Strategies to increase adenovirus-mediated gene-transfer efficiency for well-differentiated columnar airway epithelial cells. (a) “Modification of the host.” In this approach, the tight junctions are rendered permeable to vectors, which permits access to “vector-specific” receptors. (b) “Modification of the vector.” A representative seven-transmembrane (7-TM) G-protein–receptor is shown that is activated to internalize via interaction with an agonist (denoted by purple-filled circle). Representative (adenovirus) vector is directed toward an external epitope of the receptor by bispecific antibodies (bs–Ab). Upon exposure to agonist, the 7-TM receptor is sequestered into a clathrin coated pit, carrying the vector into the cell.