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

doi:10.1038/s41551-025-01360-5

. 2025 Feb 26.

doi: 10.1038/s41551-025-01360-5. Online ahead of print.

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

Ameya R Kirtane^#^{1

2}, Jianling Bi^#^{3

4

5}, Netra U Rajesh^{2

6

7}, Chaoyang Tang², Miguel Jimenez^{2

8}, Emily Witt^{3

4

5}, Megan K McGovern^{3

4

5}, Arielle B Cafi^{3

4

5}, Samual J Hatfield^{3

4

5}, Lauren Rosenstock^{3

4

5}, Sarah L Becker^{1

9}, Nicole Machado^{2

10

11}, Veena Venkatachalam¹², Dylan Freitas¹, Xisha Huang¹, Alvin Chan^{1

2

8}, Aaron Lopes^{1

2

8}, Hyunjoon Kim^{2

13}, Nayoon Kim^{2

14}, Joy E Collins^{1

2}, Michelle E Howard^{3

15}, Srija Manchkanti¹⁶, Theodore S Hong¹⁷, James D Byrne^#^{18

19

20

21}, Giovanni Traverso^#^{22

23

24

25}

Affiliations

¹ Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA.
⁴ Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA.
⁵ Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
⁶ Department of Bioengineering, Stanford University, Stanford, CA, USA.
⁷ Faculty of Applied Sciences and Engineering, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁹ School of Medicine, Oregon Health Science University, Portland, OR, USA.
¹⁰ Faculty of Arts and Science, University of Toronto, Toronto, Ontario, Canada.
¹¹ Department of Oncology, University of Oxford, Oxford, UK.
¹² Department of Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹³ Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA.
¹⁴ School of Medicine, University of Washington, Seattle, WA, USA.
¹⁵ Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
¹⁶ Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
¹⁷ Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁸ Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA. james-byrne@uiowa.edu.
¹⁹ Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA. james-byrne@uiowa.edu.
²⁰ Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA. james-byrne@uiowa.edu.
²¹ Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA. james-byrne@uiowa.edu.
²² Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. cgt20@mit.edu.
²³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. cgt20@mit.edu.
²⁴ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. cgt20@mit.edu.
²⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA. cgt20@mit.edu.

^# Contributed equally.

PMID: 40011582
DOI: 10.1038/s41551-025-01360-5

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

Ameya R Kirtane et al. Nat Biomed Eng. 2025.

. 2025 Feb 26.

doi: 10.1038/s41551-025-01360-5. Online ahead of print.

Authors

Affiliations

¹ Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA.
⁴ Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA.
⁵ Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
⁶ Department of Bioengineering, Stanford University, Stanford, CA, USA.
⁷ Faculty of Applied Sciences and Engineering, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁹ School of Medicine, Oregon Health Science University, Portland, OR, USA.
¹⁰ Faculty of Arts and Science, University of Toronto, Toronto, Ontario, Canada.
¹¹ Department of Oncology, University of Oxford, Oxford, UK.
¹² Department of Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹³ Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA.
¹⁴ School of Medicine, University of Washington, Seattle, WA, USA.
¹⁵ Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
¹⁶ Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
¹⁷ Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁸ Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA. james-byrne@uiowa.edu.
¹⁹ Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA. james-byrne@uiowa.edu.
²⁰ Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA. james-byrne@uiowa.edu.
²¹ Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA. james-byrne@uiowa.edu.
²² Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. cgt20@mit.edu.
²³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. cgt20@mit.edu.
²⁴ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. cgt20@mit.edu.
²⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA. cgt20@mit.edu.

^# Contributed equally.

PMID: 40011582
DOI: 10.1038/s41551-025-01360-5

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.

PubMed Disclaimer

Conflict of interest statement

Competing interests: A.R.K., N.U.R., H.K., J.D.B. and G.T. are co-inventors on a patent application (PCT/US2022/019236) describing the polymer transfection agents. Complete details of all relationships for profit and not for profit for G.T. are provided as Supplementary Table 2.

Cited by

Enhancing adoptive cell therapy: future strategies for immune cell radioprotection in neuro-oncology.
Groth AJ, Khasraw M, Byrne JD, Reitman ZJ. Groth AJ, et al. NPJ Precis Oncol. 2025 Jul 29;9(1):264. doi: 10.1038/s41698-025-01059-5. NPJ Precis Oncol. 2025. PMID: 40730675 Free PMC article. Review.

References

1. Jagodinsky, J. C., Harari, P. M. & Morris, Z. S. The promise of combining radiation therapy with immunotherapy. Int. J. Radiat. Oncol. Biol. Phys. 108, 6–16 (2020). - PubMed - PMC - DOI
1. Tonse, R. et al. Hospitalization rates from radiotherapy complications in the United States. Sci. Rep. 12, 4371 (2022). - PubMed - PMC - DOI
1. Bryant, A. K., Banegas, M. P., Martinez, M. E., Mell, L. K. & Murphy, J. D. Trends in radiation therapy among cancer survivors in the United States, 2000–2030. Cancer Epidemiol. Biomarkers Prev. 26, 963–970 (2017). - PubMed - DOI
1. Barnett, G. C. et al. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat. Rev. Cancer 9, 134–142 (2009). - PubMed - PMC - DOI
1. Donovan, J. L. et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N. Engl. J. Med. 375, 1425–1437 (2016). - PubMed - PMC - DOI

Grants and funding

LinkOut - more resources

Full Text Sources
- Nature Publishing Group

[1] Jagodinsky, J. C., Harari, P. M. & Morris, Z. S. The promise of combining radiation therapy with immunotherapy. Int. J. Radiat. Oncol. Biol. Phys. 108, 6–16 (2020). - PubMed - PMC - DOI

[2] Jagodinsky, J. C., Harari, P. M. & Morris, Z. S. The promise of combining radiation therapy with immunotherapy. Int. J. Radiat. Oncol. Biol. Phys. 108, 6–16 (2020). - PubMed - PMC - DOI

[3] Tonse, R. et al. Hospitalization rates from radiotherapy complications in the United States. Sci. Rep. 12, 4371 (2022). - PubMed - PMC - DOI

[4] Tonse, R. et al. Hospitalization rates from radiotherapy complications in the United States. Sci. Rep. 12, 4371 (2022). - PubMed - PMC - DOI

[5] Bryant, A. K., Banegas, M. P., Martinez, M. E., Mell, L. K. & Murphy, J. D. Trends in radiation therapy among cancer survivors in the United States, 2000–2030. Cancer Epidemiol. Biomarkers Prev. 26, 963–970 (2017). - PubMed - DOI

[6] Bryant, A. K., Banegas, M. P., Martinez, M. E., Mell, L. K. & Murphy, J. D. Trends in radiation therapy among cancer survivors in the United States, 2000–2030. Cancer Epidemiol. Biomarkers Prev. 26, 963–970 (2017). - PubMed - DOI

[7] Barnett, G. C. et al. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat. Rev. Cancer 9, 134–142 (2009). - PubMed - PMC - DOI

[8] Barnett, G. C. et al. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat. Rev. Cancer 9, 134–142 (2009). - PubMed - PMC - DOI

[9] Donovan, J. L. et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N. Engl. J. Med. 375, 1425–1437 (2016). - PubMed - PMC - DOI

[10] Donovan, J. L. et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N. Engl. J. Med. 375, 1425–1437 (2016). - PubMed - PMC - DOI

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Similar articles

Cited by

References

Grants and funding

LinkOut - more resources

Full Text Sources

Abstract

Conflict of interest statement

Similar articles

Cited by

References

Related information

Grants and funding

LinkOut - more resources

Full Text Sources