Radioprotection of healthy tissue via nanoparticle-delivered mRNA encoding for a damage-suppressor protein found in tardigrades

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...

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Bibliographic Details
Published in:Nature biomedical engineering Vol. 9; no. 8; p. 1240
Main Authors: Kirtane, Ameya R, Bi, Jianling, Rajesh, Netra U, Tang, Chaoyang, Jimenez, Miguel, Witt, Emily, McGovern, Megan K, Cafi, Arielle B, Hatfield, Samual J, Rosenstock, Lauren, Becker, Sarah L, Machado, Nicole, Venkatachalam, Veena, Freitas, Dylan, Huang, Xisha, Chan, Alvin, Lopes, Aaron, Kim, Hyunjoon, Kim, Nayoon, Collins, Joy E, Howard, Michelle E, Manchkanti, Srija, Hong, Theodore S, Byrne, James D, Traverso, Giovanni
Format: Journal Article
Language:English
Published: England 01.08.2025
Subjects:
Animals
DNA Damage
Humans
Male
Mice
Nanoparticles - chemistry
Radiation-Protective Agents
RNA, Messenger - administration & dosage
RNA, Messenger - genetics
RNA, Messenger - metabolism
Tardigrada - genetics
Tardigrada - metabolism
ISSN:2157-846X, 2157-846X
Online Access:Get more information
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Summary: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.
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ISSN:2157-846X
2157-846X
DOI:10.1038/s41551-025-01360-5