Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target

Cyclin D1 ( CyD1) is a pivotal cell cycle - regulatory molecule and a well- studied therapeutic target for cancer. Although CyD1 is also strongly up- regulated at sites of inflammation, its exact roles in this context remain uncharacterized. To address this question, we developed a strategy for selectively silencing CyD1 in leukocytes in vivo. Targeted stabilized nanoparticles ( tsNPs) were loaded with CyD1 - small interfering RNA ( siRNA). Antibodies to beta(7) integrin ( beta(7) I) were then used to target specific leukocyte subsets involved in gut inflammation. Systemic application of beta(7) I-tsNPs silenced CyD1 in leukocytes and reversed experimentally induced colitis in mice by suppressing leukocyte proliferation and T helper cell 1 cytokine expression. This study reveals CyD1 to be a potential anti- inflammatory target, and suggests that the application of similar modes of targeting by siRNA may be feasible in other therapeutic settings.