Expanding mRNA delivery using mammalian retrovirus-like protein

Using a family of mammalian proteins adopted from ancient retroviral legacy genes, researchers have developed a novel system for programmable intracellular mRNA delivery. The approach "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," write authors led by Michael Segel and Feng Zhang. While the COVID-19 vaccines have demonstrated the power and potential of the use of mRNA in a wide variety of clinical applications, nucleic acid therapeutics remain limited by a lack of robust delivery platforms that target specific cell types; existing mRNA medicine delivery has largely been restricted to intramuscular mRNA vaccine injection or liver-targeted lipid nanoparticles. Here, Segel, Zhang and colleagues show how mammalian retrovirus-like proteins can be used to enable intracellular delivery of mRNAs into specific target cell populations. Throughout evolution, retroelements, including retroviruses, have become integrated into the mammalian genome. While many of these elements have lost their original function, some have been re-tooled to provide essential roles in mammalian development and physiology. A common feature of retroviruses and retroelements is the core structural gene known as gag. Mammalian homologs of this gene are known to form viral-like capsids and transfer mRNA. Segel et al. identified several mammalian gag homologs, including PEG10, which forms virus-like capsids that preferentially bind with cells and facilitate vesicular secretion of mRNA cargo. What's more, this mRNA cargo can be reprogrammed by inserting genes of interest within Peg10's untranslated regions. Using this, the authors developed Selective Endogenous eNcapsidation for cellular Delivery, or SEND, by engineering both mouse and human PEG10 to package, secrete and deliver specific RNAs intracellularly.