PDGFRβ-mediated nuclear delivery of bioactive molecules: mechanisms, selectivity, and therapeutic applications
Every cell in our body contains a nucleus — the cell's control center, where its genetic instructions are stored. Many diseases, such as organ scarring (fibrosis) and cancer, could be stopped if we could reach this control center directly. But the nucleus is well protected, and getting medicines inside has always been very difficult.In this thesis, I developed a way to deliver therapeutic proteins — including antibodies and the gene-editing tool CRISPR-Cas9 — straight into the cell nucleus. The key is a small "address label" (called pPB) that recognizes a specific protein on the surface of diseased cells. Once attached, the cell pulls the labeled medicine inside and carries it all the way to the nucleus, using the cell's own transport machinery. We showed that this works for proteins of very different sizes, from small enzymes to large antibodies, and that the delivered proteins stay fully active. For example, we could block the signals that make cells form scar tissue, and we could edit a specific gene inside the cell, with the effect lasting several cell generations.Because the address label recognizes only certain diseased cells, the treatment is more selective and may cause fewer side effects. This approach could lead to new treatments for fibrosis, cancer, and other diseases.