Yale researchers describe a breakthrough in safe and effective administration of potential antiviral drugs — small interfering RNA (siRNA) molecules that silence genes — the first step in development of a new kind of treatment for sexually transmitted diseases (STDs). The work is reported May 4 as an advance online publication of Nature Materials. "RNA interference is a promising approach for prevention and treatment of human disease," said lead author Kim Woodrow, Yale postdoctoral fellow in Yale's School of Engineering & Applied Science. "We wanted to develop a new strategy of delivering siRNAs with a FDA-approved material." As their name suggests, siRNAs interfere and knock out the function of genes in higher organism as well as in microbes that may cause STDs. The researchers designed siRNAs to target a gene expressed widely in the lining of the female mouse reproductive tract, in this proof-of-principle work. Using densely-loaded nanoparticles made of a biodegradable polymer known as PLGA, the researchers created a stable "time release" vehicle for delivery of siRNAs to sensitive mucosal tissue like that of the female reproductive system. They found that the particles, loaded with the drug agent, moved effectively in two important ways, penetrating to reach cells below the surface of the mucosa and distributing throughout the vaginal, cervical, and uterine regions. Furthermore, the siRNAs stayed in the tissues for at least a week and knockdown of gene activity lasted up to 14 days. While past work has focused on delivery of siRNAs with liposomes, bubble-like carriers made of phospholipids similar to those found in cell membranes, liposomes are potentially more toxic to the mucosal tissues and are unable to provide sustained release. In the current work, the researchers demonstrated that PLGA nanoparticles were safer than the best current lipid vehicles.

Tiny plastic particles could smuggle therapies into cells ... Biomedical engineers have found a way of safely delivering potentially therapeutic RNAs into vaginal cells using nanoparticles. The researchers hope similar particles could be used to make topical creams containing anti-HIV RNAs. Mark Saltzman and his colleagues at Yale University wanted to find a better way to deliver short interfering RNAs (siRNAs) into vaginal cells that might come into contact with HIV. These short snippets of RNA can be designed to repress specific genes, and siRNAs against HIV genes have been shown to stop the virus reproducing in humanized mice. The most common way of getting siRNAs into cells is by attaching it to lipids, but this, Saltzman and colleagues say, is expensive and can be toxic. Instead, they found a surprisingly simple way to pack thousands of siRNAs into nano-sized bits of a biodegradable and biocompatible plastic that is already approved for medical uses by the US Food and Drug Administration. Such nanoparticles could then be incorporated into a vaginal gel, which could be applied by women before sex to help prevent infection.

BACKGROUND: Generation of robust cell-mediated immune responses at mucosal surfaces while reducing overall inflammation is a primary goal for vaccination. Here we report the use of a recombinant nanoparticle as a vaccine delivery platform against mucosal infections requiring T cell-mediated immunity for eradication. METHODOLOGY/PRINCIPAL FINDINGS: We encapsulated an immunogenic protein, the major outer membrane protein (MOMP) of Chlamydia muridarum, within hollow, vault nanocapsules (MOMP-vaults) that were engineered to bind IgG for enhanced immunity. Intranasal immunization (i.n) with MOMP-vaults induced anti-chlamydial immunity plus significantly attenuated bacterial burden following challenge infection. Vault immunization induced anti-chlamydial immune responses and inflammasome formation but did not activate toll-like receptors. Moreover, MOMP-vault immunization enhanced microbial eradication without the inflammation usually associated with adjuvants. CONCLUSIONS/SIGNIFICANCE: Vault nanoparticles containing immunogenic proteins delivered to the respiratory tract by the i.n. route can act as "smart adjuvants" for inducing protective immunity at distant mucosal surfaces while avoiding destructive inflammation.