Genetic medicines could treat certain diseases, however, the current delivery systems available—viral vectors and lipid nanoparticles (LNPs)—pose unique challenges for gene therapy applications. For example, immune responses against viruses limit these vectors’ repeated use, while the composition of LNPs directs them preferentially to the liver.
To overcome these limitations, John Lewis, a cancer biologist at the University of Alberta and his team developed a novel nanoparticle delivery unit, a proteolipid vehicle (PLV), by attaching a viral fusion protein to a lipid core.1 The PLVs exhibited improved distribution throughout the bodies of both mice and nonhuman primates with decreased toxicity and high cargo delivery. The findings, published in Cell, offer a new option for gene therapy vehicles.
“We thought if we used a fusion protein to change the way we deliver genetic medicine, we'd be able to reimagine the lipid components,” said Lewis, who is also the chief executive officer of Entos Pharmaceuticals, a company that develops genetic medicines.
To develop PLVs, Lewis and his team first screened a library of hybrid viral fusion proteins and selected one with improved fusion activity. They identified a lipid formulation that offered the best cell tolerability and cargo delivery, including removing cholesterol from the vehicle composition to eliminate the preferential homing to the liver.

The Entos Pharmaceuticals team uses proteolipid vehicles to develop and improve upon genetic medicines.
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Next, the team evaluated their delivery efficiency, cell toxicity, and distribution in the organs of mice and nonhuman primates. Unlike LNPs, PLVs traveled to many organs and did not induce a robust immune response; PLVs also maintained their delivery function after repeated administration in contrast to viral vectors. Additionally, the team delivered both DNA and mRNA payloads with PLVs.
Finally, the team loaded gene-editing cargo in their PLVs to introduce a splice variant of follistatin, which promotes skeletal muscle growth, into the follistatin gene. Delivery of this variant successfully induced follistatin expression in vitro and in vivo, validating PLV usage for gene-editing purposes.
“The two things that I find very impressive about this study is that it addresses both the ability to deliver plasmid DNA and to be able to deliver nucleic acid therapeutics beyond the liver,” said Roy van der Meel, a bioengineer at the Eindhoven University of Technology who was not involved in the study.
- Brown DW, et al. Cell. 2024;187(19):5357-5375.e24.