Mega Doctor News
By Johns Hopkins Medicine
Researchers from the Wilmer Eye Institute, Johns Hopkins Medicine Center for Nanomedicine — which designs nanotechnology-based platforms for clinical translation across specialties — developed a strategy for delivering therapeutic messenger RNA (mRNA) to the inner lining of the uterus (endometrium) in mice via modified lipid nanoparticles (LNPs), which are small capsules made of fatty molecules.
In a report funded by the National Institutes of Health and published in Nature Nanotechnology Jan. 19, the investigators say their results using an endometrial injury model show they can improve embryo implantation and highlight a new possible treatment for some forms of infertility.
Specifically, the research team says their experiments demonstrate a targeted ability to deliver therapeutic mRNA — molecular instructions produced by cells to create proteins and control cell functions — to damaged uterine linings for a controlled amount of time.
Numerous gynecologic conditions, such as endometriosis and Asherman syndrome, can cause infertility by making embryos less likely to attach to the endometrium, a necessary step for pregnancy to proceed, even with the use of assisted reproductive technologies (ART) such as in vitro fertilization. According to Laura Ensign, Ph.D., principal investigator and Marcella E. Woll Professor of Ophthalmology at Johns Hopkins Medicine, patients who cannot begin or maintain a pregnancy with ART do not have effective FDA-approved options to turn to.
“What we’re doing [with our study] is establishing a new standard of care for people to explore.”
mRNA therapies work by presenting existing cells with instructions to create highly specific functional proteins without changing the DNA in their nuclei. This approach is the basis of newer cancer therapies and the mRNA COVID-19 vaccines. Experimentally, researchers designing mRNA therapeutics encounter challenges ensuring it reaches the treatment site at concentrations high enough to provide therapeutic benefit and avoid systemic toxicity.
For the new experiments at Johns Hopkins Medicine, Saed Abbasi, Ph.D., the study’s lead author and research associate currently working in Ensign’s laboratory, says they designed their experiments to see if delivery of the fragile, fast-degrading mRNA molecules specifically to the endometrium using LNPs was possible, and if so, what conditions could be improved with it.
Because mRNA breaks down easily on its own and living cells contain enzymes that actively seek out and degrade naked mRNA, the researchers used an LNP delivery system to protect and carry the mRNA code of an immune protein called granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is believed to improve embryo attachment by increasing the thickness of the endometrium. However, while recombinant GM-CSF protein can easily be manufactured in large amounts from bacterial colonies, its short protein half-life and potential for off-target distribution have limited therapeutic application.
In their first set of experiments, the research team administered GM-CSF mRNA to the mouse endometrium via intrauterine infusion, a minimally invasive method used to administer embryos and therapeutics in ART, and observed that conventional mRNA-LNPs spread beyond their initial delivery site, resulting in liver and spleen toxicity.
To reduce the chance of off-target mRNA delivery, the researchers decorated their LNPs with a peptide — a type of small protein — called RGD (arginylglycylaspartic acid). RGD attaches to integrins, also known as cell surface proteins, that are expressed on the endometrium during the window of implantation (WOI), a period when the tissue is receptive to embryos. Modification of the mRNA LNPs helped ensure the treatment targeted the endometrium precisely, enhanced GM-CSF’s expected therapeutic benefits and minimized side effects when infused during the WOI.
After infusing mice with their tailored mRNA-LNP, the researchers discovered that GM-CSF protein expression in the mouse endometrium remained high for up to 24 hours — and was nearly threefold higher eight hours afterward versus individuals who received the recombinant GM-CSF protein infusion. GM-CSF protein levels were also sixtyfold lower in the blood of mice that received the mRNA-LNP compared to the recombinant protein group, indicating an improved safety profile with a reduced risk of unintended organ toxicity.
“While the human menstrual cycle is unusual compared to mice and other mammals, the window of implantation is one process that is shared and comparable between mice and humans,” says Ensign, “So, our findings are expected to translate to other model systems as well.”
Using the same tailored mRNA-LNP treatment in a mouse model of endometrial injury that mimicked fertility-reducing structural disturbances of the human endometrium, the researchers found embryo attachment was restored to levels comparable to those in healthy mice, while untreated mice showed 67% fewer implantation sites on average. Additionally, in the treated mice, the researchers did not find toxicity in the uterus and other mouse organs.
In future experiments, Ensign and Abbasi plan on using their LNP delivery system to test additional cytokines, growth hormones and other molecules that could potentially improve fertility. The group also believes their mRNA delivery system could address other endometrial disorders, such as endometriosis and endometrial cancer.
The study was supported by the National Institutes of Health (R01HD103124, R01HD108905), an unrestricted departmental grant from Research to Prevent Blindness, Maryland E-Nnovation Initiative Fund via the Endowed Fund in Honor of Marcella E. Woll, and the Johns Hopkins University President’s Frontier Award.
Saed Abbasi, Justin Hanes and Laura M. Ensign are inventors on patent application (PCT/US2025/043687) filed by The Johns Hopkins University, which is related to the study. The authors declare no competing interests.
Other Johns Hopkins researchers who contributed to this study include Marina Better, Kimberly Bockley, Emily Chen, Charles Eberhart, Hongyu Feng, Justin Hanes, Neomi Jerry, Jordan Miller, Jairo Ortiz and James H. Segars.
Information source: Johns Hopkins Medicine
