Yeast microcapsule-mediated oral delivery of IL-1β shRNA for post-traumatic osteoarthritis therapy
Long Zhang, Peng Hang, Meng Feng, Wan Zhang, Yankun Li
Abstract
Post-traumatic osteoarthritis is a prevalent debilitating joint disease. However, there is no FDA-approved disease-modifying osteoarthritis drug currently. Gene therapy can improve disease progression but lacks an effective delivery system. Here, we constructed an oral drug delivery system by non-virus-mediated interleukin-1β (IL-1β) short hairpin RNA (shRNA) and non-pathogenic yeast to evaluate its effect on osteoarthritis therapy. After recombinant IL-1β shRNA/yeast therapy, yeast microcapsule-mediated oral delivery of IL-1β shRNA greatly reduced the IL-1β expression in intestine macrophage, bone marrow macrophage, and articular cartilage, systematically regulate the inflammatory response. The degeneration of articular cartilage was significantly inhibited in the medial femoral condyle and medial tibial plateau of the knee joint. And the expression of osteoarthritis markers Col X and MMP13 was reduced in the knee joint. Thus, yeast microcapsule-mediated oral delivery of IL-1β shRNA may serve as a novel gene therapy strategy for treating joint degeneration through immunomodulation of the mononuclear phagocyte system from the intestine to subchondral bone marrow and ultimately preserving the articular cartilage joint. Post-traumatic osteoarthritis is a prevalent debilitating joint disease. However, there is no FDA-approved disease-modifying osteoarthritis drug currently. Gene therapy can improve disease progression but lacks an effective delivery system. Here, we constructed an oral drug delivery system by non-virus-mediated interleukin-1β (IL-1β) short hairpin RNA (shRNA) and non-pathogenic yeast to evaluate its effect on osteoarthritis therapy. After recombinant IL-1β shRNA/yeast therapy, yeast microcapsule-mediated oral delivery of IL-1β shRNA greatly reduced the IL-1β expression in intestine macrophage, bone marrow macrophage, and articular cartilage, systematically regulate the inflammatory response. The degeneration of articular cartilage was significantly inhibited in the medial femoral condyle and medial tibial plateau of the knee joint. And the expression of osteoarthritis markers Col X and MMP13 was reduced in the knee joint. Thus, yeast microcapsule-mediated oral delivery of IL-1β shRNA may serve as a novel gene therapy strategy for treating joint degeneration through immunomodulation of the mononuclear phagocyte system from the intestine to subchondral bone marrow and ultimately preserving the articular cartilage joint.