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Endometrial dysfunction can affect embryo implantation and reduce pregnancy rates. Intrauterine administration of cytokines has been shown to have potential in improving endometrial function, but this approach faces challenges due to poor targeting and systemic side effects. This study proposes a strategy to deliver therapeutic messenger RNA to the endometrium to treat reproductive disorders. The mRNA is loaded into ligand-conjugated lipid nanoparticles (LNPs), enabling multivalent interactions with integrin receptors that are overexpressed on the endometrial surface during the implantation window. By directly attaching targeting ligands to the lipid components, the approach enhances protein expression in the endometrium after intrauterine infusion while reducing systemic expression in the liver and spleen. A single infusion of cell–macrophage colony-stimulating factor (GM-CSF) mRNA–loaded LNPs can maintain local protein expression for several hours and reduce systemic GM-CSF exposure. In a mouse model of endometrial injury, GM-CSF mRNA–loaded LNPs improved embryo implantation rates, outperforming recombinant GM-CSF. Our strategy demonstrates the effectiveness of using mRNA to improve fertility outcomes.
In the field of reproductive medicine, endometrial dysfunction is one of the important causes of embryo implantation failure and declining pregnancy rates. Although therapeutic modalities such as direct intrauterine cytokines have shown potential to improve endometrial receptivity, their clinical application is limited due to issues such as inadequate targeting and systemic side effects. Recently, a study published in Nature Nanotechnology proposed a new targeted therapy strategy based on messenger RNA (mRNA) lipid nanoparticles (LNPs), which provides a new idea for the treatment of endometrial-related reproductive disorders through spatiotemporal delivery.
The research team designed a targeted modified lipid nanoparticle that directly attaches a ligand containing RGD peptide to the lipid component, allowing it to interact with integrin receptors that are highly expressed during the endometrial implantation window. This functionalization strategy, known as "BLOC", not only significantly improves the delivery efficiency and protein expression level of mRNA in the endometrium, but also unexpectedly reduces the systematic expression of non-target organs such as the liver and spleen. Experiments showed that the expression of luciferase in utero was increased by 3.9 times compared with that of non-targeted LNPs through a single intrauterine perfusion during the implantation window, while the expression in the liver and spleen was reduced by 450 times and 65 times, respectively, showing excellent tissue selectivity.
Further research found that the targeting system can effectively deliver mRNA to various cell types such as the cavity epithelium, glands and stroma of the endometrium, and achieve local continuous expression of the encoded protein. The study used granulocyte-macrophage colony-stimulating
