Scientists develop novel mRNA delivery method using extracellular vesicles

Technique used to initiate collagen replacement in photoaged skin suggests potential for other mRNA and gene therapies

In the study, published today in Nature Biomedical Engineering, the researchers use EV-encapsulated mRNA to initiate and sustain collagen production for several months in the cells of photoaged skin in laboratory models. It is the first therapy to demonstrate this ability and represents a proof-of-concept for deploying the EV mRNA therapy.

“This is an entirely new modality for delivering mRNA,” said corresponding author Betty Kim, M.D., Ph.D., professor of Neurosurgery. “We used it in our study to initiate collagen production in cells, but it has the potential to be a delivery system for a number of mRNA therapies that currently have no good method for being delivered.”

The genetic code for building specific proteins is contained in mRNA but delivering mRNA within the body is one of the largest hurdles facing clinical applications of many mRNA-based therapies.

The current COVID-19 vaccines, which marked the first widespread use of mRNA therapy, use lipid nanoparticles for delivery, and the other primary delivery systems for genetic materials so far have been viral based. However, each of these approaches comes with certain limitations and challenges.

Extracellular vesicles are small structures created by cells that transport biomolecules and nucleic acids in the body. These naturally occurring particles can be modified to carry mRNAs, which gives them the benefit of innate biocompatibility without triggering a strong immune response, allowing them to be administered multiple times. Additionally, their size allows them to carry even the largest human genes and proteins.

In the current study, the research team used EV mRNA therapy to deliver COL1A1 mRNA, which encodes the collagen protein, into the skin cells of a laboratory model that mimics aging-damaged skin in humans. The EV mRNA was administered using a microneedle delivery system via a patch applied to the skin. This single injection improved collagen production and reduced wrinkle formation in the targeted area for two months.

A microneedle delivery system for improved EV distribution in tissue

Fig. 5

a, Schematic illustration of microneedle fabrication. b, Microscope and scanning electron microscopy images of microneedle arrays. Scale bar, 500 µm. c, H&E-stained section of mouse skin shows penetration of single microneedle. Scale bar, 100 µm. d, Top: time course of HA EV microneedle tips pressed into skin; the microneedles dissolved within 15 min of application. Scale bars, 200 µm. Bottom: skin recovery after HA EV microneedle treatment shows minimal irritation. Scale bars, 5 mm. e, Skin histology of Dil-labelled EVs shows highly concentrated EVs (red) unevenly distributed in the subcutis after syringe needle injection, whereas microneedle-delivered EVs were more evenly distributed in tissue. Yellow dashed lines encircle representative subcutaneous hair bulbs and border representative rod-like portions of the follicle extending upward to the dermis. Scale bar, 100 µm. f, Representative EV distribution analysed by ImageJ software. g, In vivo fluorescence images of nude mice treated with intradermal injection or HA microneedle patch delivery of Dil-labelled EVs on days 1, 2, 4, 7, 10 and 14 after delivery (n = 3 for all groups). h, Quantification of fluorescence intensity over the 14 d treatment period. Data are normalized to the fluorescence intensity at day 1. All data are from three independent experiments and are presented as means ± s.e.m. ***P < 0.001 COL1A1-EV MN delivery group vs needle delivery group. Two-way ANOVA was used for the comparisons in h. The schematic in a was created with

While initiating collagen production in cells is a noteworthy achievement on its own, Kim said, this study opens the door for further evaluation of EV mRNA therapy as a viable platform for mRNA delivery.

“mRNA therapies have the potential to address a number of health issues, from protein loss as we age to hereditary disorders where beneficial genes or proteins are missing,” Kim said. “There is even the potential for delivering tumor-suppressing mRNA as a cancer therapy, so finding a new avenue to deliver mRNA is exciting. There is still work to be done to bring this to the clinic, but these early results are promising.”

SourceMD Anderson Cancer Center

You Y, Tian Y, Yang Z, Shi J, Kwak KJ, Tong Y, Estania AP, Cao J, Hsu WH, Liu Y, Chiang CL, Schrank BR, Huntoon K, Lee D, Li Z, Zhao Y, Zhang H, Gallup TD, Ha J, Dong S, Li X, Wang Y, Lu WJ, Bahrani E, Lee LJ, Teng L, Jiang W, Lan F, Kim BYS, Lee AS. (2023) Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy. Nat Biomed Eng [Epub ahead of print]. [article]

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