Researchers Advance mRNA Delivery to the Retina Using Stabilized Lipid Carriers

Study highlights the promise and challenges of non-viral mRNA therapies for vision disorders.

Efficient delivery of synthetic mRNA to the retina remains one of the key hurdles in developing mRNA-based treatments for vision loss. While most studies have focused on lipid nanoparticles (LNPs) as delivery vehicles, their application in ocular settings has yielded limited success. Lipoplexes—another class of lipid-based vectors—offer a simpler and more cost-effective alternative, but their instability in biological fluids remains a limitation.

A new study from vision scientists at the University of Pennsylvania School of Veterinary Medicine’s Division of Experimental Retinal Therapies, led by Tatyana Appelbaum, PhD, and William A. Beltran, DVM, PhD, DECVO published in the journal Drug Delivery, presents a potential solution: coating mRNA-lipid complexes (lipoplexes) with polyethylene glycol (PEG)-lipid derivatives to enhance their stability and penetration into retinal tissue.

The study is among the first to evaluate PEGylated lipoplexes for retinal mRNA delivery in a large-animal model. The team demonstrated that subretinal administration of stabilized mRNA lipoplexes resulted in widespread distribution of synthetic mRNA across all retinal layers, including photoreceptors, the retina’s primary light-sensing cells.

“Synthetic mRNA holds considerable potential for treating or slowing the progression of retinal disorders, but its delivery is hindered by the retina’s physical and biochemical barriers, including the outer and inner limiting membranes,” says Appelbaum, a senior research investigator in the Beltran Lab, and the first author of the study. “Our data show that PEG-lipid surface modification improves the diffusion of mRNA lipoplexes through retinal tissue and supports robust cellular uptake.”

However, the researchers found that retinal cells responded differently to mRNA delivery. While retinal pigment epithelial (RPE) cells efficiently translated the mRNA into protein, retinal neurons rapidly sequestered and degraded exogenous mRNA, limiting its translation. By 72 hours post-administration, both mRNA and protein signals outside the RPE had faded into a patchwork pattern. These results point to post-delivery barriers within neuronal cells—rather than delivery itself—as a key limitation to the effectiveness of synthetic mRNA translation.

“This study shows that getting mRNA into retinal neurons is only part of the challenge. We also need to ensure that the mRNA is translated efficiently into protein,” noted Beltran, senior author and director of the Division of Experimental Retinal Therapies program. “The untranslated regions, or UTRs, of synthetic mRNA molecules likely need to be tailored to the specific regulatory environment of retinal neurons, which possess distinct regulatory mechanisms compared to other cell types.”

Next, the Penn Vet team plans to optimize synthetic mRNA sequences by testing customized 5′ and 3′ untranslated regions designed specifically for photoreceptors and other retinal neurons. They also aim to further investigate the intracellular pathways that determine whether delivered mRNA is successfully translated or degraded.

Despite ongoing challenges with synthetic mRNA design, this research marks an important step toward efficient non-viral gene delivery to the retina. Non-viral alternatives like PEGylated lipoplexes may offer a safer and more flexible platform for future treatments, including transient delivery of gene editing tools like CRISPR/Cas9 or neuroprotective factors for degenerative conditions.

This study was supported by the National Eye Institute (grants RO1-EY017549, RO1-EY006855, P30-EY001583 and S10 OD032305-01A1), The Foundation Fighting Blindness, and The Van Sloun Fund for Canine Genetic Research.