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Courtesy of John Heiss

Your body is teeming with mysterious particles called vaults. With an average of 10,000 to 100,000 of them in every human cell, they’re thought to be one of the most abundant particles in the body. But no one knows their function.

This mystery doesn’t phase the discoverer of vaults, University of California, Los Angeles cell biologist Leonard Rome. To him, what matters about vaults is not what they do naturally in the body, but what they can do. Vaults’ structure, he says—three proteins and a small RNA molecule assembled in a hollow, barrel-like shape—makes them the perfect nanoscale delivery vehicle to encapsulate and carry therapeutic drugs or genes.

Rome’s lab first encountered vaults almost 25 years ago while studying lysosomal enzymes. In electron microscopy scans of coated vesicles, which shuttle...

The lab spent 15 years trying to pin down vaults’ function, to no avail. (The team speculates that the particle may take part in detoxifying cells, or ferrying proteins to the nucleus.) Then, in 2001, they made a discovery that transformed their efforts from disheartening to promising. Although vaults are made up of three proteins and an RNA molecule, their most abundant component is major vault protein (MVP). The researchers found that simply expressing MVP in cells caused them to form vault-like structures (J Biol Chem 276:23217–20, 2001). This finding got Rome thinking: It could be relatively easy to make delivery vehicles—just get cells to express MVP. Since vaults are endogenous molecules, they likely wouldn’t be immunogenic—a problem that has dogged drug delivery efforts to date.

They soon identified a domain in a second vault protein that acts a vault “zip code,” says Rome; when attached to other molecules, it can pull essentially any compound into the vault particles. And by adding antibodies or other targeting moieties to the c-terminal end of the MVP protein, the researchers could direct a loaded vault to a specific cell type (ACS Nano 3: 27036, 2009). They also figured out how to protect the cargo. Vaults—like other types of particles—enter cells through endosomes, but proteins brought in by endosome are often digested. Rome and Glen Nemerow, a viral immunologist at the Scripps Research Institute in California, got around that problem with the help of pVI, an adenovirus protein that springs the virus particles free from endosomes and into the cytoplasm. By attaching pVI onto vaults, they could boost how much vault cargo—here, a GFP-encoded plasmid—made it into the cytoplasm (ASC Nano, 3:691–99, 2009).

Putting a mysterious particle to work

Over the years, Rome’s lab has had many collaborators. Kathleen Kelly, a pathologist at UCLA and a coauthor on the targeting paper, learned about vaults in a UCLA seminar Rome gave; now the duo are using vaults to deliver a chlamydia vaccine, which recently showed promising results in mice (PLoS ONE 4(4):e5409, 2009). Rome’s lab, though, is probably the only one in the world studying vaults full time, he says; without a known function, they’re “not really a textbook particle.” Other researchers often ask him, “How come I don’t know about this?”

Francis Szoka, a drug delivery scientist at the University of California, San Francisco, for one, had never heard of vaults. “I really think the structural biology and biochemistry is magnificent,” he says after a look at the Rome lab’s Web site and the abstracts of a couple recent studies. But he isn’t convinced of vaults’ drug delivery potential. Modifying an already complex molecule might make vaults more immunogenic than they currently seem. “Even human proteins can elicit an immunogenic response to human antibody,” he cautions. Plus, the literature is filled with delivery systems that seemed promising but proved problematic in vivo. “You’re asking me, is their baby beautiful,” he says. “Yes, it’s a beautiful baby. But we don’t know how it’s going to grow up.”

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