Meet SEND: A ‘Mini FedEx Truck’ For Getting Treatments into Cells


The Context: Therapies that employ mRNA, such as many COVID-19 vaccines, have the capacity to treat a variety of diseases by leveraging the body’s ability to create proteins. The challenge with mRNA-based therapies has traditionally been delivering them to cells: normally, introducing mRNA into a cell will trigger the cell’s defense systems to destroy it. 

The Study: A new system called SEND (Selective Endogenous eNcapsidation for cellular Delivery) harnesses proteins in the body to deliver therapies to cells with reduced risk of an immune response. The tool, developed by NYSCF – Robertson Stem Cell Investigator Alumnus Feng Zhang, PhD, of the Broad Institute of MIT and Harvard, is described in Science.

Why it Matters: SEND could be a safer and more efficient delivery method for molecular medicines, opening the door for better treatment of a variety of diseases.

mRNA-based therapies such as COVID-19 vaccines have revolutionized the way we treat diseases by instructing cells to make certain proteins or directing gene editing machinery. This approach has immense potential for a wide range of applications, including cancer immunotherapies. 

COVID-19 vaccine developers have created effective delivery systems for mRNA vaccines, but finding new ways to efficiently deliver mRNA to cells will be imperative for other treatments.

“The biomedical community has been developing powerful molecular therapeutics, but delivering them to cells in a precise and efficient way is challenging,” Dr. Zhang, a Core Institute Member at the Broad Institute, Investigator at the McGovern Institute, and the James and Patricia Poitras Professor of Neuroscience at MIT told MIT News. “SEND has the potential to overcome these challenges.”

Harnessing The Power of the Proteins

Dr. Zhang’s team knew that some proteins can pack up molecular materials like cargo, and wondered whether any of these proteins could act as a delivery vehicle for molecular medicines (think: a mini-FedEx truck for bringing therapies to cells).

The team searched through the body’s proteins for those with this special ability, identifying one called ‘PEG10’ as an especially promising candidate. PEG10 can form a spherical, protective bubble around itself, and the team engineered PEG10 to do this while selectively packaging and delivering RNA.

“That’s what’s so exciting,” said Michael Segel, PhD, the first author of the study. “This study shows that there are probably other RNA transfer systems in the human body that can also be harnessed for therapeutic purposes. It also raises some really fascinating questions about what the natural roles of these proteins might be.”

The team was also able to decorate the PEG10 capsules with proteins called “fusogens” that help cells fuse together. Adding fusogens allows researchers to target the delivery system at different cells, organs, or tissues, and demonstrates how pulling together different capabilities of proteins in the body can optimize SEND.

“By mixing and matching different components in the SEND system, we believe that it will provide a modular platform for developing therapeutics for different diseases,” noted Dr. Zhang.

What’s Next?

Because SEND is made of proteins that the body naturally produces, it is less likely to trigger an immune response, and could act as a method for repeatedly delivering gene therapies with fewer side effects.

“The SEND technology will complement viral delivery vectors and lipid nanoparticles to further expand the toolbox of ways to deliver gene editing therapies to cells,” said Blake Lash, second author of the study and a graduate student in Dr. Zhang’s lab.

Next, the team will continue improving the system and test its efficacy in animals. They will also look for other components of proteins that could be added to the SEND platform.

“We’re excited to keep pushing this approach forward,” said Dr. Zhang. “The realization that we can use PEG10, and most likely other proteins, to engineer a delivery pathway in the human body to package and deliver new RNA and other potential therapies is a really powerful concept.”

Journal Article:

Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery
Michael Segel, Blake Lash, Jingwei Song, Alim Ladha, Catherine C. Liu, Xin Jin, Sergei L. Mekhedov, Rhiannon K. Macrae, Eugene V. Koonin, Feng Zhang. Science. 2021. DOI: 10.1126/science.abg6155

Cover image: Graphical representation of SEND. Credit: Feng Zhang & team

Diseases & Conditions:

Cancer and Blood, Genomics & Gene Editing

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