Johns Hopkins Researchers Pioneer mRNA Delivery System to improve Fertility Rates
A new nanotechnology-based approach shows promise in enhancing embryo implantation and offering potential treatment for infertility, particularly in cases where assisted reproductive technologies have failed.
Researchers at the Wilmer Eye Institute and the Johns Hopkins Medicine Center for Nanomedicine have developed a groundbreaking strategy for delivering therapeutic messenger RNA (mRNA) directly to the uterine lining – the endometrium – in mice. This innovative technique utilizes modified lipid nanoparticles (LNPs),microscopic capsules composed of fatty molecules,to overcome a significant hurdle in fertility treatment.Published January 19 in Nature Nanotechnology, the study reveals improved embryo implantation rates in an endometrial injury model, suggesting a potential new avenue for addressing certain forms of infertility.
mRNA therapies represent a rapidly evolving field, already demonstrating success in cancer treatments and, notably, the mRNA COVID-19 vaccines. However, a key challenge in mRNA therapeutics is ensuring sufficient concentration at the treatment site while minimizing systemic toxicity. The Johns Hopkins team addressed this challenge head-on.
Lead author Saed Abbasi, Ph.D., and colleagues focused on delivering mRNA encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune protein believed to enhance embryo attachment by increasing endometrial thickness. While GM-CSF can be readily manufactured, it’s rapid degradation and potential for off-target effects have limited its clinical application. To overcome these limitations, the researchers employed LNPs to protect and deliver the fragile mRNA molecules.
Initial experiments using conventional mRNA-LNPs revealed a concerning issue: the particles spread beyond the intended target, causing toxicity in the liver and spleen. To refine the delivery system, the researchers “decorated” their LNPs with a peptide called RGD (arginylglycylaspartic acid). This modification proved crucial,as RGD binds to integrins – cell surface proteins specifically expressed on the endometrium during the “window of implantation” (WOI),the period when the uterine lining is most receptive to embryos.
The tailored mRNA-LNPs demonstrated remarkable efficacy. Researchers found that GM-CSF protein expression in the mouse endometrium remained elevated for up to 24 hours, nearly threefold higher at the eight-hour mark compared to those receiving a standard recombinant GM-CSF protein infusion. Importantly, GM-CSF levels in the blood were sixtyfold lower in mice treated with the mRNA-LNPs, indicating a significantly improved safety profile and reduced risk of unintended organ damage.
“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,” stated a principal investigator. “so, our findings are expected to translate to other model systems as well.”
Further validation came from experiments using a mouse model of endometrial injury, mimicking the structural disturbances that contribute to infertility in humans. The tailored mRNA-LNP treatment restored embryo attachment rates to levels comparable to healthy mice, a stark contrast to untreated mice, which exhibited 67% fewer implantation sites.Notably, no toxicity was observed in the uterus or other organs of the treated mice.
Looking ahead, the research team plans to leverage their LNP delivery system to test a range of other cytokines, growth hormones, and molecules with the potential to further improve fertility outcomes. They also envision applications beyond infertility, including the treatment of endometrial disorders like endometriosis and endometrial cancer.
The study received funding from the National institutes of Health (R01HD103124, R01HD108905), an unrestricted departmental grant from Research to Prevent Blindness, the 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 a related patent application (PCT/US2025/043687) filed by The Johns Hopkins University. Other contributors to the study included marina Better, Kimberly Bockley, Emily Chen, Charles Eberhart, Hongyu Feng, Neomi Jerry, Jordan Miller, Jairo ortiz, and James H. Segars.
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