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<p>Dysfunctions of the endometrium, the uterus inner lining, can impair embryo implantation and reduce pregnancy rates. Intrauterine administration of cytokines has shown potential to improve endometrium function, but it is challenged by poor targeting and dose-limiting systemic side effects. Here we present a strategy for introducing therapeutic messenger RNA into the endometrium for the treatment of reproductive disorders. mRNA was loaded into a ligand-conjugated lipid nanoparticle (LNP), enabling multivalent interactions with the temporally overexpressed integrin receptors on the endometrial surface during the window of implantation. Conjugating the targeting ligand directly to the lipid component enhanced endometrial protein expression after intrauterine infusion and reduced systemic expression in the liver and spleen. A single infusion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA-loaded LNP sustained local protein expression for several hours and reduced GM-CSF systemic exposure. In a murine model of endometrial injury, GM-CSF mRNA-loaded LNP improved embryo implantation rates, outperforming recombinant GM-CSF. Our strategy demonstrates the efficacy of using mRNA to improve fertility outcomes.</p>

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Spatiotemporal targeting of messenger RNA lipid nanoparticles to the endometrium for the treatment of reproductive disorders

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月19日

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  • Saed Abbasi,
  • Jairo Ortiz,
  • Kimberly Bockley,
  • Hongyu Feng,
  • Emily Chen,
  • Jordan Miller,
  • Marina Better,
  • Charles Eberhart,
  • Neomi Jerry,
  • Justin Hanes,
  • James H. Segars,
  • Laura M. Ensign

摘要

Dysfunctions of the endometrium, the uterus inner lining, can impair embryo implantation and reduce pregnancy rates. Intrauterine administration of cytokines has shown potential to improve endometrium function, but it is challenged by poor targeting and dose-limiting systemic side effects. Here we present a strategy for introducing therapeutic messenger RNA into the endometrium for the treatment of reproductive disorders. mRNA was loaded into a ligand-conjugated lipid nanoparticle (LNP), enabling multivalent interactions with the temporally overexpressed integrin receptors on the endometrial surface during the window of implantation. Conjugating the targeting ligand directly to the lipid component enhanced endometrial protein expression after intrauterine infusion and reduced systemic expression in the liver and spleen. A single infusion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA-loaded LNP sustained local protein expression for several hours and reduced GM-CSF systemic exposure. In a murine model of endometrial injury, GM-CSF mRNA-loaded LNP improved embryo implantation rates, outperforming recombinant GM-CSF. Our strategy demonstrates the efficacy of using mRNA to improve fertility outcomes.