Novel delivery system opens doors for mRNA therapy
The method delivers mRNA via extracellular vesicles, which minimize the inflammatory complications seen in other carriers.
As demonstrated to the world during the COVID-19 pandemic, the potential of messenger RNA (mRNA) in the prevention or treatment of disease is clear. Delivery, however, is a key bottleneck.
“mRNA is the next big thing, with the advantage over DNA that it doesn’t integrate into the genome,” says Betty Kim, physician-scientist at The University of Texas MD Anderson Cancer Center. “But for mRNA to work, you need a carrier system to ensure its stability and to deliver it to specific target areas.”
mRNA delivery approaches include viruses and lipid nanoparticles (LNPs), but viruses have raised concerns about the use of live attenuated products, while LNPs have complications including links with anaphylaxis, hypersensitivity and autoimmunity. Without a one-size-fits-all solution, a wider pipeline of delivery systems is necessary.
In a proof-of-concept study, published in Nature Biomedical Engineering1, a team co-led by MD Anderson demonstrated a new method for mRNA delivery using extracellular vesicles (EVs). The researchers showed that EV-encapsulated mRNA can sustain collagen production in mice with photoaged skin. “Although our study is in dermatology, the platform has potential to be used for a number of mRNA therapies that currently have no good methods of delivery,” explains Kim, the study’s corresponding author.
EVs as mRNA delivery vehicles
EVs are naturally occurring particles that help transport biomolecules and nucleic acids, including mRNA. Unlike LNPs, they are endogenously produced, and therefore do not generate a strong inflammatory response. But applications have been limited by the technical complexity of producing EVs.
In a 2020 paper2, Kim and colleagues described a platform allowing production of EVs large enough to contain intact endogenous mRNA. The system uses a cellular nanoporation biochip containing a monolayer of donor source cells (where DNA transcription to mRNA occurs) and an array of nanochannels. When a transient electrical pulse is passed, the channels open, allowing vesicles to form from the source cells, and buffer containing plasmid DNA, which gets transcribed to mRNA, to flow into the vesicles.
For the current study, the team used EVs to deliver mRNA encoding extracellular-matrix ∝ 1Type-1 collagen (COL1A1) directly to mouse skin fibroblasts. “Using fibroblasts as the endogenous source cell allows EVs to naturally target fibroblasts in the body,” explains Kim. To mimic age-damaged human skin, the team photoaged hairless mice with ultraviolet radiation, leading to collagen depletion and wrinkle formation.
At 28 days, mice treated with a single injection of COL1A1 mRNA encapsulated in EVs demonstrated approximately 75% less wrinkle formation than control mice treated with EVs carrying a cargo of saline. Meanwhile, mice treated with RNA encapsulated in LNPs had around 50% less wrinkle formation than mice treated with saline. COL1A1 protein engraftment was extended significantly by switching from syringe injections to a biodegradable hyaluronic acid microneedle patch.
“For the first time we’ve shown that EVs with high mRNA content can be delivered to normal cells of interest,” says Kim. The next step will be to create EVs in sufficient quantities to treat patients in an economically viable way.
As well as treating collagen production aberrations and replacing proteins lacking in conditions like Duchenne muscular dystrophy, the authors believe EVs have a role in oncology. “Rather than using different mRNA to treat different cancers,” Kim says, “we want to develop a universal approach using EVs to reprogramme immune cells to have heightened responses.”
To read the full paper in Nature Biomedical Engineering, click here.
References
You, Y. et al. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-022-00989-w (2023)
Yang, Z. et al. Nat Biomed Eng. 4, 69-83 (2020).