Investigators at MIT have identified a protein capable of delivering its own mRNA to cells, and engineered that protein to deliver mRNA sequences of their choosing.

In a mouse model, the team used their approach to deliver the mRNA for two different proteins.

In the paper describing the work, which appeared in the August 20, 2021, issue of Science, the authors wrote that their selective endogenous encapsidation for cellular delivery (SEND) "has the potential to be extended into a minimally immunogenic delivery platform that can be repeatedly dosed, which greatly expands the applications for nucleic acid therapy."

COVID-19 ended up thrusting therapeutic delivery of mRNAs into the limelight. But the technology could be useful for indications far beyond infectious disease.

The pre-COVID lives of Moderna and BioNTech give examples of where else the technology could find use.

Moderna had been developing its mRNA technology in other multiple other viral diseases, but also had antitumor and rare disease programs. And BioNTech had been focused almost exclusively on oncology. The company described itself as "founded in 2008 on the understanding that every cancer patient's tumor is unique," and began seriously working on infectious disease in September of 2019, through a partnership with the Bill & Melinda Gates Foundation.

Current delivery systems for mRNA frequently set off immune responses, which means that repeated treatments face rapidly diminishing returns. The work now published in Science, by senior author Feng Zhang and his colleagues, is part of an effort to develop delivery systems that are less vulnerable to becoming ineffective as the immune system develops a memory for the delivery vehicle.

The team searched in what could be considered the Venn diagram overlap between humans and viruses: endogenous retroelements.

Retroviruses, most famously HIV, insert themselves into the host genome as part of their life cycle. And in evolutionary terms, some retroviruses have integrated themselves into the host genome and stayed there, becoming part of the human genome.

As human proteins, retroelements do not normally trigger an immune response. But some of them have retained their ability to travel between cells, and have indeed been repurposed for intercellular communication.

The team first screened the human genome for retroelements that might be able to transport cargo between cells. They initially identified nearly 50 such proteins. Among those proteins was PEG10, which could transport its own mRNA between cells. The team showed that the signals that led to packaging and transport of PEG10 mRNA could be used to direct the packaging and transport of mRNA for other proteins as well. As proof of principle, they successfully delivered mRNA for the reporter protein mCherry and for a CRISPR gene editing system.

The findings could address several current limitations of mRNA delivery, the paper's corresponding authors told BioWorld Science via E-mail.

SEND "can efficiently package large cargoes, such as CRISPR-based gene editing machinery, which are too large to be packaged in many existing viral vectors," the author wrote. It can also "potentially target many different types of cells because it is a modular platform and the 'cell entry key,' which enables the PEG10 capsids to enter recipient cells, can be swapped out for other 'keys'."

In a press release, first author Michael Segel, a postdoctoral researcher in Zhang's lab, elaborated that "there are probably other RNA transfer systems in the human body that can also be harnessed for therapeutic purposes."

Combining components of those transfer systems with different cell-targeting proteins could be used to develop a mix and match system whose components could be adjusted to different therapeutic needs.

Finally, "because SEND uses endogenous components, it may be less immunogenic than other delivery methods. This is particularly important because it may allow repeated dosing of a gene therapy without causing serious side effects."

The immune system is, of course, capable of recognizing human proteins that are unusual, including fusion proteins. That ability is the basis of antitumor immune responses.

The authors acknowledged that "any delivery system, including SEND, will need extensive empirical testing to characterize the immune response and ensure safety. However, by using cell-targeting proteins that are naturally found in the human body, we are optimistic that they may be well tolerated by the immune system."