Message in a Bottle: The Therapeutic Potential of Domesticated Capsid Proteins

Domesticated gag genes derived from long terminal repeat (LTR) retrotransposons are widespread in mammals and occur in other metazoans, including Drosophila and zebrafish. Their protein products commonly contain a capsid (CA) domain, and many retain the ability to assemble capsid-like particles that package RNA, and potentially other biomolecules, with emerging roles in intercellular communication, neuronal signaling, placental gene regulation, and fertility. Biochemical, genetic, and structural studies have identified the core domains that are necessary and sufficient for capsid formation, even in the absence of accessory proteins. Several systems also exhibit selective self-RNA packaging directed by cis elements, suggesting rules that could be harnessed for programmable cargo selection. Building on this foundation, recent efforts have developed host-encoded Gag CA proteins for delivery applications, ranging from engineered systems to approaches that exploit naturally preloaded capsids. In addition to established platforms such as adeno-associated viruses (AAVs), lipid nanoparticles (LNPs), and nonintegrating lentiviral systems, domesticated Gag CA proteins may offer complementary features such as lower immunogenicity, flexible cargo capacity, and tissue-specific targeting. Open questions remain regarding release and cellular entry mechanisms, in vivo tropism, determinants of immunogenicity across family members, and safety.