Smart Bombs for Targeted Delivery of Therapeutic Small RNAs

RNA interference (RNAi) has been touted as a powerful new therapeutic approach for the treatment of a variety of diseases. The triggers for RNAi are short double stranded RNAs called small interfering RNAs (siRNAs). A major roadblock in the therapeutic application of siRNAs is their delivery to target cells and tissues. Targeted delivery of siRNAs is considered a safe pathway to avoid undesired inhibition of gene expression in non-diseased tissues.

The strategies for targeted delivery to date include complexing of siRNAs with antibodies, ligand containing nanoparticles, vitamins, cholesterol, peptides and receptor targeting aptamers. Each of these approaches has merit, but all are limited to some extent by trapping of the siRNAs in the endosome (a compartment within the cell), which prevents the therapeutic siRNAs from distributing throughout the cell.

The manuscript by Palanca-Wessels et al., in the July issue of Molecular Therapy, provides a novel solution to the problems of targeted siRNA delivery accompanied by endosomal escape. This group of researchers took advantage of a monoclonal antibody (a cell that triggers an immune response to cancer), that binds to CD22 which is a protein detected in 60 to 80 percent of B-cell malignancies. Common B-cell malignancies include many forms of cancer, such as lymphoma. Antibodies that bind to CD22 are rapidly internalized making use of CD22 advantageous for delivery of therapeutic siRNAs. In order to combine the siRNAs with antibodies and at the same time neutralize the low pH of endosomes where the therapeutic siRNAs end up, they developed a “diblock” polymer that consists of a positively charged siRNA condensing block fused to a pH responsive block which neutralizes the acidic endosomes. In order to make this diblock functional for antibody mediated siRNA delivery, they covalently coupled the block with biotin and the CD22 antibody with Streptavidin, allowing a complex to form between the two entities. The resulting complexes bind several siRNAs and contain several antibody molecules in a nanoparticle.

They demonstrated selective delivery of the siRNAs only to cells that express the CD22 protein on the cell surface. Moreover they showed that the pH neutralizing block allowed good release of the siRNAs into the RNAi machinery, resulting in potent inhibition of the targeted transcripts. Overall, this new strategy should greatly accelerate the use of antibodies for delivery of siRNAs, and in particular the use of antibodies which have dual functions of blocking receptor function and inhibiting the growth of cancer cells.