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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年2月26日

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  • Ameya R. Kirtane,
  • Jianling Bi,
  • Netra U. Rajesh,
  • Chaoyang Tang,
  • Miguel Jimenez,
  • Emily Witt,
  • Megan K. McGovern,
  • Arielle B. Cafi,
  • Samual J. Hatfield,
  • Lauren Rosenstock,
  • Sarah L. Becker,
  • Nicole Machado,
  • Veena Venkatachalam,
  • Dylan Freitas,
  • Xisha Huang,
  • Alvin Chan,
  • Aaron Lopes,
  • Hyunjoon Kim,
  • Nayoon Kim,
  • Joy E. Collins,
  • Michelle E. Howard,
  • Srija Manchkanti,
  • Theodore S. Hong,
  • James D. Byrne,
  • Giovanni Traverso

摘要

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.