancer Center Support Grant for the Holden Comprehensive Cancer Center P30 CA086862 (J.D.B.), Koch Institute Support (core) Grant P30-CA014051 (A.R.K. and J.D.B.), NCI K08CA276908 (J.D.B.), NIH Director's New Innovator Award DP2CA301081 (J.D.B.), Department of Mechanical Engineering, MIT (G.T.), and Advanced Research Projects Agency for Health (ARPA-H) D24AC00040-00 (G.T.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Advanced Research Projects Agency for Health.
- Language
- English
- Electronic publication date
- 02/26/2025
- Date published
- 08/2025
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Iowa Neuroscience Institute; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984795474602771
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