Protein-lipid particles to deliver genetic medicine

Researchers at Entos Pharmaceuticals report today in Cell that they have developed a particle that can deliver DNA and RNA to many tissues without triggering an immune response (2024, DOI: 10.1016/j.cell.2024.07.023). The particle, a modified lipid nanoparticle that includes a viral protein called a fusogen, could solve an important problem in delivering genetic medicines such as vaccine mRNA, small interfering RNA, and DNA-based gene therapies.

Lipid nanoparticles (LNPs) deliver nucleic acids into cells by endocytosis—a process in which cells wrap external material in a membrane while internalizing it. The nucleic acid in an LNP must escape from this wrapping to be effective as a genetic medicine, and research suggests that most nucleic acids never escape. The best alternatives—nonreplicating viruses modified to deliver a cargo—are limited because people quickly develop antibodies to neutralize them.

Some viruses bypass endocytosis by merging their membranes directly with a cell’s membrane, injecting nucleic acids straight into the cytoplasm. Viruses rely on fusogens to accomplish this feat. Researchers have experimented with incorporating fusogens into lipid particles, but “the problem is that all of the known viral fusogens are gigantic,” says John Lewis, CEO of Entos and corresponding author on the paper. Their size makes these proteins easy targets for neutralizing antibodies, which means that medicines using them are effective for one dose but ineffective after that.

Lewis and coauthor Roy Duncan founded Entos based on their research into an unusually petite family of fusogens. Using the smaller proteins and a new lipid formulation, the company’s researchers produced hybrid particles called proteolipid vehicles, which can deliver DNA and RNA directly into the cytoplasm. In studies in mice and monkeys treated with the new particles, they saw little evidence of neutralizing antibodies that could potentially block repeat dosing. They also saw very little inflammation compared to LNPs that are currently used in medicines. The researchers found that mRNA reached various nonliver tissues like the lungs, brain, and heart more efficiently when carried in fusogen-enriched particles than in currently available LNPs.

According to Cecília Leal, a biomolecular materials scientist at the University of Illinois Urbana-Champaign whose lab works on other ways to free LNPs from the endosome, this is a significant advance in the field. She says there’s still room for more specific tissue targeting and would like to know more about how cells handle diverse types of cargo, such as small interfering RNAs compared to long plasmid DNA.

Entos is testing a codeveloped COVID vaccine that uses this technology in humans and developing therapies for genetic diseases. The company has licensed its particles to larger companies, including Eli Lilly and Oisín Biotechnologies.