Lipid Nanoparticle-mRNA Topical Aids Diabetic Wound Healing in Mice

Uncontrolled accumulation of reactive oxygen species (ROS) and sustained inflammation make diabetic wounds difficult to treat with conventional wound healing approaches.

To address the problem, scientists engineered a formulation of diverse ROS-responsive trisulfide-derived lipid nanoparticles, which significantly reduced ROS at wound sites. And they’ve figured out a way to make the lead trisulfide-derived lipid nanoparticle deliver interleukin- (IL-)4 mRNA to the area to temper the wound inflammation microenvironment.

The investigational system worked to safely and effectively accelerate diabetic wound healing in a mouse model, with the Icahn Mount Sinai Medical Center researchers who developed it publishing their findings in the May 21 Proceedings of the National Academy of Sciences (PNAS).

“Overall, this [trisulfide-derived lipid nanoparticle-mRNA] platform not only provides a safe, effective, and convenient therapeutic strategy for diabetic wound healing but also holds great potential for clinical translation in both acute and chronic wound care,” study authors wrote.

One-two punch

Understanding ROS and macrophages in the wound microenvironment were key for developing the therapy, according to the study’s corresponding author Yizhou Dong, Ph.D., professor of immunology and immunotherapy at Icahn School of Medicine at Mount Sinai.

The body naturally produces ROS molecules, which are involved in cell signaling and immune responses. But too much ROS production can lead to oxidative stress, which damages cells, proteins, and DNA. While some phenotypes of macrophages — which are immune cells — help reduce inflammation, others cause it, impeding wound healing.

“[I thought,] maybe we can design some system that on one hand can catch all those ROS species and on the other hand we can have certain therapeutic cargo that can help modulate the phenotype of macrophages, an important immune cell type at the wound microenvironment. By combining those two aspects, then we can help the wound microenvironment’s condition for the healing process,” Dong told MD+DI.  

The system uses lipid nanoparticles loaded with mRNA encoding IL-4 to target dysfunctional macrophages while simultaneously reducing inflammation and ROS in diabetic wounds. The scientists put the lipid nanoparticles into a hydrogel for easy topical application on wounds.

Dong described the two characteristics that make his platform unique among wound healing therapies. “First, we designed a new library of lipids, which contains trisulfide linkers,” he said. “Trisulfide functional groups are very reactive with ROS species. So, if we have those components in the wound microenvironment, trisulfide-derived lipids help reduce the levels of ROS species at the wound site. Another point is our therapeutic cargo is mRNA encoding IL-4, which is a cytokine. This cytokine is a very important component that can help the macrophage conversion from M1 to M2. M2 is anti-inflammatory, which is helpful for wound healing.”

Next steps

Next steps to further the therapy in the pipeline include studies on additional wound types in other animal models. Feasibility and safety studies will also be needed to move to phase 1 clinical trials.

“In the near future, we will evaluate this platform for the wound healing process in large animal models, which will facilitate clinical trials in human patients,” Dong said. “For other applications, we think this LNP platform is very unique and could be applied to a broad category of disease which requires an anti-inflammatory environment.”